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Breast

Disclaimer

  • This manual is not a substitute for consultation with an appropriate specialist.
  • The contents of this manual have been developed through consensus of a Provincial Tumour Group. Please note the various update dates for each section as some of the content of the manual may not be up to date.


1. Demographics and Risk Factors

Updated February 2016

Breast cancer is the most common life-threatening cancer among women in British Columbia and the second most common cause of cancer mortality. Age-standardized incidence rates increased somewhat over the 15 year period from 1977-1991,  declined slightly for 10 years, and now are essentially stable. Mortality from breast cancer appears to have decreased by 30% over the last decade in British Columbia, Canada, the US and UK. The reasons for this decline appear multifactorial and are likely a combination of screening, earlier diagnosis and multi-disciplinary care including more adjuvant therapy. In British Columbia, the estimated number of cases for the year 2012 was 3200.  This number is estimated to be 3400 in 2015. Although breast cancer is more frequently seen in older women, due to the demographics of the population, the actual number of women diagnosed with breast cancer is highest in the 50-60 year age range. 

Numerous risk factors for breast cancer have been well established, including age, mammographic density, nulliparity or late age at first birth, early menarche, late menopause, and use of hormonal replacement therapy. All these factors increase risk, while early age at first delivery, physical activity and lactation appear to reduce risk. 

There is growing evidence that premenopausal and post-menopausal breast cancer may be different entities. International differences in breast cancer incidence curves have led to the hypothesis that environmental factors predominantly influence the development of postmenopausal breast cancer whereas genetic and other endogenous factors predominantly influence premenopausal breast cancer.

A summary of known risk factors for breast cancer is shown in Table 1 below, which also indicates the strength of the risk factor in the development of breast cancer.

Table 1. 

Risk Factors Associated with Breast Cancer by Level of Risk

Weak risk factors for breast cancer (RR <2)

  • Family history of postmenopausal breast cancer, except if associated with male breast cancer + bilateral disease
  • High Socioeconomic status
  • Nulliparity
  • Later age at first birth (> 30 yr vs >20 yr)
  • Later age at menopause (>55 yr vs >45 yr)
  • Early age at menarche (<11 yr vs >15 yr)
  • Postmenopausal obesity
  • Alcohol consumption
  • Diet
  • Hormone replacement therapy (long term usage)
Moderate risk factors for breast cancer (RR 2-4)

  • Older age
  • North American and Northern European residence
  • Family history of premenopausal breast cancer
  • Personal history of breast cancer
  • Breast hyperplasia without atypia
  • Mammographic density occupying >50% of the breast volume
Strong risk factors for breast cancer (RR>4)

  • Family history of premenopausal bilateral breast cancer or premenopausal breast cancer in mother, grandmother, sister, daughter and aunt or DEL of ovarian cancer in mother, grandmother, sister, aunt or of male breast cancer or of breast cancer at any age in multiple (≥3) female relatives
  • Evidence of susceptibility gene including, but not restricted to, BRCA1/ BRCA2, PTEN, TP53, CDH1, STK11, PALB2
  • Personal history of lobular carcinoma in situ
  • Breast atypical hyperplasia
  • Mammographic density occupying > 75% of the breast volume
Reference: (BC Med J 1997;39:496-500)


2. Prevention

Updated 28 September 2011

Several strategies are available for primary prevention among women with an increased risk of developing breast cancer. For women with confirmed BRCA1 or BRCA2 mutations, or other gene mutations predisposing to breast cancer, referral to the high risk screening program at BC Cancer and counselling about cancer prevention and screening options for breast and other associated hereditary cancers is available. Referral to the Hereditary Cancer Program (PDF) is discussed further in "Referral to Hereditary Cancer Program" in the Screening subsection.
 
Three drugs have been shown to effectively reduce the risk of developing estrogen receptor positive pre invasive (ductal carcinoma in situ, DCIS) and invasive breast cancer among women with elevated risk, as determined by the sum of their risk factors using a validated risk prediction tool (including, but not restricted to, the Gail model or Tyrer-Cuzick (IBIS) model).

Tamoxifen reduces the risk of developing primary breast cancer by 50%. In the largest study, among 13,388 women randomized to tamoxifen or placebo, DCIS and invasive breast cancer occurred in the 244 placebo group and 124 in the tamoxifen group over a 5.5 year period.1 Taking tamoxifen for five years in this population resulted in a doubling in the incidence of endometrial cancer, from 0.09% increased to 0.23%, a small increase in the incidence of stroke, from 0.36% to 0.58%, and of deep venous thrombosis (0.08 vs 0.13% per year). Other primary prevention studies have shown similar effects.2,3 The protective effect of 5 years of tamoxifen persists after its discontinuation, to at least ten years from treatment start. There was no increase in cardiac events and there was a modest reduction in hip, wrist, and vertebral fractures in the tamoxifen group.

Raloxifene has also demonstrated reduction in both DCIS and invasive breast cancer by the same degree as tamoxifen in a large clinical trial comparing the two drugs.4 The advantage of raloxifene over tamoxifen is a greatly reduced incidence of postmenopausal vaginal bleeding, the need for endometrial investigations, and of endometrial cancer (incidence 0.2% for tamoxifen versus 0.12% for raloxifene). Long term follow up again shows an effect that lasts beyond five years of exposure.5

Exemestane, an irreversible steroidal aromatase inhibitor, has recently been shown to reduce the risk of ER+ breast cancer in postmenopausal women by 65% compared to placebo in a large prevention trial.6 The placebo group had a 0.55% annual incidence rate of breast cancer compared with 0.19% in the exemestane group. There was no increased incidence of cardiovascular events, second cancers, fractures, or self reported development of osteoporosis. More women on exemestane reported joint and musculoskeletal pain while on medication (30% versus 17%). Long-term follow-up is clearly warranted for more safety data and to determine the duration of the protective effect that five years of therapy provides. Ongoing trials are exploring the effectiveness of other aromatase inhibitors in this setting.

The effectiveness of secondary prevention on breast cancer mortality through screening mammography has been clearly demonstrated in randomized controlled trials, even though 10% of breast cancers will not show up on a mammogram. Asymptomatic women between the ages of 40-79 should be encouraged to have regular screening mammography at the Screening Mammography Program of BC (SMPBC) centres or mobile vans, at intervals as set out in the SMPBC. See Chapter 3. Screening/Early Detection. Appointments can be booked through 1-800-663-9203.

References

  1. Tamoxifen for Prevention of Breast Cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. Fisher B, Costantino JP, Wickerham DL, et al. Journal of the National Cancer Institute, 90 (18), 1998.
  2. Long-Term Results of Tamoxifen Prophylaxis for Breast Cancer—96-Month Follow-up of the Randomized IBIS-I Trial. Cuzick J, Forbes JF, Sestak I, et al. J Natl Cancer Inst 99: 272 – 82, 2007.
  3. Twenty-Year Follow-up of the Royal Marsden Randomized, Double-Blinded Tamoxifen Breast Cancer Prevention Trial. Powles TJ , Ashley S, Tidy A Smith IE , Dowsett M. J Natl Cancer Inst 99: 283 – 90, 2007.
  4. Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes. The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial.. Vogel VG, Costantino JP, Wickerham DL, et al. JAMA, June295: 2727, 2006.
  5. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial:Preventing Breast Cancer. Vogel VG, Costantino JP, Wickerham DL, et al. Cancer Prev Res; 3(6); 696–706, 2010.
  6. Exemestane for Breast-Cancer Prevention in Postmenopausal Women Paul E. Goss, M.D., Ph.D., James N. Ingle, M.D.,  José E Alés-Martínez, This article (10.1056/NEJMoa1103507) was published on June 4, 2011, at NEJM.org. N Engl J Med 2011.
  7. Benefit of screening mammography in women aged 40-49: a new meta-analysis of randomized controlled trials. Hendrick RE, Smith RA, Rutledge JH 3rd, Smart CR. J Natl Cancer Inst Monograph.22:87-92,1997.
  8. Efficacy of screening mammography among women aged 40 to 49 years and 50 to 69 years: comparison of relative and absolute benefit. Kerlikowske K. J Natl Cancer Inst Monogr. 22:79-86, 1997.

3. Screening/Early Detection

Updated August 2015

About one in eight women living to age ninety will eventually be diagnosed as having breast cancer. Risk increases with advancing age. 

3.1 Breast Self-examination

Women may do regular breast self-examination (BSE). For premenopausal women, this is best done in the week following the menstrual period. For postmenopausal women, a specific day of the month should be chosen. 

If done, the examination should include inspection of the breast and palpation of the breast and axilla. To perform adequate BSE the patient needs instruction in the technique and the manner in which she is carrying this out. This should be checked at subsequent examinations by her family physician.

There is no evidence that BSE improves survival, but regular self-examination does allow a woman to know her own body and therefore recognize early changes in the breast texture or appearance.  She should be encouraged to bring any concerns to her health care provider. 

3.2 Screening physical exam by Family Physician

The combination of physical examination by a physician and mammographic screening has been shown to reduce mortality from breast cancer. The relative importance of the physical examination vis-a-vis the mammogram remains unclear. As 10% of breast cancers in older women and 25-30% of breast cancers in women age 40 to 49 will not be detected by a screening mammogram, physical examination by the family physician may improve early detection.

3.3 Screening Mammography

The policy of the Screening Mammography Program of BC reflects the latest evidence and our commitment to reducing breast cancer deaths by finding cancer at an early stage. Key policy recommendations are:

Average Risk, Ages 40-49 

Health care providers are encouraged to discuss the risks and benefits  of screening mammography with asymptomatic women in this age group. 

If screening mammography is chosen, patients will be recalled every two years. A health care provider’s referral is not required but is recommended.

Average Risk, Ages 50-74

Routine screening mammograms are recommended every two years for asymptomatic women at average risk of developing breast cancer. Patients will be recalled every two years. A health care provider’s referral is not required.

Average Risk, Ages 75+

Health care providers are encouraged to discuss the benefits and limitations of screening mammography with asymptomatic women in this age group.

Health care providers should discuss stopping screening when there are comorbidities associated with a limited life expectancy or physical limitations for mammography that prevent proper positioning.

If screening mammography is chosen, it is available every two to three years. Patients will not be recalled by the Screening Mammography Program of BC. A health care provider’s referral is not required but is recommended.

Higher than average risk, e.g. Ages 40-74 with a first degree relative with breast cancer

Routine screening mammograms are recommended every year. Patients will be recalled every year. A health care provider’s referral is not required.

High risk, with a known BRCA1 or BRCA2 mutation or prior chest wall radiation or strong family history of breast cancer

Age 40-74: Routine screening mammograms are recommended every year. Patients will be recalled every year. A health care provider’s referral is not required.

Under age 40: The Screening Mammography Program accepts women at high risk of developing breast cancer with a health care provider’s referral, provided they do not have breast implants or an indication for a diagnostic mammogram. Please discuss patient with a screening program radiologist before referral.

3.4 Magnetic Resonance Imaging (MRI)

Routine screening with breast MRI of women at average risk of developing breast cancer is not recommended.

Patients who are mutation carriers or from families with confirmed mutations are recommended to have annual screening breast MRI from age 25 to 65. Referral to the Hereditary Cancer Program can facilitate these arrangements. Women who have had chest radiation between 10 and 30 years of age are also recommended to have annual screening breast MRI alternating with annual mammograms, i.e. screening imaging every 6 months, starting the earlier of 10 years after radiation or the age of 40. 

More information about the utility of MRI in the screening and diagnosis in the setting of breast cancer is discussed in the Diagnosis section.

3.5 Other Methods

There has been considerable interest in methods of detection of non-palpable abnormalities in the breast that do not use ionizing radiation. Such methods include thermography, ultrasound and diaphanography, but in the screening of asymptomatic women none of these techniques approach the sensitivity or the specificity of mammography and cannot be recommended at the present time as the sole screening method. 

Ultrasound may be very useful, in conjunction with mammogram, for diagnosis of (to assess) breast lesions, and in that situation is part of the workup of a mass. However, in the absence of any abnormality on physical examination or mammogram, ultrasound is not required, is not a validated screening method, and is not funded.
 
Referral to Hereditary Cancer Program

The Hereditary Cancer Program is a joint activity of BC Cancer and the Provincial Medical Genetics Program. Testing is available for families at risk of mutations in breast cancer predisposition genes including, but not restricted to, BRCA1 or BRCA2. Women with gene mutations are candidates for programs of special surveillance.

Specific criteria for referral to the Hereditary Cancer Program are listed separately.

Referral should be offered to asymptomatic women with increased risk of hereditary breast cancer, including those with the following:

  • Family history of bilateral breast cancer
  • Family history of breast cancer at age <35 years
  • Multiple cases of close relatives with breast cancer
  • Family or personal history of ovarian cancer 
  • Family history of male breast cancer
  • Ashkenazi Jewish heritage

4. Diagnosis

Updated August 2016

4.1 Overview

The diagnosis of a breast cancer depends on the presentation of the lesion by mammographic screening, other radiological imaging (such as ultrasound) or by physical presentation. In all cases, it is important to combine the radiologic assessment of the entire affected breast and the contralateral breast with the general health of the woman, examination of the breast and nodal areas, and a pathological diagnosis. The treatment of the breast cancer will depend on combining the results of these investigations. Although most breast lumps are not cancerous, the practitioner must be aware that breast cancer can appear at any age, and if there is any suspicion, a definitive diagnosis should be obtained promptly.

The diagnosis of breast complaints and breast cancer has evolved significantly over the past 20 years with advances in imaging and pathology techniques and increased interdisciplinary management of breast problems. Core needle biopsy of breast lesions is now the standard of care and surgical biopsy should be performed only when core needle biopsy is not possible.3,4,8

A complete review of management of breast complaints and benign breast disease is beyond the scope of this document.  

Breast complaints should be evaluated by physical examination of the breast and axilla, imaging of the breast, and consideration of biopsy- the so called “Triple Test”. In all cases there should be a concordance assessment of the physical exam, imaging, and biopsy results and if these results are not concordant, further investigation is necessary to rule out malignancy.  

History and physical exam

History and physical examination should be performed in patients with breast complaints to determine the nature of clinical presentations, such as clarify features of discharge, assess masses for suspicion for breast cancer, and determine the etiology of breast pain.  

Physiologic nipple discharge should be differentiated from pathologic nipple discharge. The former is characterized as bilateral, involving multiple ducts, is milky/yellow/green in colour and non-spontaneous. This type of discharge does not require diagnostic medical imaging.  Pathologic nipple discharge is unilateral, involves a single duct, is clear/bloody/serosanguinous in colour and spontaneous.15

Physical examination is the first step in the evaluation of breast pain. The location and characteristics of the pain help to differentiate breast pain from chest wall pain. Chest wall pain is commonly located at the costochondral junctions and over the lateral chest wall, rather than in the breast itself. Physiologic breast pain is characterized as cyclical, non-focal and bilateral and is typically due to hormonal or age-related changes. Physiologic and chest wall pain do not require diagnostic breast imaging as pain of this nature has not been shown to correlate with the presence of breast cancer.14 Breast pain that is persistent, non-cyclical, unilateral and, most importantly, focal, may indicate underlying breast pathology.15

Diagnostic imaging is indicated when a breast mass, suspicious skin or nipple changes, or pathologic nipple discharge is confirmed on physical examination. In the absence of suspicious physical examination findings, screening mammography is recommended.  

Imaging

Diagnostic imaging should be requested for patients with pathological clinical exam findings. In general, bilateral diagnostic mammograms and targeted ultrasound are recommended for women over 35. Tomosynthesis is becoming increasingly available and MRI is used for problem solving in particular circumstances. Imaging assessment involves correlating findings on the different imaging modalities. Final guidance regarding further management (e.g. further imaging, clinical follow up, or biopsy) is usually found in breast radiology reports.  

It is recommended that radiologists report the degree of suspicion for breast cancer on imaging studies using a recognized reporting system6 such as the BIRADS system5 as this risk assessment determines the need for an image guided needle biopsy. Imaging that is determined to be negative (BIRADS 1) or benign (BIRADS 2) does not require further follow up. Lesions that are determined to be BIRADS 4 have a risk of malignancy of 2-95% and are recommended for biopsy. Lesions designated BIRADS 5 have a risk of malignancy of >95% and require core needle biopsy and should have surgical excision if the core needle biopsy is not malignant. Lesions that are BIRADS 3 have an estimated risk of malignancy of less than 2% and are recommended to have follow up imaging in 6 months and are followed for 2 years.

It is known that about 10% of breast cancer will not been seen on a mammogram and a negative mammogram  should not be a cause for delay in diagnosis of breast cancer. Any suspicious physical exam findings require further imaging and biopsy.


CategoryManagementLikelihood of cancer
0
Needs additional imaging or prior exams
Recall for additional imaging or obtain prior studies
n/a
1
Negative
Routine Screening
Essentially 0
2
Benign
Routine Screening
Essentially 0
3
Probably Benign
Short interval Follow-up (6 months)
0-2%
4
Suspicious for malignancy
Tissue diagnosis
4a. low suspicion for malignancy- 2-10%
4b. moderate suspicion for malignancy 10-50%
4c. high suspicion for malignancy 50-95%
5
Highly Suspicious for malignancy
Tissue diagnosis
>95%
6
Biopsy proven malignancy
Surgical excision when clinically appropriate
n/a

Table 1.  BIRADS Final Assessment Categories10 

Biopsy

Core needle biopsy (CNB) diagnosis of breast lesions is the preferred initial invasive diagnostic procedure3,4,13, and imaging guidance is recommended to increase accuracy of targeting8. CNB is able to accurately diagnose most breast lesions and results in an improved cosmetic  outcome for the patient, cost savings to the system, and decreases the number of operations that a patient requires.3,4 CNB of breast lesions is now the standard of care and surgical biopsy should be performed only when core needle biopsy is not possible.3,4,8,13 Obtaining preoperative core needle biopsy diagnosis of breast lesions in more than 90-95% of patients is a quality indicator in breast surgery internationally.1,2,8 CNB results are classified as benign, high-risk, or malignant.4,7
      
Concordance assessment of initial investigations

Concordance assessment is an important part of CNB. For an image guided CNB, concordance is the agreement of imaging and histopathological findings such that the histopathology satisfactorily explains the imaging findings.6 Discordance refers to the situation when a breast CNB demonstrates benign histology while the imaging findings are concerning for possible malignancy. Discordance presents a diagnostic situation that requires further evaluation, including the options of (a) repeating CNB, perhaps with consideration of larger gauge or vacuum-assisted techniques, (b) surgical excisional biopsy, or (c) clinical and imaging surveillance.6,7

Failure to resolve imaging-pathology discordance can lead to a delay in breast cancer diagnosis. Imaging-Pathology correlation should be provided by the doctor performing the biopsy6,7 and this is typically done by issuing a radiology-pathology addendum report which should outline whether further investigation, follow up, or surgical excision is recommended.
  
For patients with a clinical presentation, there needs to be correlation between physical exam, imaging, and pathology7 by the clinician who has ordered/reviewed the investigations. If the physical examination remains suspicious for malignancy, but imaging and/or core needle biopsy is benign, then further investigations, such as skin biopsy, surgical biopsy, repeat core needle biopsy or further imaging are necessary to rule out malignancy.  

Borderline or High Risk Lesions on core needle biopsy

Concordance assessment also involves assessing the situation for risk of under-sampling by core needle biopsy. When the chance of this occurring is increased, the lesion is regarded as being a high risk lesion. High risk lesions found on CNB are usually recommended to have surgical excision of the area to rule out malignancy due to under-sampling. The risk of under-sampling varies by diagnosis and is affected by factors such as the number and size of CNB specimens taken, size of lesion, and institution.4,7 Institutions that have documented a low upstage rate to breast cancer following surgical resection for specific diagnoses may offer their patients follow up rather than surgical excision.4,7,9

Surgical excision is recommended/considered for the following CNB results:

Surgical Excision Recommended
Atypical Ductal Hyperplasia
Papillary Lesions with atypia
Radial scar/complex sclerosing lesions
Fibroepithelial lesions with cellular stroma
Mucocele-like lesions
Spindle cell lesions
Pleomorphic LCIS
Surgical Excision Considered
Lobular Neoplasia (classic LCIS and ALH)
Flat Epithelial Atypia/DIN 1a
Papillary lesion without Atypia
Discordance

Concordance assessment after surgical excision

Specimen imaging of fine wire guided excisions is recommended and all breast surgical specimens should be oriented for the pathologist. Concordance assessment is recommended after surgical excision of breast lesions to ensure that the lesion of interest has been accurately targeted and excised. In rare circumstances, the lesion found by the patient was different from the lesion biopsied under imaging guidance and this is suggested by discordance between preoperative diagnosis and surgical pathology. The finding of the core needle biopsy scar in the excised tissue suggests accurate targeting, but this can also be present in adjacent tissue. If there is discordance between the surgical pathology and the preoperative diagnosis, further investigations are indicated and can include further imaging, image guided localization, or surgical re-excision.  Interdisciplinary review is recommended to guide management.  

Image Detected breast abnormalities

Non-palpable breast lesions (masses, calcifications, asymmetries, architectural distortion) can be found on screening mammograms and breast imaging done for other symptoms. The evaluation of such lesions is described above in the "Imaging" section and focuses on assessing risk for malignancy. The BIRADS reporting system and radiology-pathology concordance statements are particularly useful in determining the need for further management and follow up due to the absence of physical examination findings to guide the treating clinician. 

Navigating the diagnostic system and wait times

With the development of increased diagnostic breast imaging options and the introduction of image-guided breast biopsy, patients may need to attend a number of appointments to obtain a diagnosis. It is recommended that patients have their mammograms, breast ultrasound, and ultrasound guided core needle biopsy performed by a consistent radiology group to facilitate comparison, limit duplication, and decrease wait times. When more specialized biopsy or imaging techniques are required such as stereotactic biopsy, MRI, or MRI guided biopsy, the patient may need to attend additional centres.  

The potential for fragmented care and extended wait times has been recognized and the 2012 BC Provincial Breast Health Strategy (BHS)11 has recommended target wait times of 21 days to diagnosis without biopsy and 28 days to diagnosis when biopsy is required. The BHS has also recommended facilitation of necessary investigations and increasing navigation resources for patients to help facilitate a prompt diagnosis.  

The Screening Mammography Program of BC introduced Fast Track booking for evaluation of screen detected lesions in 2010 and many breast diagnostic teams in the province have introduced care pathways and clinics to decrease wait times.  Currently each community has a slightly different system with regards to how breast imaging and biopsies are arranged. Next steps are sometimes facilitated by radiology and sometimes ordered by family physicians. With these divergent approaches pitfalls can arise, particularly if patients have mammograms outside of the usual community. Referring physicians should be aware of these differences and the role they are expected to play in arranging investigations for their patient.

References

  1. Eusoma  http://www.eusoma.org/Engx/Guidelines/Other/OtherMT.aspx?cont=MT
  2. ACS breast centres:  https://www.facs.org/~/media/files/quality%20programs/napbc/2014%20napbc%20standards%20manual.ashx
  3. Kristy Cho, Scott Tyldesley, MD, FRCPC, Caroline Speers, BA, Barbara Poole Lane, MPA,  Karen A. Gelmon, MD, FRCPC, Christine Wilson, MD, FRCPC.  The utilization and impact of core needle biopsy diagnosis on breast cancer outcomes in British Columbia.   Issue: BCMJ, Vol. 56, No. 4, May 2014, page(s) 183-190 Articles
  4. Melvin J. Silverstein, Abram Recht, Michael D. Lagios, Ira J. Bleiweiss, Peter W. Blumencranz, Terri Gizienski, Steven E. Harms, Jay Harness, Roger J. Jackman, V. Suzanne Klimberg, Robert Kuske, Gary M. Levine, Michael N. Linver, Elizabeth A. Rafferty, Hope Rugo, Kathy Schilling, Debu Tripathy, Pat W. Whitworth, Shawna C. Willey.  Image-Detected Breast Cancer: State-of-the-Art Diagnosis and Treatment.  Journal of the American college of Surgeons.  p504–520.  Published online: August 20, 2009
  5. http:www.acr.org/Quality-Safety/Resources/BIRADS      Accessed Sept 4 2016
  6. http://www.acr.org/Quality-Safety/Standards-Guidelines/Practice-Guidelines-by-Modality/Breast%20imaging     Accessed Aug 1 2016
  7. American Society of Breast Surgeons.  https://www.breastsurgeons.org/new_layout/about/statements/PDF_Statements/Concordance_and_High%20RiskLesions.pdf.  Accessed Jan 9, 2017. 
  8. https://www.breastsurgeons.org/new_layout/about/statements/PDF_Statements/Image-Guided_Percutaneous_Biopsy_Palpable_Nonpalpable.pdf    Accessed Aug 1 2016
  9. Becker AK1, Gordon PB, Harrison DA, Hassell PR, Hayes MM, van Niekerk D, Wilson CM  Flat ductal intraepithelial neoplasia 1A diagnosed at stereotactic core needle biopsy: is excisional biopsy indicated?  AJR Am J Roentgenol. 2013 Mar;200(3):682-8. doi: 10.2214/AJR.11.8090.
  10. Sickles EA, D’Orsi CJ, Bassett LW et al. ACR BI-RADS Atlas, In: ACR BI-RADS Atlas, Breast Imaging Reporting and Data System: Mammography. 5th ed. Reston, VA: American College of Radiology, 2013
  11. Lynn Pelletier:  Breast Health Strategy Summary Report 2012.  Provincial Health Services Association.  
  12. https://www.breastsurgeons.org/new_layout/about/statements/PDF_Statements/PerformancePracticeGuidelines_ExcisionalBreastBiopsy.pdf
  13. https://www.breastsurgeons.org/statements/QM/ASBrS_Preoperative_diagnosis_of_breast_cancer.pdf
  14. American College of Radiology.   ACR Appropriateness Criteria: Breast Pain https://acsearch.acr.org/docs/3091546/Narrative/.  Accessed Mar 10, 2017. 
  15. Padilla-Thornton A, Farrel J, Gordon P, et al.  Diagnosis of Breast Cancer:  Current Concepts.  BCMJ.  In Press.  


4.2 MRI (Magnetic Resonance Imaging)

Updated July 2009

Clinical Indications for Breast MRI

Introduction

Although MRI has advanced some areas of oncologic imaging, as well as neurological and musculoskeletal imaging, the transformation is less complete in breast imaging where other well established and less expensive techniques can often provide necessary information.

The purpose of these recommendations is three-fold, in the absence of substantial randomized controlled trial data on the usefulness and value of breast MRI:

  • To provide education and awareness to ordering physicians on the potential uses and pitfalls of breast MRI.
  • To help radiologists and ordering physicians utilize the resource effectively in the appropriate clinical settings.
  • To encourage collaboration in useful clinical research projects for the above.
Mammography is the standard breast imaging modality against which other modalities can be judged since there is an extensive body of trial data and a long period of surveillance follow-up. MRI has not yet met the challenge of proving that it can help to decrease mortality, recurrence or impact of treatment. Nor do we know its true positive predictive value. Specificity is variable, particularly in premenopausal women where incidental enhancing lesions are often identified.  There is currently no literature of level 1 evidence to support the use of MRI for any specific indication. It is not certain which women or imaging questions will be best served by this modality and at what costs.

Breast MRI should be used in a problem-solving mode only after high quality mammography and ultrasound have been carried out. As well, it should be done by a radiologist with expertise in breast MRI, as these images require specialized knowledge for interpretation.

MRI sensitivity rates for the detection of invasive breast cancer are estimated to be as high as 95-100%, which compares well to mammography at 85%. However, a significant limitation is specificity, which is highly variable ranging from 37-97%. Like all breast imaging studies, breast MRI must be correlated with other imaging findings in light of clinical findings.

The Breast Tumour Group (of BC Cancer) has discussed these indications which have been developed by Drs. Patricia Hassell and Moira Stilwell. The consensus was that as there is not level one evidence we cannot claim that these are standard Guidelines but are suggested clinical indications and are divided into those that are more established in terms of benefit, those that are not established but may be indicated for specific patients and those that should not be routinely recommended. MRIs within the context of clinical trials should be considered outside of these indications.

Other than cancer indications, breast MRI can be utilized to evaluate silicone implants.

Evaluation of silicone implants

MRI has been shown to be more reliable than CT, ultrasound or mammography for assessment of rupture/integrity/complications of silicone breast implants. The mean sensitivity was 38% for mammography, 59% for ultrasound and 78% for MRI.   

4.2.1 Recommended Uses of Breast MRI for Cancer (highest level of evidence)

1. Screening of high-risk patients – patients with hereditary cancer risk

In patients who have tested positive for mutations of the BRCA 1 and 2 genes or who are at high risk of breast cancer due to a family history of the disease, MRI has been shown to detect cancers before mammography, ultrasound or clinical examination could detect the malignancy. The greater incidence of high-grade invasive malignancies in this high-risk group does provide the rationale for using MRI as a screening modality in known mutation carriers (including, but not restricted to, BRCA1 and BRCA2). In these women, screening is done using annual imaging with mammography and MRI concurrently or alternately. In British Columbia, the role of breast MRI screening in high-risk women with a strong family history of breast cancer but no known gene mutation is under review. Studies have suggested that ultrasound may also have a role in following these women but recent literature does not support continued ultrasound screening in asymptomatic high-risk women. As scientific evidence concerning the role of MRI in patients with biopsy proven ADH or LCIS has shown that although more cancers are detected, this has not yet translated into decreasing mortality, MRI is not used in this situation.

2. Evaluation of occult breast cancer

In patients with an occult primary presenting with axillary lymphadenopathy or Paget's disease, MRI has been shown to identify the primary in many patients, thus allowing for conservative surgery rather than mastectomy. This is not indicated if mammography clearly shows a suspicious lesion. Trials are ongoing studying the impact of MRI on this group of patients.

B. Possible Uses of Breast MRI

These include a number of clinical scenarios where other imaging modalities have not provided adequate assessment and where a further evaluation with an MRI showing more disease may impact and/or change management.

1. Evaluation of local extent of breast cancer

MRI can be useful in pre-operative assessment of local disease extent when this is unclear either by physical examination, mammography or ultrasound.  Mammography is more accurate in determining the size and additional sites of malignancy. However, not all women benefit from having an MRI as 8% underwent additional biopsy or surgery for findings detected on the MRI which subsequently proved to be benign. This may be particularly indicated in lobular carcinoma where mammography may be less sensitive and where there may be multicentric disease.

2. Positive margins – post segmental resection

MRI can be useful in determining the extent of residual disease when margins are positive and the mammogram is not helpful. In the majority of cases however, as further surgery is indicated, it will not necessarily impact on treatment. 

3. Post surgical scar vs. recurrent tumour

In cases in which mammography and ultrasound can not conclusively confirm suspected recurrent disease, MRI can be helpful. Breast tissue can show enhancement for up to 18 months following radiation therapy, however. In many of these situations, a biopsy will be necessary to rule out disease and may be a preferable diagnostic test.

4. Problem mammogram

MRI can be useful in a small number of patients when there is an equivocal mammographic finding, i.e. a possible architectural distortion, or mass seen only in one view, in whom there is no ultrasound or clinical correlate. Many of these patients have heterogeneously dense breasts. 

5. Response to chemotherapy

MRI has been used to monitor treatment response to neoadjuvant chemotherapy in patients with locally advanced cancer. There is controversy over the ability of MRI to determine complete or partial response to treatment. Changes in tumour vascularity/enhancement appear to explain changes in functional dynamic contrast assessment and can be seen after only one cycle of chemotherapy. MRI tends to underestimate residual disease. At this time this should only be used in association with a clinical trial.  

4.2.2 Inappropriate Use of Breast MRI

1. Screening of general population

At present there is no data to support the use of MRI as a screening tool. To date, there are no studies demonstrating decreased mortality by the use of screening MRI. Not all cancers seen on mammography can be identified in MRI. This is especially true for DCIS. 

2. Differentiation of benign vs malignant lesions

Because of an overlap between the enhancement and morphological characteristics of benign and malignant lesions, MRI cannot be used as a substitute for biopsy.

4.3 Diagnostic Pathology

Updated January 2017

Surgical Specimens 

At the time of excision, the Surgeon should clearly mark and orient the specimens for the Pathologist. When image detected abnormality is removed, the specimen should then be radiographed to ensure that the area of concern was removed. The specimen, together with any specimen radiograph, should then be sent directly to the Pathologist who should carefully mark the resection margins, prior to cutting the specimen, so that the relationship of the lesion to the surgical margins can be ascertained.


4.4 Pathology Reporting for Breast Cancer

Updated October 2015

4.4.1 Hormone Receptor Levels and HER2 Testing

The estrogen receptor status of breast carcinoma can be determined by immunocytochemical staining of tissue specimens or of aspirates. When possible it is preferable to submit the specimens unfixed immediately to the pathologist who can select the most appropriate technique for handling each individual specimen. Progesterone receptors are also indicated as they may provide evidence of a potentially hormone sensitive tumour.

Immunocytochemical staining is the standard technique to test for estrogen receptors. It can be performed on fresh tissue, frozen tissue, core biopsies scrapings obtained from the surface of small lesions or frozen sections, and on aspirates with reliable results. Staining may also be performed on fixed tissue blocks, but the results may not be as accurate depending upon the fixative used and on delay in fixation of the specimen. In addition, estrogen receptor staining may be a useful technique in evaluating metastases in patients with unknown primaries in whom the possibility of metastatic breast carcinoma is in the differential diagnosis. For further information consult your hospital pathologist or regional pathologist as several hospitals, including BC Cancer, provide estrogen receptor staining.

HER2/neu (cerbB2) (human epidermal growth factor receptor 2) is an oncogene which is over-expressed in approximately 20% of breast cancers. Testing is done on the primary tumour and/or the recurrent tumour. HER2 overexpression is associated with a poor prognosis, possibly differences in response to different cytotoxics and is a predictor for responsiveness to Herceptin® (trastuzumab).

Accurate and reliable identification of HER2 overexpression is necessary. The DAKO 04B5 is the choice initial IHC screen. For 2+ tests, FISH testing is of value to identify true HER2 positive over-expression which may benefit from Herceptin® therapy and may be of greater predictive value than the IHC testing.

4.4.2 Pathologic Handling of Surgical Specimens

All specimens should be measured and margins inked. Ideally, all wire-guided biopsies and wide excisions short of complete mastectomy should be processed in entirety.

Where the specimen is very large, acceptable alternative methods of sampling and blocking can be found in guidelines from the Royal College of Pathologists.

The pathologist should mark the margins of the specimen with silver nitrate or India ink and, if this has not already been done, send a portion of tumour for receptor studies. Label all blocks separately and designate each block as to site in the gross description (e.g. Block A = Nipple; B-E = Tumour; F = deep margin etc.). Blocks from wire-guided biopsies and wide excisions should be taken sequentially so the size of the tumour can be assessed by calculating the number of blocks involved multiplied by the block thickness.

Margin status: State how the block is taken in relation to the margin. Usually blocks are taken perpendicular to the margin but if taken "en face" this must be recorded in the dictation or on a specimen diagram.

Submit all lymph nodes and state the number included in each cassette. In general the entire node should be processed.

Sentinel nodes should be handled as in the separate SLN biopsy protocol

Frozen sections should be avoided if possible as it results in distortion of the tissue and may complicate definitive diagnosis - especially on lesions, which measure <1cm. in diameter.  Frozen section may be considered if the Surgeon is proceeding directly to further definitive surgery after excisional biopsy.

4.4.3 Breast Cancer Surgical Pathology Reporting

In order to assist with optimal management of patients with breast cancer, the oncologists in British Columbia have requested the following information to be included in pathology reports. For the convenience of the reporting pathologist, the required information is presented in the form of a checklist. This information may be incorporated in the standard report format or may be listed in the form of a synoptic report.

Breast Cancer Pathology Reporting Checklist

Gross Assessment

Side: Right/Left (note - if bilateral please describe each side individually).
Specimen Type:
FNA, Needle Core Biopsy
Surgical Biopsy (incisional/excisional), Wide Excision/ Partial Mastectomy
Total Mastectomy +/- sentinel node biopsy/axillary dissection
Measurement of Specimen: Largest piece
Presence or Absence of Tumour
Number of Tumours: solitary/ multiple
Size of Tumour: 3 dimensions if possible
Gross Relationship of Tumour to Margins: measurement to closest margin
Gross Involvement of Skin or Skeletal Muscle.

Histological Assessment

Histological Diagnosis: State any specific type of carcinoma.
Size: check if greater than gross estimate; use a micrometer if possible. Greatest dimension.
Grade: note - see below
Lymphatic Invasion Outside the Tumour: Yes/ No
Venous Invasion: Yes/ No
Margins (Invasive ca.): 
Distance to Closest Margin
State Which Margin If Possible
Look for deep fascia
Skeletal Muscle: State If Invaded.
Skin: 
Ulceration 
Dermal Invasion
Dermal Lymphatic Invasion
Nipple: 
Paget's Disease
Stromal Invasion
Estrogen Receptor Status: see below
PR Status
Her-2 neu Status
Intraductal Component: 
Present/ Absent
Pattern of DCIS (Type)
Grade of DCIS
EIC Pattern: Yes /No (note - see below)
For DCIS Alone, Measurement of Size is Important.
Margin Status: - measure distance of DCIS to closest margin.
ER status now required
Calcification in the Tumour (or DCIS): Yes/ No
Lymph Nodes: 
Number of sentinel nodes removed
Number of sentinel nodes positive for metastases

Number of non-sentinel nodes removed

Number of non-sentinel nodes positive for metastases
Size of Biggest Metastasis
Extranodal Extension - measure distance from capsule

Pathological TNM Stage: see below.

4.4.2.1 Detailed Description of Pathology Report Components

Grading System for Invasive Carcinoma of Breast

General Guidelines:

  1. The system is applicable to all invasive carcinomas.
  2. Special subtypes of breast carcinoma (lobular, tubulolobular, tubular, papillary, mucinous, cribriform, medullary, adenoid cystic, sarcomatoid (metaplastic), squamous, adenosquamous) should be noted separately but should also be assigned an overall grade. Strict criteria should be used to recognise these special types of breast cancer which have prognostic significance (Ellis 1992; Tavassoli 1992; Rosen 1993).
  3. Since the term "differentiation" used in the context of breast carcinoma is an ambiguous term, it is recommended that grades 1, 2 or 3 be used instead of, or at least in addition to, the terms "well, moderately, or poorly differentiated".
  4. Grading cannot be performed adequately on material that has been frozen for the purposes of "frozen section" or "quick section". Well-fixed, well-cut, and optimally stained H&E sections are essential.
  5. The Nottingham modification of the Bloom and Richardson method of grading is used most widely and is recommended for BC Cancer. The system described below incorporates modifications suggested by Elston, Contesso, and Helpap. The three separate parameters are scored independently as follows:
(I) Nuclear Grade

Nuclear score 1: Nuclei are small to medium-sized, relatively uniform in size and shape, and lacking clumped chromatin or prominent nucleoli. Nuclei may have small, inconspicuous nucleoli. Uniformity of size and shape are the most important features.

Nuclear score 2: Nuclei are medium to large in size but exhibit only moderate variability in size, shape and intensity and pattern of staining. Nucleoli may be quite prominent as long as the nuclei are relatively monotonous in appearance. Nucleoli with irregular outlines, giant or "macronucleoli" are absent. Bizarre giant cells are absent.

Nuclear score 3: Nuclei are large and vesicular and/or contain coarse clumps of chromatin. There is considerable variation in the size and shape of nuclei. Typically, nucleoli are very large, often multiple and may have irregular outlines. Giant nuclei, polylobated nuclei and multinucleate tumour giant cells may be present. Karyorrhexis, karyolysis and pyknosis of nuclei are often encountered.

Note: The above descriptions are given as guidelines, which may be supplemented by study of illustrations of the different nuclear grades in the references, cited below. Furthermore, since there is a morphological continuum in the nuclear appearance in breast carcinomas, the extremes of the spectrum are easily recognised but, in some cases, the scoring of nuclei is to some extent subjective and differences of interpretation between pathologists are to be expected. It must be stressed that it is impossible to assign a nuclear score based on the frozen section or post-frozen paraffin embedded material.

(II) Tubule Formation

The assessment of tubular differentiation or tubule formation applies to the neoplasm overall and requires examination of several sections at scanning magnification. A reliable tubular score cannot be assigned when only needle biopsies or small pieces of the tumour are examined.

Tubule score 1: >75% of the neoplasm is composed of tubular structures with visible lumina. Solid trabecula, vacuolated single cells, alveolar nests and solid sheets of cells comprise less than 25% of the tumour.

Tubule score 2: 10-75% of the tumour has a tubular pattern.
Tubule score 3: <10% tubule formation.

(III) Mitosis Score

The mitosis score is assessed in the peripheral areas of the neoplasm and not the sclerotic central zone. The neoplasm is scanned at intermediate magnification to determine the area in which mitoses are most abundant (usually areas of poor tubule formation where cells are arranged in sheets or large nests). Only definite mitotic figures are counted with care to avoid including pyknotic nuclei in the count. Although the Nottingham grading system uses a scoring system based on the number of mitoses per 10HPF's, the Oncologic Standards Committee considers that a mitotic count per square millimetre is most accurate. Mitoses are only counted in the invasive component of the lesion.

Score 1: <4 mitoses per square mm.
Score 2: 4-7 mitoses per square mm.
Score 3: >7 mitoses per square mm.

Alternatively the number of mitoses in 10 high power fields (HPFs) is counted. Using a Nikon Labophot microscope with a 40X objective lens (i.e. X400) and a field surface area of 0.152mm2, the scores are as follows :-

Score 1: 0-5 mitoses
Score 2: 6-10 mitoses
Score 3: >10 mitoses

In practice, Contesso's method of scoring of mitoses is quicker and easier to perform especially on small biopsies (e.g. Core biopsies). At least 20HPF's of the same area as stated above are assessed and scored as follows :-

Score 1: No field contains more than 1 mitosis.
Score 2: Two mitoses present in any one HPF.
Score 3: Three or more mitoses present in any one HPF.

Composite Score

The scores for the three separate parameters (tubules, nuclei and mitoses) are summated and the overall grade of the neoplasm is determined as follows :-

Grade 1: 3-5 points.
Grade 2: 6-7 points.
Grade 3: 8 or 9 points.

Pathology of Ductal Carcinoma In Situ (DCIS)

The following patterns of DCIS are recognized:

  1. Cribriform
  2. Micropapillary - papillary structures lack fibrovascular cores.
  3. Papillary - fibrovascular cores present within papillary structures.
  4. Solid
  5. Comedocarcinoma - defined as DCIS with extensive central necrosis (>2/3 the diameter of the duct). The latest consensus committee abandoned the requirement for high nuclear grade in combination with necrosis.
  6. Others:
    • Clinging
    • Apocrine DCIS.
    • Signet ring cell DCIS
    • Low-grade endocrine DCIS
Grading of DCIS

Low Grade (Grade 1): Grade 1 or 2 nuclei and no zonal necrosis.
Intermediate grade (Grade 2): Grade 1 or 2 nuclei with zonal necrosis
High grade (Grade 3): Grade 3 nuclei with or without necrosis

Quantitation: In addition to the maximal linear size of the DCIS, a rough estimate of the volume of DCIS relative to the overall tumour should be given as a percentage. "Extensive intraduct component (EIC)" is used to qualify invasive carcinomas with DCIS, which may take two forms as follows :

  1. Prominent DCIS within the invasive tumour mass (comprising 25% or more of the volume) AND DCIS in adjacent breast ducts and/or lobules extending clearly beyond the boundaries of the invasive carcinoma.
  2. Widespread DCIS with microscopic stromal invasion is also placed in the EIC category.
This assessment is important because EIC carcinomas treated with breast conservation have a higher risk of local recurrence within the breast unless the margins are well clear.15

Grading of Invasive Lobular Carcinoma

In general, it is possible to grade lobular carcinoma. Usually, classical lobular carcinoma will attain a total score of 5 (tubules 3; nuclei 1; mitoses 1) giving the tumour an overall grade 1. Although some of the data are somewhat inconclusive, histological variants of lobular carcinoma are thought to differ in their degree of aggressiveness as follows:

  1. Good Prognosis (Grade 1): Tubulolobular carcinoma. This variant features tubular structures that are lined by very uniform small cells resembling those of classical lobular carcinoma. Single-file strands of identical cells are also present. Some authorities would regard this variant as a ductal carcinoma (tubular type).
  2. Fairly good Prognosis (Grade 1): (marginally better than that of ductal carcinoma NOS.) Classical lobular carcinoma. Criteria include: 
    • Small uniform cells; grade 1 nuclei 
    • Single-file rows in a fibrous stroma
    • Targetoid (concentric, "bull's-eye") pattern around pre-existing ducts
  3. Intermediate prognosis (Grade 2):
    • Classical pattern with Grade 2 nuclei
    • Alveolar variant - round and oval nests of uniform small cells
    • Large cell variant
    • Mixed patterns of lobular carcinoma
  4. Poor prognosis patterns (Grade 3):
    • Solid variant - large sheets of uniform small cells with round nuclei
    • Pleomorphic lobular carcinoma - pattern resembles classical lobular carcinoma but the nuclei are grade 2-3, mitoses are easily identified, apocrine change is common, and ER is often negative.
    • Signet-ring cell variant (>20% of cells should be signet-ring type)
Lymphatic Invasion

Only invasion of lymphatics beyond the advancing edge of the tumour is important.

If in doubt call it negative.

Please state if there is extensive lymphatic/vascular invasion (>10 lymphatics involved).

Venous Invasion

Large calibre, thick-walled blood vessels containing tumour emboli either within the tumour in the surrounding tissue are included.

Neural Invasion

Neural invasion has been shown not to be of prognostic significance in most studies. This is confirmed in a recent analysis of BC Cancer data.

Extranodal Extension

Tumour cells must be outside the nodal capsule.

Please state if "minimal" extra nodal spread (<1mm from capsule) or extensive infiltration of perinodal tissues with "matting" of nodes.

Breast Markers

Breast markers on invasive carcinoma should be done on the core biopsy sample where relevant. Only if the results appear incongruous with the histology, should the markers be repeated on the excision specimen.

DCIS should be stained for ER in the excision specimen. PR and Her2-neu status of DCIS is not relevant for management of the patient.

1) Estrogen Receptors

Please select a block containing invasive carcinoma and normal breast tissue if possible.

Immunostains are graded subjectively on a scale 0-3+.

0 :- Negative nuclear staining; positive internal control staining. Allred scores 0(1,2)
1+ :- Allred scores 3-4
2+ :- Allred scores 5 and 6
3+ :- Allred scores 7 and 8

Allred Score: Percentage of nuclei staining + Intensity + Total score

% Nuclei staining
Score
0
0
<1%
1
1-10%
2
11-33%
3
34-66%
4
>67%
5

Intensity score:

No staining
0
Weak
1
Moderate
2
Strong
3

2) Progesterone Receptors: Recommended on all invasive breast cancers.
PR is graded as for ER using the Allred (UKNEQUAS) scoring method.

3) Her-2neu: Required on all invasive breast cancers.

Pathological TNM Stage and UICC Stage Groupings

Tumour

pTX : unable to assess size

pTis: Carcinoma In Situ

pT1mic: <0.1 mm microinvasive
pT1a: Tumour diameter 0.1-5mm
pT1b: 6-10mm
pT1c: 11-20mm

pT2: 21-50mm

pT3: >50mm

pT4a: Tumour spread to chest wall, but not pectoral muscle
pT4b: Skin involvement
pT4c: Both T4a + T4b
pT4d: Inflammatory breast cancer

Nodes – please see official TNM publication for details of complicated classes.

pNX: Nodal Status Unknown

pN0: Negative Nodes
pN0i+: <0.2mm metastases (single cells or isolated tumour cell clusters)

pN1mi: micrometastases 0.2-<2mm diameter
pN1a: 1-3 positive nodes, metastases >2mm diameter
p
N1b: Internal mammary LN positive not clinically apparent
pN1c: Internal mammary LN +ve (clinically occult) plus 1-3 axillary nodes +ve.

pN2a: 4-9 axillary nodes +ve.
pN2b: Internal mammary nodes +ve, axillary nodes negative

pN3a: >10 axillary nodes +ve or infraclavicular nodes +ve
pN3b: clinically detected ipsilateral internal mammary LN in presence of > 1 axillary LN +ve
pN3c: Supraclavicular node +ve

Distant Metastases

pMX : Unknown Status
pM0 : No Distant Metastases
pM1: Distant Metastases Present

UICC Stage Grouping

Stage O
TisN0M0
Stage I
T1N0
Stage IIA
T0N1M0
T1N1M0
T2N0M0
Stage IIB
T2N1M0
T3N0M0
Stage IIIA
T0N2M0
T1N2M0
T2N2M0
T3N1M0
T3N2M0
Stage IIIB
T4N0M0
T4N1M0
T4N2M0
Stage IIIC
AnyTN3M0
AnyT4d
Stage IV
Any M1

BC Cancer Pathology Reviews

Updated March 2018

BC Cancer breast pathologists can be asked to review slides in the following situations:

  1. It is the suggestion of the BC Cancer Breast Tumour Group to consider a formal pathology review for node negative invasive breast cancers in which  a change in pathology could significantly change the prognosis of the  breast cancer and initiate a change in clinical management. 
  2. Cases in which clarification of specific aspects of the tumour would impact treatment decisions, e.g. margin size, can be reviewed prior to a final decision regarding treatment.  These reviews are typically requested as needed by a treating oncologist - radiation, medical, or surgical.
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Lobular carcinoma

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DCIS Grading

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  5. Holland R, et al. Microcalcification associated with ductal carcinoma in situ: mammographic-pathologic correlation. Semin Diagn Pathol 1994;11:181-192
  6. Holland R, et al. Ductal carcinoma in situ: a proposal for a new classification. Semin Diagn Pathol 1994;11:167-180.
  7. Leal CB, et al. Ductal carcinoma in situ of the breast; histological categorization and its relationship to ploidy, and immunohistochemical expression of hormone receptors, p54, and c-erbB-2 protein. Cancer 1995;75:2123-2131.
  8. Sneige N, et al. Ductal carcinoma in situ treated with lumpectomy and irradiation: histopathological analysis of 49 specimens with emphasis on risk factors and long term results. Hum Pathol 1995;26:642-649.
  9. Douglas-Jones AG, et al. A critical appraisal of six modern classifications od ductal carcinoma in situ of the breast (DCIS): correlation with grade of associated invasive carcinoma. Histopathology 1996;29:397-409.
  10. Consensus conference on the classification of ductal carcinoma in situ. Human Pathology 1997;28:1221-1225.

Estrogen Receptors

  1. Allred DC, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Modern Pathology 1998;11(2):155-168
  2. Leake R, et al. Immunohistochemical detection of steroid receptors in breast cancer: a working protocol. J Clin Pathol 2000;53:634-635
  3. Pertschuk LP, et al. Immunocytochemical estrogen and progestin receptor assays in breast cancer with monoclonal antibodies. Histopathologic, demographic and biochemical correlations and relationship to endocrine response and survival. Cancer 1990;66:1633-1670.
  4. Pertschuk LP, et al. Estrogen receptor immunocytochemistry in paraffin embedded tissues with ER1D5 predicts breast cancer endocrine response more accurately than H222Spgamma in frozen sections or cytosol-based ligand assays. Cancer 1996;77:2514-2519.
  5. Andersen J, et al. Immunohistochemical estrogen receptor determination in paraffin-embedded tissue. Prediction of response to hormone treatment in advanced breast cancer. Cancer 1989;64:1901-1908.
  6. Goulding H, et al. A new immunohistochemical antibody for the assessment of estrogen receptor status on routine formalin-fixed tissue samples. Human Pathol 1995;26:291-294.



5. Staging

Updated February 2016

Breast Staging Diagram

5.1 Preoperative Investigations

History and physical examination should be undertaken to assess any physical signs and symptoms, which may suggest metastatic disease. History and physical exam should include examination of breasts, nodal basins (axillary, cervical, supraclavicular), lungs, liver and bones. If history and physical examination are normal, other staging investigations may not be necessary. If there are any abnormal findings, these should be further investigated as appropriate.

Investigations recommended prior to surgery include:

  • Bilateral mammography
  • Investigation of suspicious findings on history and physical exam

If the patient presents with locally advanced breast cancer (large tumour, node positive) or inflammatory breast cancer, the risk of metastatic disease is higher Staging prior to any treatment (bone scan, chest CT or x-ray, abdominal CT or US and, laboratory investigations including liver enzymes) should be considered. In the absence of symptoms suggesting metastatic disease, staging should be done postoperatively based on final pathology.

5.2 Postoperative Investigations

Staging of breast cancer is based on final pathology. In asymptomatic patients with newly diagnosed cancer, the following staging investigations are recommended based on the pathologic staging:

Stage 0 (DCIS)
No further investigations
Stage 1
Laboratory investigations (CBC, liver enzymes)
Stage 2
Laboratory investigations, consider bone scan, CXR, abdominal imaging 
Stage 3
Laboratory investigations, CXR/Chest CT, abdominal imaging, bone scan

Baseline tumour markers including CEA, CA15-3 and CA125 should only be considered as part of the initial staging for patients with metastatic disease. If normal, they need not be repeated, unless there is a documented or suspected progression. 

Other than these investigations, prior to chemotherapy, a hematology and chemistry panel should be done to rule out bone or liver metastases and to ensure adequate marrow, hepatic and renal function.



6.1.0 Introduction

Revised November 2017

A diagnosis of breast cancer requires patients and their caregivers to make a number of important decisions during the course of the disease. Surgery, systemic therapy, and radiotherapy are important treatments that optimize local, regional, and systemic control of the disease and optimize quality of life for patients with breast cancer. Multi-disciplinary care is an important resource that can aid in making these difficult decisions.

The mainstay of definitive treatment among patients with non-metastatic invasive and in situ breast cancer is surgical resection of the breast cancer, with consideration of neoadjuvant or adjuvant therapy. Those patients with inoperable, non-metastatic breast cancer may potentially be cured by neoadjuvant therapy, possibly followed by surgery. Patients with either recurrent or metastatic breast cancer may benefit significantly from treatment, with the primary goal of optimizing quality of life for those patients.   

Weekly conferences are held (Tuesday AM at the Vancouver Island Cancer Centre; Friday PM at the Vancouver Cancer Centre; Friday PM at the Cancer Centre for the Southern Interior, Monday at noon at the Fraser Valley Cancer Centre and Abbotsford Cancer Centre) to discuss the multi-disciplinary management of patients. Diagnostic radiologists, medical oncologists, pathologists, radiation oncologists and surgeons typically attend these conferences. The clinical history, physical examination, pathology slides and diagnostic imaging studies are reviewed and management options are discussed. Family physicians and surgeons are welcome to attend these conferences.

Patients with breast cancer should be supported in their decision-making about what treatment pathway is best for them. There are a number of online resources, including a Patient Information Kit (PDF), that we encourage patients to access. The BC Cancer library has videos, pamphlets and books for loan available to patients provincially - call 604-675-8001 or 1-888-675-8001, local 8001. See also BC Cancer Centres and Clinics and information for patients and the public.

The information in this section of the Cancer Management Guidelines is our current approach to patients with breast cancer. It is not intended to be a comprehensive manual on breast cancer and its treatments nor is it intended to imply that the approach given here is the only acceptable approach. 

Referral information for the new patient visit to BC Cancer

People with a suspected diagnosis of breast cancer should undergo percutaneous core biopsy , to confirm the pathology. This may be facilitated by the patient’s family physician in consultation with a surgeon.
Patients with a new diagnosis of non-metastatic breast cancer should be referred initially to a surgeon with experience in breast cancer surgery for assessment regarding operability and discussion of surgical options.  

Most commonly, women with operable breast cancer are referred to BC Cancer by their surgeon after their definitive breast +/- axillary surgery, when prognostic information from their surgery is available to guide discussions about adjuvant treatment.  Women with operable breast cancer who have difficulty making decisions about what type of surgery they would like to pursue after discussion and assessment by the surgeon can be referred to BC Cancer in the preoperative setting. 

Women with inoperable, locally advanced disease or women being considered for neo-adjuvant therapy should be referred to BC Cancer for assessment and management as soon as possible.  Women with metastatic breast cancer should also be referred to BC Cancer for assessment and management as soon as possible, as long as their performance status is sufficient to allow them to be assessed at BC Cancer.

6.2.0 In Situ Disease

Updated April 2021

6.2.1 Paget's disease of the Nipple-Areolar Complex

Paget's disease is a lesion involving the epidermis of the nipple-areolar complex characterized by Paget cells. The majority of cases of Paget’s disease is associated with an invasive or in-situ breast cancer. The breast should be imaged with a mammogram and ultrasound, and if these investigations are non-diagnostic, an MRI of the breast should be carried out. Biopsy of any suspicious abnormalities found on imaging should be done. 
Paget’s disease in association with in-situ or invasive carcinoma

Paget’s disease in association with in situ or invasive carcinoma should be resected with clear margins to the in situ disease, invasive disease and to the Paget’s disease. In-continuity resection of the breast carcinoma and Paget’s disease is not required. Recommendations for radiation and systemic therapy are based on the pathology of the underlying breast cancer. 

Isolated Paget’s Disease

If a co-existent breast cancer is not identified pre-operatively, local excision and adjuvant radiation can be offered for treatment of Paget’s disease. A margin of underlying breast tissue should be excised with the nipple-areolar complex to evaluate for an associated in-situ or invasive cancer. Axillary staging is not initially required in the context of breast conserving therapy. Mastectomy represents a surgical option.

A referral to plastic surgery for reconstruction of the nipple-areolar complex should be considered.

6.2.2 Ductal Carcinoma in Situ (DCIS)

Appropriate management of pure DCIS requires detailed mammographic evaluation of the breast to obtain an assessment of the preoperative extent of the lesion. Close cooperation and communication between the radiologist, surgeon, pathologist and oncologist is crucial to ensure adequate local therapy in patients treated with breast conservation. Treatment for patients with concomitant microinvasive and invasive disease should be based on the presence of the invasive disease, as discussed in separate sections.

Axillary staging is not routinely recommended for patients with pure DCIS because the risk of axillary nodal involvement is <1%. Sentinel lymph node biopsy is advised for patients undergoing mastectomy for DCIS due to the possibility of an invasive component in the final surgical specimen.1 

DCIS is a non-obligate precursor of invasive disease.  At present, all patients with pure DCIS are offered treatment. Patients with pure DCIS may be treated with breast conserving therapy or mastectomy. Both management strategies are associated with survival exceeding 98%. Patients undergoing breast conserving surgery (including partial mastectomy, lumpectomy, wide excision, or excisional biopsy) with a positive margin (defined by ink on DCIS) after surgery should undergo wider local excision. A 2-mm margin is associated with a decreased risk of in-breast tumour recurrence compared to narrower margins. Margin widths greater than 2 mm do not confer a significant benefit in local control compared to a 2 mm margin and thus re-excision for margins wider than 2-mm should not be routinely carried out2. Clinical judgment should be utilized for determination of the need for re-excision in patients with a smaller negative margin width (0.1-1.9 mm).2

Radiotherapy reduces the incidence of in situ and invasive breast recurrences after breast conserving surgery by half.3,4,5,6 Currently, adjuvant radiotherapy is recommended after breast conserving surgery for women with DCIS with higher risk features, e.g. younger age, high nuclear grade, larger tumour, comedo carcinoma, or close margins (<5mm) of excision. Women with well differentiated DCIS (cribriform, solid, papillary) that are <1cm in diameter with complete radiographic and pathologic excision (at least 5 mm of normal breast tissue between foci of DCIS and the inked margins) may be considered for management by wide excision alone. All patients should be referred to BC Cancer after breast-conserving surgery for an individualized discussion of the risks and benefits of adjuvant radiotherapy.

Radiotherapy should optimally start once healing from the partial mastectomy is complete, generally within 10 weeks of partial mastectomy. If post-operative problems occur, including hematoma, large seroma, infection, breast edema with erythema, or wound dehiscence occur, the start of radiotherapy may be delayed to allow resolution. There is no randomised trial evidence showing detriment to delay the start of radiotherapy however, retrospective data from British Columbia shows that there is no detriment to delay up to 20 weeks after BCS for patients with invasive disease7, which likely also applies to DCIS. Radiotherapy planning and prescription is similar to those with invasive disease and are described separately.

Women with very diffuse areas of DCIS (e.g., >5 cm or greater than or equal to ¼ of the breast on mammogram) have a substantial risk of recurrence, even after partial mastectomy and radiotherapy, and mastectomy is recommended.8 

There are a number of prognostic models (VNPI, MSKCC)9,10 that can be used to estimate the risk of local recurrence considering factors such as age, margin status, nuclear grade, size of the DCIS lesion, but the performance of these models has been variable.11,12 In the future, tests using a combination of biomarkers, e.g. tumour gene profiling, may be useful for prognostication.

The use of adjuvant hormonal therapy is somewhat controversial. Adjuvant tamoxifen has been shown to decrease the occurrence of ipsilateral and contralateral breast cancers in women with in situ disease.4 This benefit is limited to those patients with ER positive tumours. No randomized trial has shown an improvement in survival with tamoxifen.4,5,6 The benefit must be weighed against the increased risk of thromboembolic events and uterine cancer. Adjuvant tamoxifen should not be considered for women with bilateral mastectomies, those with an increased risk of endometrial cancer or thromboembolic events, those with a life expectancy of <10 years or those who have taken tamoxifen for prevention. If used, the recommended tamoxifen dose is 20 mg/day for 5 years. Contraindications to tamoxifen are discussed more thoroughly below.

The role of adjuvant aromatase inhibitors is not clearly established. A randomized study of adjuvant tamoxifen versus anastrozole in women with DCIS treated with lumpectomy showed that anastrozole offers a similar degree of benefit and similar number of side effects as tamoxifen, although the side effect profile differed.13

References
    1. Lyman GH1, Giuliano AE, Somerfield MR, Benson AB 3rd, Bodurka DC, Burstein HJ, Cochran AJ, Cody HS 3rd, Edge SB, Galper S, Hayman JA, Kim TY, Perkins CL, Podoloff DA, Sivasubramaniam VH, Turner RR, Wahl R, Weaver DL, Wolff AC, Winer EP; American Society of Clinical Oncology. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol. 2005 Oct 20;23(30):7703-20. Epub 2005 Sep 12.
    2. Morrow M, Van Zee KJ, Solin LJ, Houssami N, Chavez-MacGregor M, Harris JR, Horton J, Hwang S, Johnson PL, Marinovich ML, Schnitt SJ, Wapnir I, Moran MS. Society of Surgical Oncology-American Society for Radiation Oncology-American Society of Clinical Oncology Consensus Guideline on Margins for Breast-Conserving Surgery with Whole-Breast Irradiation in Ductal Carcinoma In Situ.  Ann Surg Oncol. 2016 Nov;23(12):3801-3810.
    3. F Wärnberg, H Garmo, S Emdin , et al: Effect of radiotherapy after breast-conserving surgery for ductal carcinoma in situ: Twenty-year follow-up in the randomized SweDCIS trial J Clin Oncol 32: 3613– 3618,2014
    4. IL Wapnir, JJ Dignam, B Fisher , et al: Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS J Natl Cancer Inst 103: 478– 488,2011
    5. M Donker, S Litière, G Werutsky , et al: Breast-conserving treatment with or without radiotherapy in ductal carcinoma in situ: 15-year recurrence rates and outcome after a recurrence, from the EORTC 10853 randomized phase III trial J Clin Oncol 31: 4054– 4059,2013
    6. J Cuzick, I Sestak, SE Pinder , et al: Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: Long-term results from the UK/ANZ DCIS trial Lancet Oncol 12: 21– 29,2011
    7. Olivotto IA, Lesperance ML, Truong PT, Nichol A, Berrang T, Tyldesley S, et al. Intervals longer than 20 weeks from breast-conserving surgery to radiation therapy are associated with inferior outcome for women with early-stage breast cancer who are not receiving chemotherapy. J Clin Oncol. 2009 Jan 1;27(1):16-23
    8. Hamilton SN, Nichol A, Wai E, Gondara L, Velasquez Garcia HA, Speers C, et al. Local relapse after breast-conserving therapy versus mastectomy for extensive pure ductal carcinoma In Situ ≥4 cm.  Int J Radiation Oncol Biol Phys. 2019 Feb1;103(2):381-388.
    9. Di Saverio S1, Catena F, Santini D, Ansaloni L, Fogacci T, Mignani S, Leone A, Gazzotti F, Gagliardi S, De Cataldis A, Taffurelli M. 259 Patients with DCIS of the breast applying USC/Van Nuys prognostic index: a retrospective review with long term follow up.Breast Cancer Res Treat. 2008 Jun;109(3):405-16. Epub 2007 Aug 9.
    10. Rudloff U, Jacks LM, Goldberg JI, et al. Nomogram for predicting the risk of local recurrence after breast-conserving surgery for ductal carcinoma in situ. J Clin Oncol. 2010;28:3762–3769.
    11. Yi M, Meric-Bernstam F, Kuerer HM, Mittendorf EA, Bedrosian I, Lucci A, Hwang RF, Crow JR, Luo S, Hunt KK. Evaluation of a breast cancer nomogram for predicting risk of ipsilateral breast tumor recurrences in patients with ductal carcinoma in situ after local excision. J Clin Oncol. 2012 Feb 20;30(6):600-7. doi: 10.1200/JCO.2011.36.4976. Erratum in: J Clin Oncol. 2012 Jul 1;30(19):2424.
    12. A population-based validation study of the DCIS Score predicting recurrence risk in individuals treated by breast-conserving surgery alone.  Rakovitch E, Nofech-Mozes S, Hanna W, Baehner FL, Saskin R, Butler SM, Tuck A, Sengupta S, Elavathil L, Jani PA, Bonin M, Chang MC, Robertson SJ, Slodkowska E, Fong C, Anderson JM, Jamshidian F, Miller DP, Cherbavaz DB, Shak S, Paszat L.  Breast Cancer Res Treat. 2015 Jul;152(2):389-98. doi: 10.1007/s10549-015-3464-6.
    13. Forbes JF, Sestak I, Howell A, Bonanni B, Bundred N, Levy C, von Minckwitz G, Eiermann W, Neven P, Stierer M, Holcombe C, Coleman RE, Jones L, Ellis I, Cuzick J; IBIS-II investigators.   Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial. Lancet. 2016 Feb 27;387(10021):866-73. doi: 10.1016/S0140-6736(15)01129-0.

6.2.3 Lobular Carcinoma In Situ (LCIS)

Use of this term is controversial. Most modern authors regard this as indicating a high risk for the development of infiltrating carcinoma in either or both breasts. The risk for subsequent carcinoma is not confined to the segment of the breast involved by the in situ change. The risk to each breast is approximately equal and approaches fifteen percent within ten to fifteen years. When LCIS is identified on a core needle biopsy, a surgical excisional biopsy should be considered to rule out an associated malignancy as typically LCIS alone does not explain an imaging finding. When LCIS is identified on an excision specimen, re-excision is not required, although should be considered in pleomorphic LCIS if the margin is not adequate. Patients can be given the option of either careful follow-up or occasionally, bilateral mastectomy with or without immediate or delayed reconstruction. Tamoxifen was shown to decrease the risk of invasive cancer in women with LCIS in the NSABP prevention trial using tamoxifen 20 mg daily for 5 years, although there was no improvement in survival. Tamoxifen can be considered if breast cancer prevention is the primary goal. 

6.2.4 Pleomorphic LCIS

Classic LCIS behaves as an indicator lesion for higher risk of breast malignancy in any region of the breast. Pleomorphic LCIS (PLCIS) has pathologic features similar to DCIS and is frequently associated with DCIS or invasive breast cancer.  When detected in isolation, PLCIS has a pattern of recurrence more similar to a precursor lesion such as DCIS with a higher risk of malignancy within that region of the breast.  There are no randomized trials that describe what margin should be achieved with surgery or the efficacy of adjuvant breast radiotherapy in the setting breast conserving surgery for PLCIS. It is recommended that patients with PLCIS on biopsy have excision to rule out additional pathology and achieve clear margins for PLCIS and should also have a discussion regarding the possible benefits of adjuvant breast radiotherapy or more definitive breast surgery.

6.3.0 Early Invasive Breast Cancer (T1T2NON1: T3N0)

Updated February 2016

Management of Invasive Breast Cancer

Invasive breast cancer requires multimodality management that is specific to the stage of the disease. The majority of patients with invasive breast cancer have ductal breast cancer and, less commonly, lobular breast cancer. While there is a slight difference in the natural history of lobular and ductal breast cancer, patients with these two different pathologies are treated in the same way. The management sections that follow, aside from the section about less common histologies, refer in particular to those with invasive ductal or lobular breast cancer.

6.3.1 Locoregional Management

6.3.1.1 Surgical Treatment

Breast Surgery

Definitive treatment of early invasive breast cancer is surgery. Typically, the primary tumour is excised and axillary lymph nodes are removed for staging. The decision of when to proceed to surgery and which procedure is best for an individual patient has become more complicated with the options of neoadjuvant chemotherapy and immediate breast reconstruction, and with changing recommendations for radiotherapy and chemotherapy. Sequencing of breast cancer treatment is more commonly done with multidisciplinary input.
A general overview of breast cancer surgery is outlined below and additional information on special circumstances, such as young women, elderly patients, pregnant patients, and male breast cancer are found in following sections.

Breast Conserving Surgery

Breast conserving surgery (BCS, lumpectomy, partial mastectomy or segmental mastectomy) or breast conserving surgery plus radiotherapy has been shown in multiple randomized control studies to be equivalent to mastectomy in terms of survival and breast cancer outcomes for patients with early-stage disease1,2.  It is recommended that most patients with early stage disease be offered BCS3,4,5 as long as the tumour to breast ratio would give a reasonable cosmetic outcome following the procedure. Additional strategies such as oncoplastic lumpectomy resections and tumour shrinkage with Neoadjuvant Chemotherapy (NAT) can increase the number of patients eligible for BCS. 

MRI is not recommended in the routine assessment of unilateral breast cancer as there has been no improvement in survival or repeat surgery rates by using MRI and the additional investigations and findings can result in delay or overtreatment to the known cancer.6,7

Patients with a positive margin should be evaluated for further surgery.8

Patients having BCS should be referred to radiation oncology as radiotherapy significantly lowers the risk of in-breast recurrence in the setting of BCS. However, there is a group of patients felt to be at low risk of recurrence with BCS alone who may be spared radiotherapy.9 Patients in remote communities who have traditionally opted for mastectomy to avoid travel for radiotherapy might be eligible for BCS alone and if this is considered, a preoperative discussion with radiation oncology is recommended.

Surgical Margins after Breast Conserving Surgery for Invasive Disease

For most patients it is reasonable to try to achieve an ipsilateral breast tumour recurrence (IBTR) rate of <1% per year. The addition of a radiation boost to the tumour bed reduces the risk of IBTR. However, re-excision to obtain negative margins may reduce IBTR more than using a radiation boost. The use of systemic therapy also minimally reduces IBTR.

Those with positive margins have double the risk of IBTR compared to those with negative margins. There is conflicting data regarding the risk of IBTR with close margins. Most of the randomized trials of breast conservation with radiation vs mastectomy were in the context of no tumour seen at ink at pathologic examination of the resection specimen, although retrospective studies demonstrate an increased IBTR with both positive or close margins.

There is no evidence that re-excision alters survival compared to radiotherapy boost. The degree of survival impact of either, in the setting of close margins in particular, is expected to be small, or negligible, particularly in the absence of other risk factors.

For patients with a high systemic failure risk (e.g. those with numerous positive axillary lymph nodes), it may be reasonable to accept a higher risk of IBTR. It may also be reasonable to accept a higher risk of IBTR in patients for whom further local breast surgery would result in an unacceptable cosmetic result, but for whom there is a strong desire to avoid a mastectomy, or if medical problems preclude further surgery. In these situations, a radiation boost would likely be used, albeit this can also affect the cosmetic outcome.

Guidelines for Re-excision and Radiation Boost following breast-conserving surgery

  1. For patients with invasive disease, invasive or in situ disease at the margin will be treated in the same manner.
  2. The definition of a negative margin is no tumour at the inked margin. A positive margin is defined as tumour touching ink. In British Columbia, a close margin is currently defined as less than 2 mm margin.
  3. Re-excision to obtain negative margins is recommended for patients with positive margins.
  4. If a margin is close (< 2 mm), a re-excision is not routinely recommended but could be considered if the risk of IBTR is high and systemic risk is low, for example. A radiotherapy boost is usually recommended in the setting of a close margin.

    Re-excision may be considered for close margins in the following circumstances:

    Margin < 2 mm and
    extensive intraductal component present
    Age < 40
    No systemic therapy planned or the patient declines systemic therapy
    Margin close at multiple sites
    Margin status unknown
  5. When the deep margin is positive, and the surgeon has dissected down to fascia, then a radiotherapy boost should be given instead of re-excision
  6. When the anterior margin is positive, and the surgeon has removed the breast tissue underlying the skin, then a radiotherapy boost should be given instead of re-excision.
Patients with close or positive margins who decline re-excision should be advised that the risk of IBTR is increased. The relative risks/benefits of re-excision vs boost in the context of local control and cosmesis should be discussed.

Timing of Re-excision

Early consultation with a radiation oncologist is recommended if there is uncertainty about whether re-excision is recommended. This will facilitate a timely re-excision. Re-excision should be carried out prior to adjuvant radiation but does not need to occur prior to systemic therapy.

Lobular Carcinoma In Situ at margin

Lobular carcinoma in situ at the margins does not constitute a positive margin.

Pathology Report Reviews

If a pathology report does not contain the necessary information to determine margin status, then the reading pathologist should be consulted or a BC Cancer pathology review should be obtained. If, after this, it is still not possible to accurately determine the margins, then the margins should be treated as unknown in which case a re-excision (or radiation boost) is generally recommended.

Mastectomy

Total mastectomy (TM) is defined as the removal of entire breast. "Mastectomy requires the elevation of skin flaps sufficiently thin to remove all of the breast tissue, and extended to the anatomic limits of the breast (the sternal border medially, the clavicle superiorly, the latissimus laterally, and the rectus sheath/inframammary fold inferiorly)."10

Skin sparing mastectomy (SSM) is used in conjunction with immediate breast reconstruction and studies have shown no increased recurrence risk with use of this technique10. Nipple sparing mastectomy (NSM) is a viable option by the properly trained surgeon in women with small to moderate sized breasts, minimal ptosis, and favorable tumour features11  Evidence is accumulating that there is a low recurrence risk in properly selected patients.  When assessing a patient for a NSM, considerations include location of the tumour, nodal status and need for radiotherapy, and tumour biology.11 A nipple margin (core) should be taken when a NSM is performed.11

Total Mastectomy (TM, SSM, NSM) is an option for patients with early stage breast cancer particularly for patients with contraindications to radiotherapy or desire to avoid radiotherapy, patients who would have a poor cosmetic outcome with breast-conserving therapy or those with multicentric disease or associated diffuse, extensive DCIS. Mastectomy should also be considered in those who continue to have positive margins of invasive disease after multiple breast-conserving surgeries.

Axillary Surgery

Axillary surgery provides important prognostic information and can improve regional control for some patients with invasive breast cancer. Traditionally, level I and II axillary node dissection (ALND) had been the standard of care for all patients with invasive breast cancer. ALND has now been replaced by Sentinel Lymph Node biopsy (SLNB) for most patients with clinically N0 breast cancer12,13.  Sentinel lymph node biopsy is associated with less morbidity than ALND12 and similar staging accuracy and oncologic outcomes in early breast cancer12,13,14,15 and should be offered to all eligible patients. 

Axillary lymph node dissection is recommended12,13,14,15,16,17 (Surgical Breast Tumour group consensus 2016) in the following situations:

  1. Inflammatory breast cancer
  2. Occult breast cancer presenting as axillary node metastasis
  3. Clinically node positive axilla, confirmed by FNA or core biopsy in a patient for whom neoadjuvant chemotherapy is not planned
  4. Axillary nodes that remain positive after neoadjuvant chemotherapy
  5. Axillary recurrence following previous breast cancer treatment.  
Axillary lymph node dissection should be considered12,13,14,15,16,17 (Surgical Breast Tumour group consensus 2016):

  1. Failed Sentinel node mapping in invasive cancer with high risk features
  2. Positive sentinel lymph nodes not meeting eligibility criteria for Z0011 study15* (multidisciplinary discussion recommended)
  3. Node positive disease prior to NAT (evidence evolving around the role of SLNB, multidisciplinary discussion recommended)
  4. Axillary staging required in the setting of previous mastectomy
Axillary lymph node dissection not recommended12,13,14,15,16,17 (Surgical Breast Tumour group consensus 2016):

  1. Clinically T1-T2 N0 breast cancer (sentinel node biopsy should be offered)
  2. Positive sentinel nodes meeting criteria for Z0011 study15*
  3. DCIS
* Z0011 Eligibility criteria: T1T2 Invasive breast cancer, no palpable axillary nodes, 1-2 Sentinel nodes positive, treated with BCS with clear margins (no tumour at ink), no matted nodes / gross extranodal disease / neoadjuvant hormonal or chemotherapy 

Level 1 and 2 axillary dissection is generally recommended for those with three or more pathologically positive sentinel nodes and those at high risk for gross residual nodal disease after sentinel node procedure (e.g. those with three or more pathologically positive sentinel nodes, or gross extracapsular extension) to improve regional control, although the elevated risk of lymphedema of axillary dissection in the setting of regional radiotherapy must also be considered in the absence of a proven survival advantage. 

Synoptic Reporting for Breast Cancer Surgery

The Surgical Breast Tumour group developed a Breast Cancer Checklist (Synoptic Report) in conjunction with medical and radiation oncology. It is recommended that surgeons report breast cancer procedures using this template to facilitate communication of relevant details to other care providers.
  
Pathology considerations for Partial and Modified Radical Mastectomy

The specimen removed at partial mastectomy must be oriented by the surgeon. At least two boundaries should be marked with sutures of different colour or length so that the specimen can be oriented in three dimensions (e.g. long suture = lateral, short suture = superior). With a correctly marked specimen the pathologist will then be able to make an accurate estimate of the size of the tumour-free margin and to identify the location of any margin thought to be inadequately excised. If the margin is inadequate in a location where it is possible to improve the situation surgically, then a re-excision should be carried out.

For a modified radical mastectomy, axillary end should be marked for orientation so that the location as well as the number of nodes removed and involved by malignancy can be ascertained.

Contralateral Prophylactic Mastectomy

Patients who require a mastectomy to treat unilateral breast cancer often enquire about contralateral prophylactic mastectomy (CPM). A detailed history and family history is required to assess the risk of a contralateral breast cancer (CBC). For the average woman the risk of CBC is less than 0.7% per year. CBC rate is increased in higher risk populations (eg BRCA mutation carriers). CPM reduces the risk of CBC but never eliminates it completely. Systemic treatments also reduce the risk of CBC. Rates of CPM are rising at more then 1% per year and have been known to almost double the risk of complications after surgery. CPM in an average risk woman does not improve cancer outcomes.  

As such, CPM is not recommended for women with unilateral breast cancer. CPM may be considered in selective cases when a patient is deemed to be of moderate risk of CBC (e.g.very young age, strong family history of breast cancer, non-BRCA mutations, other high risk features such as atypical ductal hyperplasia or lobular carcinoma in-situ), or  when issues arise surrounding asymmetry after unilateral mastectomy (with or without breast reconstruction).

High risk populations (BRCA mutation carriers, history of mantle field radiation) with unilateral breast cancer should be counselled on the risk of CBC and often CPM is recommended.  

A Canadian expert consensus statement on this issue is a work in progress. The link will be posted here once it is available. Other groups, including the American Society of Breast Surgeons18 and Choosing Wisely19, have similar consensus statements discouraging the routine use of CPM.   

Breast Reconstruction

All women undergoing mastectomy should be offered a reconstruction and referral to a plastic surgeon if they are clinically candidates. Reconstruction can be performed at the time of mastectomy (immediate reconstruction) or as a second procedure (delayed reconstruction). Options for reconstruction include autologous tissue vs implant reconstruction.20

Current review of breast reconstruction is found in the Surgical Oncology Network Newsletter Spring 2016.

References

  1. Fisher B, Anderson S, Bryant J et al Twenty year follow up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer.  N Engl J Med 2002;347:1233-41
  2. Veronesi U, Cascinelli N Mariani L et al.  Twenty year follow up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer.  N Engl J Med 2002; 1227-32. 
  3. Eusoma  http://www.eusoma.org/Engx/Guidelines/Other/OtherMT.aspx?cont=MT
  4. ACS breast centers:  https://www.facs.org/~/media/files/quality%20programs/napbc/2014%20napbc%20standards%20manual.ashx
  5. https://www.breastsurgeons.org/new_layout/about/statements/PDF_Statements/PerformancePracticeGuidelines_Breast-ConservingSurgery-PartialMastectomy.pdf
  6. Peters NH1, van Esser S, van den Bosch MA, Storm RK, Plaisier PW, van Dalen T, Diepstraten SC, Weits T, Westenend PJ, Stapper G, Fernandez-Gallardo MA, Borel Rinkes IH, van Hillegersberg R, Mali WP, Peeters PH. Preoperative MRI and surgical management in patients with nonpalpable breast cancer: the MONET - randomised controlled trial. Eur J Cancer. 2011 Apr;47(6):879-86. doi: 10.1016/j.ejca.2010.11.035. Epub 2010 Dec 30.
  7. Turnbull L1, Brown S, Harvey I, Olivier C, Drew P, Napp V, Hanby A, Brown J. Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomised controlled trial. Lancet. 2010 Feb 13;375(9714):563-71. doi: 10.1016/S0140-6736(09)62070-5.
  8. Meena S. Moran, Stuart J. Schnitt, Armando Giuliano et al. Society of Surgical Oncology–American Society for Radiation Oncology Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Stages I and II Invasive Breast Cancer.  March 2014, Volume 21, Issue 3, pp 704–716
  9. Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 2004;351: 971: l
  10. https://www.breastsurgeons.org/new_layout/about/statements/PDF_Statements/PerformancePracticeGuidelines_Mastectomy.pdf
  11. Headon HL, Kasem A, Mokbel K.The Oncological Safety of Nipple-Sparing Mastectomy: A Systematic Review of the Literature with a Pooled Analysis of 12,358 Procedures.  Arch Plast Surg. 2016 Jul;43(4):328-38. doi: 10.5999/aps.2016.43.4.328. Review.
  12. https://www.breastsurgeons.org/statements/QM/ASBrS_Management_of_Axilla.pdf
  13. https://www.breastsurgeons.org/new_layout/about/statements/PDF_Statements/PerformancePracticeGuidelines_SLN.pdf
  14. Krag DN, Anderson SJ, Julian TB et al.  Sentinel lymph node resection compared with conventional axillary lymph node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomized phase 3 trial.  Lancet Oncol 2010;11:927-33.
  15. Giuliano A, Ballman K, McCall L.  Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases.  Long term follow up from the ACOSOG Z0011
  16. https://www.breastsurgeons.org/new_layout/about/statements/PDF_Statements/PerformancePracticeGuidelines_ALND.pdf
  17. Lyman et al. Sentinel lymph node biopsy for patients with early-stage breast cancer:  American society of clinical oncology clinical practice guideline update.  JCO.  http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.54.117. Accessed April 21, 2016
  18. Judy C. Boughey, Deanna J. Attai, Steven L. Chen et al. Contralateral Prophylactic Mastectomy (CPM) Consensus Statement from the American Society of Breast Surgeons: Data on CPM Outcomes and Risk. Annals of surgical oncology.  October 2016, Volume 23, Issue 10, pp 3100–310
  19. https://www.breastsurgeons.org/docs/2016_asbrs_cw_recommendations.pdf. Accessed Sept 14, 2016
  20. Joon Y Choi, MD, Amy K Alderman, MD, Lisa Ann Newman, MD, MPH, FACS. Aesthetic and Reconstruction Considerations in Oncologic Breast Surgery. JACS 2006; 202:943-952.

6.3.1.2 Radiation Therapy (RT)

Updated May 2022

Introduction

The indications for different adjuvant radiotherapy options are discussed below.  It is important to note that not all patients will be eligible for all radiotherapy techniques and dose and fractionation regimens.  Radiotherapy treatment options will be presented and discussed with the patient by their radiation oncologist to determine the most effective, safe, and efficient treatment based on the individual patient and disease factors.

Radiation Therapy following Breast Conserving Surgery (pT1T2;N0)

Patients treated with breast conserving surgery (BCS; lumpectomy, partial or segmental mastectomy) for stage I or II breast cancer should have a consultation with a Radiation Oncologist regarding the role of radiation therapy (RT).

RT to the breast following BCS reduces the risk of breast recurrence and may lower the risk of systemic recurrence and breast cancer death.1,2,3,4,5 In a meta-analysis of 17 older breast cancer trials, at 10 years after diagnosis, a 20% absolute reduction in the risk of breast recurrence (from 30% to 10%) translated into a 4-5% reduction in the chance of dying from breast cancer.1 However, in newer breast cancer radiotherapy trials, in lower-risk patients, in-breast local recurrences were closer to 1-3% after radiotherapy with no difference in survival.6,7 RT should be considered following BCS but patients with multiple comorbidities, limited life expectancy, who desire to avoid RT, or who have a low risk of recurrence may be considered to omit RT (see below section). In addition to breast RT, regional nodal RT may be indicated in select node-negative patients, such as those with a number of high-risk features including large tumour, high grade, lymphovascular involvement, central/inner quadrant location, or those with triple-negative (i.e. ER/PR negative, her-2-neu negative) disease.5

Timing of Adjuvant Radiotherapy

  1. RT should optimally start once healing from the BCS is complete and generally within 16 weeks of BCS
  2. If post-operative problems occur, including hematoma, large seroma, infection, breast edema with erythema, or wound dehiscence occur, the start of RT may be delayed to allow resolution. In such cases or to accommodate patient convenience, there is no randomised trial evidence showing detriment to delay the start of RT until 20 weeks after BCS. Longer intervals may be associated with reduced RT efficacy and inferior local control.8
  3. If the patient receives adjuvant chemotherapy, then RT should follow the chemotherapy and start approximately 3-6 weeks after the last intravenous chemotherapy. Trastuzumab as a single agent may be delivered concurrently with radiation therapy. Adjuvant hormonal therapy may be commenced prior to or after RT.

Boost Radiotherapy

Randomized trials have shown improved local control with a boost of RT to the surgical bed following tangential RT for selected patients.  Boost RT can increase radiation induced breast fibrosis and decrease cosmetic outcome. 9,10,11

Indications for supplemental boost dose of RT:

  1. close or positive margins (less than or equal to 2 mm) post-breast conserving surgery, without possibility of further excision
  2. age 50 years or younger, even if the margins are greater than 2 mm

Patients who might be spared radiation therapy after breast conserving surgery

Radiation therapy consistently reduces the relative risk of local recurrence by 60-70%. Patients with a < 5% risk of local recurrence at 10 years are challenging to identify but might reasonably be considered for treatment with BCS alone. Women with the following factors likely have a 10 year risk of breast recurrence of 5% or less, if also prescribed adjuvant hormonal therapy: age >60 years, pN0, ER strongly positive, Grade 1 ductal carcinoma without lymphatic or vascular invasion and clear margins. Such women should be informed that RT will further decrease the risk of breast recurrence, but that the absolute benefit of RT on long-term survival is small.12,13,14,15

Partial breast radiotherapy following breast conserving surgery

Multiple randomized trials have tested the efficacy, safety and convenience of partial-breast irradiation (PBI) as an alternative to conventional whole-breast irradiation (WBI) for early-stage, favorable breast cancer. The rationale for this approach is that most recurrences occur at, or near, the primary tumour bed. PBI refers to the use of focused radiation to only the part of the breast where the tumour was removed. Accelerated partial breast irradiation (APBI) describes PBI treatment over a short period of time.  There are three common modalities for PBI: 1) external beam radiotherapy (short tangents, 3D conformal radiotherapy and IMRT), 2) brachytherapy, and 3) intraoperative radiotherapy

Trials have shown similar outcomes with a low rate of ipsilateral breast tumour recurrence (IBTR) for women who received WBI or PBI (accelerated and conventionally fractionated).6,7,16,17,18 Long-term data from two large randomized studies, the RAPID trial and the NSABP B-39/RTOG 0413, comparing WBI with APBI were recently published. In the RAPID trial, which used external-beam radiotherapy in both arms(6) there was no difference in the rate of IBTR between APBI and WBI (3.0% versus 2.8% respectively). Compared to the WBI arm, in which only 21% were treated with boost radiotherapy, the twice daily regimen was associated with an increase in moderate late toxicity and adverse cosmesis. In the NSABP B-39 trial Ref), the 10-year IBTR was 3.9% for WBI and 4.6%for APBI. The trial did not meet its goal of establishing equivalence, but the small absolute difference in recurrence-free interval (0.7%) is not likely to be clinically significant. In addition, the 10-year IBTR outcomes were nearly identical for patients treated with external beam radiotherapy: 3.8% for WBI and 3.7% for APBI. Compared to the WBI arm, in which 80% were treated with the addition of boost radiotherapy, the twice daily regimen was not associated with an increase in moderate late toxicity and adverse cosmesis. Other previously reported randomized trials evaluating different PBI methods have demonstrated equivalent early and late toxicity to that of whole-breast irradiation.

The American Society of Therapeutic Radiation and Oncology (ASTRO)19, the American Brachytherapy Society (ABS) 20, and the Groupe Européen de Curiethérapie- European Society for Therapeutic Radiation and Oncology (GEC-ESTRO)21 have all published evidence-based guidelines on the appropriate selection of patients for APBI following breast-conserving surgery and surgical lymph node evaluation. The BC Cancer Breast Tumour Group has reviewed the published guidelines and concluded that PBI is a standard of care treatment in appropriately selected patients who meet the following criteria:

    • Age ≥ 40 years
    • Invasive ductal carcinoma or DCIS < 3 cm
    • Pathologically node negative
    • Margin negative for invasive carcinoma
    • Margin ≥ 2 mm for pure DCIS 
    • Clinically unifocal (by physical examination and breast imaging)
    • Clearly visible operative bed 

Patients with minimal lymphovascular invasion may be suitable for PBI if their other breast cancer risk factors are favorable. Microscopic multifocality may be suitable for PBI, provided the total lesion size (including foci of multifocality and intervening normal breast parenchyma) is < 3 cm. Patients with (1) anterior (at skin) and/or posterior (at pectoralis fascia) positive margins that cannot be rendered negative with further surgery (2) mixed invasive and DCIS component with clear invasive margins but close DCIS margins (≤ 2 mm) and (3) pure DCIS and a single close non-anterior, non-posterior margin can have PBI with a boost. Patients over 70 with low-risk disease who are clinically node negative and did not have SLNB or ALND may have PBI as per the discretion of the treating oncologist.

Patients with lobular breast cancer and patients treated with neoadjuvant chemotherapy are not suitable for PBI.

PBI can be delivered using external beam radiation treatment (short tangents, 3D conformal radiotherapy or IMRT) or permanent seed brachytherapy.22,23 Due to concerns of adverse late cosmetic outcomes, the use of 38.5 Gy / 10 APBI twice daily fractionation over 5 days (ie accelerated partial breast RT) is not recommended.6,18 Based on the results of the FAST-Forward trial, comparing whole breast irradiation with 40 Gy / 15 versus 27 Gy / 5 and 26 Gy / 5, it is recommended to use 26 Gy / 5 PBI for patients whose dosimetry meets the planning constraints of the FAST-Forward trial and 40 Gy / 15 for patients whose breast separation is too large to meet the planning constraints of the FAST-Forward trial.24 If a boost is indicated when using 26Gy/ 5 PBI, the recommend boost dose is 10 Gy / 5 or 16 Gy / 8, as was used in the FAST-Forward trial.24

Short-course adjuvant radiotherapy

Five-fraction breast radiotherapy can be offered to patients undergoing tangent, breast-only, adjuvant treatment.  It is a 5-fraction regimen delivered over 5 consecutive working days as used in the FAST-Forward Phase III trial.24  Five-year follow-up data demonstrated that local control with 26 Gy in 5 daily fractions was not inferior for local control with 40 Gy in 15 daily fractions.  Cosmetic outcomes were also equivalent at 5 years.  Greater than 5-year follow-up data has not yet been published.  Although a wide range of patients were included in the trial, some patient, disease, and treatment characteristics were uncommon and therefore the overall conclusions may be less applicable to these sub-groups.  Patients should only be treated with one-week breast radiotherapy if their plans meet the dosimetric constraints used in the trial.  Patients with DCIS and with very low risk invasive breast cancer were not included in the FAST-Forward trial because they had a very low likelihood of outcome events occurring.  The results of the FAST-Forward could be extrapolated to include these groups of patients.  It is recommended that patients undergoing nodal radiotherapy and patients with breast reconstruction should not be treated with short-course at this time unless participating in a clinical trial.

Radiation therapy following mastectomy (pT1,T2;N0)

The majority of patients with pT1-T2 pN0 disease will not derive a benefit from adjuvant RT.25  Some patients may have a higher risk of locoregional recurrence and may benefit from adjuvant radiotherapy for local control but an overall survival benefit has not been demonstrated.  This group would include: patients with close or positive margins with pT2 tumour plus other high risk features, such as grade 3 histology, high volume lymphatic or vascular invasion, age<50 years, and central or inner quadrant tumours26 and patients with clear margins post-mastectomy with central/inner quadrant tumours, or those with T2 tumour size with other high risk features, e.g. high grade, lymphovascular involvement, or triple-negative (i.e. ER/PR negative, her-2-neu negative) disease.27 Patients with these high-risk features should be referred after mastectomy for discussion of adjuvant RT with a radiation oncologist.

Radiation therapy following mastectomy or breast conserving surgery (pT1,T2;N1, and T3;N0)

Locoregional RT improves outcomes following mastectomy or breast conserving surgery for patients with node-positive breast cancer or node-negative T3 breast cancer. 25,27,28,29,30,31  A reduction in loco-regional recurrence and reduced breast cancer mortality is seen even for patients with only a moderate risk (e.g. 1-3 nodes positive) of loco-regional recurrence.25,28,29,32  The breast cancer specific-outcomes improvement   may not translate to an overall survival benefit.5,32  Patients with lymph node positive disease and increased risk of internal mammary chain involvement may derive proportionally more benefit from adjuvant loco-regional radiotherapy. 33  Patients with pT1-T2 pN1 and T3N0 should be referred for discussion of adjuvant RT with a radiation oncologist.

Radiation therapy following mastectomy or breast conserving surgery (pT1-T3;N2-3, and T4;N0-3)

Locoregional RT is recommended for patients with locally advanced breast cancer following mastectomy or breast conserving surgery.  Adjuvant RT has been shown to decrease locoregional recurrence and reduce breast cancer mortality even in patients treated with adjuvant chemotherapy.25,28,29,30

Timing of adjuvant radiotherapy following mastectomy or in lymph node positive patients: Timing is as described above in the post-BCS for node-negative patients.

**Details of radiotherapy planning and prescription in the post-breast conserving surgery and post-mastectomy setting are described separately (Section 6.10).


References
    1. EBCTCG (Early Breast Cancer Trialists' Collaborative Group), McGale P, Taylor C, Correa C, Cutter D, Duane F, Ewertz M, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011 Nov 12;378(9804):1707-16. doi: 10.1016/S0140-6736(11)61629-2. Epub 2011 Oct 19. Review. PMID: 22019144
    2. Fisher B, Bryant J, Dignam JJ, Wickerham DL, Mamounas EP, Fisher ER, et al. Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol. 2002 Oct 15;20(20):4141-9.
    3. Vinh-Hung V, Verschraegen C. Breast-conserving surgery with or without radiotherapy: Pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst. 2004 Jan 21;96(2):115-21.
    4. Veronesi U, Salvadori B, Luini A, Greco M, Saccozzi R, del Vecchio M, et al. Breast conservation is a safe method in patients with small cancer of the breast. long-term results of three randomised trials on 1,973 patients. Eur J Cancer. 1995 Sep;31A(10):1574-9.
    5. Whelan TJ, Olivotto IA, Parulekar WR, Ackerman I, Chua BH, Nabid A, et al.  Regional Nodal Irradiation in Early-Stage Breast Cancer. N Engl J Med. 2015 Jul 23;373(4):307-16. doi: 10.1056/NEJMoa1415340.
    6. Whelan TJ, Julian JA, Berrang TS, Kim D-H, Germain I, Nichol AM, Akra M, et al. External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial.  Lancet 2019 394: 2165-72.
    7. Coles CE, Griffin CL, Kirby AM, Titley J, Agrawal RK, Alhasso A, et al. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT Low trial): 5-year results from a multicenter, randomised controlled phase 3, non-inferiority trial.  Lancet 2017; 390: 1048-60
    8. Olivotto IA, Lesperance ML, Truong PT, Nichol A, Berrang T, Tyldesley S, et al. Intervals longer than 20 weeks from breast-conserving surgery to radiation therapy are associated with inferior outcome for women with early-stage breast cancer who are not receiving chemotherapy. J Clin Oncol. 2009 Jan 1;27(1):16-23.
    9. Bartelink H, Horiot JC, Poortmans PM, Struikmans H, Van den Bogaert W, Fourquet A, et al. Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol. 2007 Aug 1;25(22):3259-65.
    10. Bartelink H1, Maingon P2, Poortmans P3, Weltens C4, Fourquet A5, Jager J, et al. Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. Lancet Oncol. 2015 Jan;16(1):47-56. doi: 10.1016/S1470-2045(14)71156-8. Epub 2014 Dec 9.
    11. Romestaing P, Lehingue Y, Carrie C, Coquard R, Montbarbon X, Ardiet JM, et al. Role of a 10-gy boost in the conservative treatment of early breast cancer: Results of a randomized clinical trial in Lyon, France. J Clin Oncol. 1997 Mar;15(3):963-8.
    12. Fyles AW, McCready DR, Manchul LA, Trudeau ME, Merante P, Pintilie M, et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med. 2004 Sep 2;351(10):963-70.
    13. Hughes KS, Schnaper LA, Berry D, Cirrincione C, McCormick B, Shank B, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med. 2004 Sep 2;351(10):971-7.
    14. Kunkler IH, Williams LJ, Jack WJ, Cameron DA, Dixon JM; PRIME II investigators. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol. 2015 Mar;16(3):266-73. doi: 10.1016/S1470-2045(14)71221-5. Epub 2015 Jan 28
    15. Blamey RW, Bates T, Chetty U, Duffy SW, Ellis IO, George D, et al. Radiotherapy or tamoxifen after conserving surgery for breast cancers of excellent prognosis: British Association of Surgical Oncology (BASO) II trial. Euro J Cancer. 2013;49:2294-2302.
    16. Polgar C, Ott OJ, Hildebrandt G, Kauer-Dorner D, Knauerhase H, Major T, et al. Late side-effects and cosmetic results of accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: 5-year results of a randomised, controlled, phase 3 trial. Lancet Oncol 2017 Feb;18(2):259-268.
    17. Vicini FA, Cecchini RS, White JR, Arthur DW, Julian TB, Rabinovitch RA, et al. Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer: a randomised, phase 3, equivalence trial (NSABP B-39/RTOG 0413). Lancet 2019 Dec 14 394(10215):2155-2164
    18. Olivotto IA, Whelan TJ, Parpia S, Kim DH, Berrang T, Truong PT, et al. Interim cosmetic and toxicity results from RAPID: a randomized trial of accelerated partial breast irradiation using three-dimensional conformal external beam radiation therapy. J Clin Oncol 2013 Nov 10;31(32):4038-4045.
    19. Correa C, Harris EE, Leonardi MC, Smith BD, Taghian AG, Thompson AM, et al. Accelerated Partial Breast Irradiation: Executive summary for the update of an ASTRO Evidence-Based Consensus Statement. Pract Radiat Oncol 2017 Mar - Apr;7(2):73-79.
    20. Shah C, Vicini F, Shaitelman SF, Hepel J, Keisch M, Arthur D, et al. The American Brachytherapy Society consensus statement for accelerated partial-breast irradiation. Brachytherapy 2018 Jan - Feb;17(1):154-170.
    21. Polgar C, Van Limbergen E, Potter R, Kovacs G, Polo A, Lyczek J, et al. Patient selection for accelerated partial-breast irradiation (APBI) after breast-conserving surgery: recommendations of the Groupe Europeen de Curietherapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) breast cancer working group based on clinical evidence (2009). Radiother Oncol 2010 Mar;94(3):264-273.
    22. Pignol JP, Caudrelier, Crook JM, McCann C, Truong P, Verkooijen H. Report on the Clinical Outcomes of Permanent Breast Seed Implant for Early-Stage Breast Cancers. IJROBP Vol 9(3) 2015: pp 614-621
    23. Crook J, Hilts M, Batchelar D, Milette MP, Korzeniowski M, Pilote L, Pignol JP. Permanent Breast Seed Implant for Partial Breast Radiotherapy following Partial mastectomy for Favorable Breast Cancer: Technique, Results and Applications to various Seroma Presentations. Brachytherapy. 2019 Jul - Aug;18(4):510-520. doi: 10.1016/j.brachy.2019.04.003
    24. Brunt AM, Haviland J, Wheatley D, Sydenham M, Alhasso A, Bloomfield D, et al.  Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial. Lancet 2020;395(10237):1613-1626
    25. EBCTCG (Early Breast Cancer Trialists' Collaborative Group), McGale P, Taylor C, Correa C, Cutter D, Duane F, Ewertz M, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-yearbreast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials.  Lancet. 2014 Jun 21;383(9935):2127-35. doi: 10.1016/S0140-6736(14)60488-8. Epub 2014 Mar Erratum in: Lancet. 2014 Nov 22;384(9957):1848.
    26. Truong PT, Olivotto IA, Speers CH, Wai ES, Berthelet E, Kader HA. A positive margin is not always an indication for radiotherapy after mastectomy in early breast cancer. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):797-804.
    27. Poortmans PM., Collette S, Kirkove C., Van Limbergen, E, Budach V, Struikmans H, et al. Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer.  N Engl J Med 2015; 373:317-327July 23, 2015DOI: 10.1056/NEJMoa141536
    28. Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy.Danish Breast Cancer Cooperative Group 82b trial. N Engl J Med. 1997 Oct 2;337(14):949-55.
    29. Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet. 1999 May 15;353(9165):1641-8.
    30. Ragaz J, Olivotto IA, Spinelli JJ, Phillips N, Jackson SM, Wilson KS, et al. Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. J Natl Cancer Inst. 2005 Jan 19;97(2):116-26.
    31. Whelan TJ, Julian J, Wright J, Jadad AR, Levine ML. Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol. 2000 Mar;18(6):1220-9.
    32. Poortmans PM, Weltens C, Fortpied C, Kirkove C, Peignaux-Casasnovas K, Budach V, et al. Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial. Lancet Oncol 2020: 21: 1602-10.
    33. Thorsen LBJ, Offersen BV, Dano H, Berg M, Jensen I, Pedersen AN, et al. DBCG-IMN: A population-based cohort study on the effects of internal mammary node irradiation in early node-positive breast cancer.  J Clin Oncol. 2016 Feb 1;34(4):314-320.


6.3.2 Systemic Management 

6.3.2.1 Introduction

Revised 18 January 2013

Adjuvant systemic therapy has been demonstrated to reduce the risk of cancer recurrence and improve survival. Adjuvant systemic therapy with either chemotherapy or hormonal therapy should be offered to women according to the treatment policies as defined in Adjuvant Systemic Therapy. These policies are reviewed continuously by the provincial breast systemic policy group and updated accordingly. BC Cancer maintains current Chemotherapy Protocols.

Systemic Management, Early Breast Cancer

The systemic management of invasive non-metastatic breast cancer is complex. The management of locally advanced and of metastatic breast cancer is discussed separately. The prognosis for a patient following treatment of early breast cancer varies according to their age, co-morbidities, and the stage and the biomarker profile of their cancer. The majority of patients with early breast cancer will be cured with appropriate multi-disciplinary therapy.

Invasive breast cancer can be divided into three broad groups that influence systemic treatment decisions:

  • hormone receptor positive/her2 negative cancers;
  • her2 positive cancers;
  • and triple marker negative (ER-PR-her2-, "triple-negative") cancers.
Within each of these groups, treatment recommendations are also influenced by patient age, co-morbidity, and personal preferences, as well as the stage and other histopathologic features of the cancer.

Clinical Trials

The majority of advances in the management and improvements in the cure rates of early breast cancer have come from successful completion of scientifically rigorous clinical trials. Patients should be given the opportunity to participate in clinical trials if available for their stage and type of breast cancer.

6.3.2.2 Hormone Receptor Positive Breast Cancer

Revised 18 January 2013

1. Definition

Hormone receptor positive breast cancers express estrogen receptors (ER) and or progesterone receptors (PR, PgR) on their nuclei, as evinced by immunohistochemical (IHC) assay. There are two main immunohistochemical scoring systems used by the province to describe the degree of ER and PR expression. The Allred score is made up of a measure of the intensity of the IHC stain and the percentage of cells which take up the stain for the receptor.1 The maximum score (strongest expression) is 8. A simpler scoring method is often used in which the hormone receptor staining strength is expressed from 0 (no staining) to 3 (strong, ubiquitous staining). Cancers with an IHC score of 0 or an Allred score of 2 or 0 do not benefit from hormone receptor targeted therapy. Cancers with an Allred score of 3 have weak staining in a small percentage of cells, and the benefit of therapy targeted at the receptor is debatable in this setting. An IHC score of 1+ is similar to an Allred score of 3 or 4. An IHC score of 2+ can be considered comparable to an Allred score of 5 or 6, and an IHC score of 3+ would be roughly equivalent to an Allred score of 7 or 8.

2. Hormone therapy 

Hormone therapy for five years should be considered for all women with hormone receptor positive breast cancer (estrogen receptor [ER] and/or progesterone receptor [PR] Allred score 4-8/8; or 1+ , 2+ or 3+) based on robust large clinical trial data sets establishing a significant survival benefit.2 The absolute benefit depends on both the absolute recurrence risk and the relative strength of hormone receptor expression. The decision to treat cancers with an Allred score of 3 with hormone therapy should be individualized.

2A. Premenopausal women

For premenopausal women, the hormone therapy of choice is tamoxifen (BRAJTAM). An alternative for women with contraindications to tamoxifen is surgical oophorectomy (permanent) or medical menopause (LHRHa; reversible), with or without an aromatase inhibitor (BRAJLHRHT).3 For select low stage, non grade 3 disease, hormone therapy with both tamoxifen and an LHRHa may be an acceptable and/or superior alternative to chemotherapy.4

Duration of therapy:

The current standard of care for most premenopausal women is 5 years of hormone therapy. Women who remain premenopausal after 5 years of tamoxifen may derive a small additional survival benefit from continuing tamoxifen to a total of 10 years.5 Women becoming menopausal near the end of five years of tamoxifen should be considered for extended adjuvant therapy with an aromatase inhibitor for a further 3-5 years, based on evidence of disease free survival and, for node positive disease, modest overall survival benefits.6 When menopausal status is uncertain, extended adjuvant therapy should be with tamoxifen, given that aromatase inhibitors are not beneficial in premenopausal women.

2B.  Postmenopausal women

For postmenopausal women, there are several hormone therapy options. They include 5 years of an aromatase inhibitor; 5 years of tamoxifen; and the sequential use over a total of 5 years of tamoxifen and aromatase inhibitor for about 2 and half years each (BRAJTAM, BRAJANAS, BRAJEXE, BRAJLET). Compared with 5 years of tamoxifen, the use of an aromatase inhibitor (for either five years, or for 2.5 years preceded or followed by tamoxifen) is associated with 3% fewer disease free survival events (defined as any of contralateral breast cancer, relapse of prior breast cancer, and death from any cause).7 Despite this, overall survival gains from the introduction of aromatase inhibitors in adjuvant therapy remain elusive.

Duration of therapy:

Menopausal women completing five years of tamoxifen should consider an additional 3-5 years of an aromatase inhibitor or of tamoxifen (if unable to tolerate aromatase inhibitors), depending on the recurrence risk of the original cancer. This is associated with a modest disease free survival improvement over stopping therapy at five years, and for women with node positive breast cancer, a small survival gain.5,6

Ongoing studies are examining whether longer than 5 years is beneficial if the first five years of therapy included an aromatase inhibitor.

The choice of treatment strategy must take into consideration patient co-morbidities and drug side effects, as well as the absolute recurrence risk associated with their cancer. As a guideline, the BC Cancer Breast Tumour group recommends the following:

Table 1. BC Cancer Breast Tumour Group guidelines for hormone therapy in menopausal non- metastatic hormone receptor positive breast cancer

Disease characteristics Hormone therapy
T1N0 grade 1
Tamoxifen for 5 years, unless not tolerated or contraindicated
Any of

Grade 3

4+ nodes involved

ER1+ (allred score 3, 4)
Aromatase inhibitor for 5 years, unless not tolerated or contraindicated.
All other stages, grades
Tamoxifen for 2-3 years then aromatase inhibitor to complete 5 years

OR

Aromatase inhibitor for 2-3 years, then tamoxifen to complete 5 years

Table 2. Contraindications to starting or continuing Tamoxifen

Issue Type of contraindication Notes
Personal DVT, PEAbsoluteUnless patient anticoagulated for duration of tamoxifen use
Close family history of DVT, PERelativeCoagulation studies may rule out a familial hypercoagulable state making tamoxifen safer
Newly diagnosed Endometrial cancerAbsolute
Patients should discontinue tamoxifen permanently if they develop endometrial cancer while on tamoxifen.  Patients with remote history of low stage curatively treated endometrial cancer may safely take tamoxifen
Severe depressionRelativeTamoxifen may exacerbate depression
Patients taking buproprion (Wellbutrin), fluoxetine (Prozac), or paroxetine (Paxil)Relative
These drugs are metabolized by the same enzyme which metabolizes tamoxifen to its active metabolite endoxifen. Whether this is clinically important is controversial. Each case must be considered individually balancing the potential benefits and risks of switching to a different antidepressant. Patients who can safely and easily switch to a different anti-depressant are encouraged to do so.


DVT=deep venous thrombosis; PE=pulmonary embolism

Table 3. Contraindications to Aromatase Inhibitors

Issue Type of contraindication Notes
PremenopausalAbsoluteUnless a patient is continuously menopausal, aromatase inhibitors are ineffective. Patients under the age of 50 who have a chemotherapy induced menopause may recover ovarian function thus for women pre or perimenopausal at diagnosis, tamoxifen is recommended as initial therapy.
Severe osteopenia or osteoporosisRelativeAromatase inhibitors increase the rate of normal bone mineral losses in menopausal women. Women with normal bone density carry a 20-50% risk of developing osteopenia and a 1% risk of osteoporosis with 2-5 years of AIs; women with osteopenia have a 10% risk of developing radiologic osteoporosis with 2-5 years of AIs. (Bone Health).
Moderate to Severe joint painRelativeAIs cause joint and muscle pain in about 1/3 of patients and may increase pre-existing pain. AIs do not cause erosive joint changes.
Moderate to severe dyslipidemiaRelativeAIs can cause elevation of triglycerides and cholesterol. These values should be monitored and a switch in hormone therapy or addition of lipid lowering agent should be considered for marked elevations.

For a complete list of side effects refer to the product monographs and BC Cancer specific patient and professional education information.

2C. Secondary Prevention

An added benefit of adjuvant hormone therapy for women who have not undergone bilateral mastectomy (ie women who have an intact contralateral breast) is the reduction in risk of contralateral breast cancer (40-50% relative risk reduction for tamoxifen; 65% relative risk reduction for aromatase inhibitor with / without prior tamoxifen).8,9

3. Chemotherapy

3A. Criteria for Consideration of Chemotherapy

Chemotherapy may be indicated for some hormone receptor positive breast cancers in addition to hormone therapy and local management. The decision to recommend chemotherapy is based on a number of patient and tumour factors weighed together. In general, if the cancer exhibits any or several of the characteristics listed below, the benefits of chemotherapy should be considered:

  • Tumour >2cm
  • Lymphatic and/or vascular invasion present
  • Grade 3
  • Weak ER and PR expression (Allred score 3-5; ER 1+ by IHC)
  • Node positive
None of these features alone or in combination mandates the use of chemotherapy. The decision making process is complex and involves balancing the potential benefits of adjuvant chemotherapy with the potential harms (side effects) and must be considered on a case by case basis. Other important factors in this decision making process include patient factors such as age, life-expectancy, and co-morbidities. Patient preference and willingness to accept chemotherapy side effects must also be considered. Cancers without any of the above features arising in very young women (35 and younger) may still warrant chemotherapy, as young age is an independent adverse prognostic factor.10 Clinicians must make individual recommendations based on clinical judgment and specialized knowledge of breast cancer management. Recurrence risk assessment tools such as Adjuvant! Online can facilitate discussion with patients and illustrate the probable benefits of hormone therapy and chemotherapy in individual cases.

There are several tissue based prognostic tools which may be of value in guiding management recommendations for some women with node-negative, ER-positive and HER-2 negative breast cancer. One such test is the Oncotype Dx Recurrence Score Assay® which is performed on a tissue sample of the resected breast cancer by Genomic Health (GH), an American company which developed the assay. A Recurrence Score (RS) is generated based on the level of mRNA expression for several genes within the tumour sample. This score provides an estimated risk of breast cancer recurrence over 10 years in the context of appropriate locoregional management and 5 years of hormonal therapy. Furthermore, retrospective analyses suggest that only cancers with a high RS (31 or higher) derive additional protective benefit from chemotherapy.11,12 These preliminary findings are being prospectively tested in node negative breast cancer in the fully accrued TAILORx trial.

The BC Cancer Breast Tumour Group has outlined minimum eligibility criteria for provincially funded Oncotype Dx Assay®. These may not be the same as criteria established by other jurisdictions. At present a provincially funded Oncotype Dx Assay can only be obtained through consultation with a Medical Oncologist and with compassionate access program (CAP) approval. Patients may choose to pay for the test through their own means; their medical oncologist can facilitate the process.

Table 4. Minimum eligibility criteria for BC funded Oncotype Dx Assay®

Eligible for funded Oncotype Dx Assay Ineligible for funded Oncotype Dx Assay
§ 80 years of age or younger, and

Fit for chemotherapy, and fit for chemotherapy, with hormone receptor positive (ER+ and/or PR+) and HER-2 negative

1.  Node-negative or N0i+ breast cancer which is hormone receptor positive (ER+ and/or PR+) and HER-2 negative

PLUS

§ Any grade 3 cancers

OR

§ Grade 2 cancers and T1b or larger

OR

§ Any Grade 1-2 cancers (any size) in women 40 years of age and younger

2.  Node-positive (pN1mi only) (0.3-2mm micrometastases in ONE lymph node)
§ Node positive breast cancer

§ HER-2 positive breast cancer

§ Grade 1 cancers in women older than 40 years of age at diagnosis

§ Grade 2 cancers smaller than T1b in women older than 40 years of age

§ Patients unwilling to consider or unfit to receive chemotherapy

§ Patients who have only had core biopsy and not definitive surgery


The Breast Tumour Group feels that there is insufficient data at this time to warrant the routine use of the Oncotype Dx Assay® for clinical decision making in node positive breast cancer. An ongoing clinical trial (RESPONDRx) may establish its role in determining the benefit of chemotherapy in low volume1,2,3 node positive breast cancer.

3B. Chemotherapy Regimens

There are numerous active adjuvant chemotherapy regimens. The choice of regimen (drugs, doses, and number of cycles) should be evidence based whenever possible. The standard regimens available to Oncologists practicing in British Columbia can be found on the chemotherapy protocol, breast webpage. Within British Columbia, deviations from these protocols require CAP approval.

Premenopausal women

In general terms, 4-6 months of chemotherapy containing both an anthracycline and taxane is preferred for premenopausal women with node positive breast cancer (BRAJACTG, UBRAJACTW, BRAJFECD, UBRAJDAC, BRLAACD).13,14 Among women with node negative, but large and/or grade 3 cancers, acceptable chemotherapy options include shorter regimens such as DC (BRAJDC), and longer regimens with and without taxanes (BRAJFEC, BRAJFEC-D, BRAJACTG, UBRAJACTW, BRAJAC).

Postmenopausal women

Postmenopausal who are relatively young and fit may be considered for the same chemotherapy regimens as for premenopausal women with similar cancer stage and grade. For older (>60 years old) and less fit menopausal women, the choice of chemotherapy regimen must consider the fact that this population may derive considerably less benefit and more toxicity than younger, fitter women receiving the same regimen.13 Shorter, less toxic regimens, or no chemotherapy, may be the most suitable recommendation in these cases. 

Patients with cardiac co-morbidity

There are a number of adjuvant chemotherapy regimens that do not incorporate anthracyclines. These are particularly good choices for patients at risk for cardiac injury. Patients with significant cardiac co-morbidities should undergo left ventricular ejection fraction assessment prior to initiating chemotherapy. Patients with an LVEF that is below the institutional lower limit of normal should not receive anthracycline based chemotherapy. Anthracyclines may also be best avoided in patients with multiple cardiac risk factors even if they have a normal LVEF. Cumulative lifetime anthracycline exposure for an otherwise healthy individual should not exceed 480mg/m2 (the equivalent cardiotoxic dose of epirubicin is 860mg/m2). Patients who have received anthracyclines for a prior malignancy are more safely treated with non-anthracycline regimens (BRAJDC, BRAJCMF).

References

  1. Elledge RM, Green S, Pugh R, et al. Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immunohistochemistry in predicting response to tamoxifen in metastatic breast cancer: A Southwest Oncology Group study. Int J Cancer 2000; 89:111-117
  2. Early Breast Cancer Trialists' Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365:1687-1717
  3. Gnant, M, Blineritsch B, Schippinger W et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Eng J Med 2009; 360:679-691
  4. Thurlimann B, Price KN, Gelber RD, et al. Is chemotherapy necessary for premenopausal women with lower-risk node-positive, endocrine responsive breast cancer? 10-year update of International Breast Cancer Study Group Trial 11-93. Breast Cancer Res Treat 2009; 113:137-144
  5. Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Online publication Dec 5, 2012, Lancet
  6. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Eng J Med 2003; 349:1793-1802
  7. Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010; 28:509-518
  8. De Schryver A, Huys J, Vakaet L. Systemic treatment of early breast-cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31000 recurrences and 24000 deaths among 75000 women. Lancet 1992; 339:1-15.
  9. the ATAC Trialists' Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359:2131-2139
  10. Aebi S, Gelber S, Castliglione-Gertsch M, et al. Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer? Lancet 2000; 355:1869-74
  11. Paik S, Shak S, Tang G, et al. A multi-gene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Eng J Med 2004; 351:2817-2826
  12. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 2006; 24: 3726-3734.
  13. De Laurentiis M, Cancello G, D'Agostino D, et al. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol 2008; 26:44-53
  14. Hayes DF, Thor AD, Dressler LG, et al. HER2 and response to paclitaxel in node-positive breast cancer. N Eng J Med 2007; 357:1496-1506

6.3.2.3 HER2 Positive

Revised 18 January 2013

1. Definition of HER2 Positive

All breast cancer cells have some HER2 receptors. So called Her2 positive (her2+) cancers express a 20+ fold higher level of surface receptors than her2 negative cancers. This confers a more aggressive natural history to these cancers, which also more frequently have grade 3 than other grade histology.15 Her2 is most commonly tested using either IHC or fluorescence in situ hybridization (FISH). In BC, all breast cancers should be tested for Her2, usually on the core biopsy, although any specimen, including archival tissue, can be used. Cancers with an IHC score of 0 or 1+ are considered negative; those with a 2+ score are equivocal and a FISH test is done to determine if there is gene amplification. In randomized clinical trials exploring the benefit of adding trastuzumab (Herceptin) to chemotherapy for breast cancer, cancers that had a FISH ratio of 2.0 or higher, or an IHC of 3+ were considered to be Her2 positive and eligible to participate.16,17 A FISH ratio between 1.8 and 2.2 may technically be considered equivocal18 but for treatment related decisions a FISH ratio of 2.0 or higher is considered positive and eligible for trastuzumab (Herceptin). Her2 positive cancers can be hormone receptor (ER or PR) negative or positive.

2. Systemic Treatment of HER2+ Cancer

The standard of care adjuvant treatment of her2+ early breast cancer of stage T1cN0 or higher in British Columbia is combination chemotherapy with trastuzumab (BRAJACTT, BRAJFECDT, BRAJDCARBT, BRLAACDT). The preferred regimen contains both an anthracycline and taxane.14 The trastuzumab can be given concurrently with the non-anthracycline portion of the chemotherapy (preferred) or following completion of chemotherapy, and should be continued for one year (17 treatments, given 3 weeks apart).

Chemotherapy and trastuzumab may also be given to patients with a T1bN0 her2+ cancer, particularly if the cancer is hormone receptor negative, recognizing that the risk of recurrence exceeds 25% and is dramatically reduced with therapy.19 T1aN0 cancers derive less absolute benefit than higher stage cancers from chemotherapy and trastuzumab because they have a lower recurrence risk. Clinicians wishing to offer chemotherapy and trastuzumab to a patient for a T1aN0 cancer must receive CAP approval first.

The most commonly used regimen is AC followed by paclitaxel (BRAJACTT), however for node negative, T1b and T1c ER2 positive breast cancers, a shorter regimen may be sufficient, such as DC combined with trastuzumab (BRAJDCT) or AC followed by trastuzumab (BRAJAC and BRAJTR). To avoid anthracyclines, clinicians may prefer a regimen that includes docetaxel and carboplatin (BRAJDCARBT). Other regimens include an anthracycline and docetaxel (BRAJFECDT; BRLAACDT). Despite a more aggressive natural history, her2+ breast cancers treated with appropriate local therapy and chemotherapy/trastuzumab have a very favourable prognosis with low rates of relapse.20

Trastuzumab does not to be interrupted for delivery of adjuvant radiation.21

3. Contraindications to Trastuzumab

The primary contraindication to trastuzumab is a left ventricular ejection fraction (LVEF) below the institutional lower limit of normal, indicating left ventricular dysfunction or borderline function. Because of synergistic toxicity with concomitant administration, trastuzumab should not be given concurrently with anthracyclines.22 About 40% of patients experience an infusion reaction with the first dose of trastuzumab, characterized by chills, shakes, fever, and shortness of breath. This is usually transient, self-limited, and responsive to acetaminophen and supportive care measures. With rare exceptions, infusion reactions do not occur after the first infusion, so pre-medication is not required. Care should be taken to determine whether an observed reaction is due to trastuzumab or an accompanying drug, such as a taxane, as reactions to the latter drug can recur with subsequent infusions.

4. Cardiac Monitoring

LVEF assessment with ECHO or MUGA should be considered prior to chemotherapy start for women with cardiac risk factors, as there are several chemotherapy options that do omit anthracylines. LVEF assessment is required prior to starting trastuzumab, and every three months during trastuzumab therapy. Patients with subnormal LVEF should not be treated with trastuzumab. Each trastuzumab containing BC Cancer protocol (BC Cancer Chemotherapy Protocols) contains an algorithm to guide continuing or interrupting trastuzumab in the event of changes in LVEF. Cardiology referral is advised for patients developing signs and symptoms of cardiac dysfunction, and caution should exercised in resuming trastuzumab in these cases, even if LVEF recovers and symptoms resolve. If trastuzumab is restarted after an interruption due to cardiac toxicity, more frequent LVEF monitoring is recommended, as outlined in the BC Cancer trastuzumab containing protocols.

5. Hormone Therapy

HER2 positive cancers that are also hormone receptor positive should also receive hormone therapy as described above for hormone receptor positive cancers.

References

  1. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of HER-2/neu oncogene. Science 1987; 235: 177-182
  2. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab After Adjuvant Chemotherapy in HER2-Positive Breast Cancer. N Eng J Med 2005; 353: 1659-1672
  3. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Eng J Med 2005; 353: 1673-1684
  4. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/college of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007; 25:118-145
  5. Chia S, Norris B, Speers C, et al. Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of node-negative breast cancers. J Clin Oncol 2008; 26:5697-5704
  6. Viani GA, Afonso SL, Stefano EJ, De Fendi LI, and Soares FV. Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer 2007; 7:153
  7. Halyard MY, Pisansky TM, Dueck AC, et al. Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG phase III trial N9831. J Clin Oncol 2009; 27:2638-2644
  8. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Eng J Med 2001; 344: 783-792

6.3.2.4. Triple Negative Breast Cancers

Revised 18 January 2013

Triple negative breast cancers (TNBC) are cancers, which are negative for ER, PR, and HER2 expression. Cancers that have Allred scores of 3/8 for ER and PR are generally considered to benefit minimally from hormone therapy and are often treated as triple negative cancers.

Triple negative cancers are associated with a higher recurrence risk than hormone receptor positive breast cancers of the same stage.23 In addition to a more adverse natural history, these cancers do not benefit from hormone therapy or any identified adjuvant targeted therapy.

Chemotherapy is strongly recommended for all fit patients with TNBC of T1cN0 or higher stage, regardless of age and menopausal status. Younger, fit patients may also benefit from chemotherapy for T1aN0 and T1bN0 cancers, although the absolute benefits are smaller. For every patient, particularly those who are frail, elderly, or have multiple debilitating co-morbidities, one must always weigh the benefits of chemotherapy against the potential risks of giving it.

The Breast Tumour group recommends anthracycline-taxane based chemotherapy of 4-6 months duration for fit patients with T1cN0 or higher stage triple negative breast cancers (BRAJACTG, UBRAJACTW, BRAJFECD, BRLAACD). The choice of regimen depends on patient factors, tumour stage, and clinician judgment. In select older patients, or patients with small T1c or with T1bN0 disease, shorter regimens (BRAJDC, BRAJAC) may be acceptable alternatives to longer therapy.

Reference

  1. Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer : clinical features and patterns of recurrence. Clin Cancer Res 2007; 13:4429-4434

6.3.2.5 Neoadjuvant Therapy

Updated October 2015

Neoadjuvant therapy (NAT) has been studied in multiple settings, tumour subtypes, and with many different types of agents. NAT may be considered in certain patients with early stage breast cancer.

In British Columbia, in patients with early stage breast cancer, most decisions about chemotherapy are made after surgery. However, there are certain features of a cancer known from a core biopsy that favour the use of chemotherapy as part of the overall management of the cancer. Given that many randomized controlled trials of neoadjuvant chemotherapy included tumours that did not meet the LABC definition8, and given that there is no survival detriment in starting with chemotherapy, any patient who is a candidate for adjuvant systemic chemotherapy can be considered for neoadjuvant systemic therapy. This is of particular benefit for patients who may be able to convert from a planned mastectomy to breast conserving surgery in the presence of good clinical response. The main disadvantage of NAT in non-LABC is in cases where the axilla is clinically negative prior to NAT, because it leaves uncertainty regarding the need for and benefit of regional radiation.

If the need for chemotherapy is uncertain based on core biopsy, the best option is to proceed to surgery first (ie small tumour, unclear if there is any nodal involvement, ER+, older and less healthy patient).

Details of NAT are further described below. 

6.3.2.6 Miscellaneous Considerations

Revised 18 January 2013

1. Order of systemic and local therapy

Chemotherapy for non-locally advanced breast cancer is generally preferable after rather than before surgery, although survival and cure rates do not appear to be affected by this order.1 Surgical excision of the tumour and nodes provides optimal histopathologic information upon which to make the best systemic and radiation recommendations. If on the basis of a core biopsy and patient characteristics, there is sufficient information to recommend chemotherapy, it is acceptable to proceed with chemotherapy first, even when a cancer is not locally advanced. Reasons to choose chemotherapy first include time delay to scheduling immediate reconstruction in patients electing or requiring mastectomy; down sizing a tumour in patients who are borderline for breast conservation; and participation in pre-operative therapy clinical trials. If chemotherapy is given prior to surgery, clinically/radiologically suspicious lymph nodes should be biopsied prior to delivery of chemotherapy to aid in planning of radiotherapy after chemotherapy and surgery. 

2. Bone Modifying Agents

There is insufficient evidence to routinely recommend bisphosphonate therapy as adjuvant therapy for breast cancer patients. Several trials have suggested a modest benefit to adding zoledronic acid to the adjuvant therapy in women who are already menopausal or in whom menopause is induced.2,3 Studies with earlier generation bisphosphonates did not show a benefit, however. Data from longer follow up and corroborating evidence from ongoing trials are anticipated. While not funded by BC Cancer, Oncologists may recommend intermittent zoledronic acid for three years in selected early breast cancer patients based on existing evidence.

References

  1. Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 26: 778-785
  2. Coleman RE, Marshal H, Cameron D, et al. Breast-cancer adjuvant therapy with zoledronic acid. N Eng J Med 2011; 365:1396-1405
  3. Hillner BE, Ingle JN, Berenson JR, et al. American Society of Clinical Oncology Guideline on the role of bisphosphonates in breast cancer. J Clin Oncol 2000; 18:1378-1391
  4. Aebi S, Gelber S, Lang I, et al. Chemotherapy prolongs survival for isolated local or regional recurrence of breast cancer: the CALOR trial (chemotherapy as adjuvant for locally recurrent breast cancer; IBCSG 27-02, NSABP B-37, BIG 1-02). Cancer Treatment 2012: 24 suppl 3: abstract S3-3

6.3.2.7 Hepatitis B Screening & Prophylaxis in Setting of Adjuvant Systemic Therapy

Published 23 November 2005

Recommendations

  • Patients known to be HBsAg positive should receive lamivudine prophylaxis 100mg/day starting the week before chemotherapy and continuing until 8 weeks after the chemotherapy finishes.
  • A Special Access Form must be completed for lamivudine to contribute to a patient's deductible. This is available at: PharmaCare.
  • Decisions regarding baseline screening for HBsAg carrier status should take into account the patient's risk factors and the marked regional variation in HBsAg carrier rates.
  • Patients with identifiable risk factors should be screened for HBsAg.  Screening is optional for patients from regions with low HBsAg prevalence and without known risk factors.
  • Screening and the use of lamivudine for hepatitis C is not recommended
Risk Factors for HBV

  1. Patients from endemic regions Southeast Asia, China, Africa, and the Inuit
  2. Sexual activity ¨C accounts for 50% cases in USA (esp. promiscuity/prostitution)
  3. Percutaneous (IVDU, sharing razors/tooth brushes, tattoo, piercing, acupuncture
  4. Blood transfusion5. Organ transplantation
Of note, there is no clear risk factor in 20-30% cases (possible under-reporting).1

Prevalence of HBsAg Positivity in Various Regions of BC

Based on a prenatal screen in 1215 BC women aged 15-44 years old the age-standard HBsAg positivity rate (active carriers) was 1.4%.2 This was similar to the crude 1.0% rate for BC and the Yukon for 1996-2000 detected by Canadian Blood Services. Results from Nova Scotia were 0.1% and Barrie Ontario 0.3%. There is a marked regional variation amongst the 35,000 carriers in BC.3  The extrapolated carrier rates are: Interior BC 0.1%, Northern BC 0.15%, Vancouver Island 0.19%, Fraser Region 0.65%, Vancouver Coastal 1.94%.

HBV Review:  HBV is a partially double stranded, hepatotropic DNA virus that replicates through an RNA template using the enzyme DNA polymerase.

  1. Approximately 350 million people worldwide are infected. Eight percent of the population of Southeast Asia, China, and Africa, and 10% of the population of Hong Kong are chronic carriers of the virus.  These patients are serum-positive for Hepatitis B surface Antigen, HBsAg.
Life Cycle:  When an adult is infected with the virus there is a 2-4 week incubation period during which the patient has no symptoms and liver enzymes are normal as the virus itself is usually not cytopathic. Hepatic inflammation and elevated liver enzymes are secondary to the patient developing an immune response to antigens presented on infected hepatocytes in an attempt to eradicate the virus.  Over 95% of infected adults will clear the virus and become HBsAg negative and develop antibodies to HBsAg. If this is unsuccessful the patient will remain HBsAg positive and will be a chronic carrier of the virus. However, in endemic parts of the world the majority of infections occur in the perinatal period (vertical transmission to the neonate). Unlike adults, most neonates do not clear the infection and 95% become chronic asymptomatic carriers of HBV.

Antibodies/Antigens

HBsAg
HBV surface antigen; patient is actively infected
Antibody to HBsAg
Develops when patient clears the virus
Antibody to HBcAg
Antibody to HBV core antigen; remains positive in all patients who were exposed to the virus (whether they clear it or not).  Patients who were vaccinated against HBV are negative for antibodies to HBcAg but are positive for antibodies to HBsAg.
HBeAg
Marker of active viral replication

Chemotherapy and HBV

Patients who are HBsAg positive can have a flare of hepatitis while on chemotherapy. This is usually defined as a ≥ 3x increase in ALT (or an absolute ALT over 100 u/L) compared to baseline levels with a ≥10x increase in HBV DNA level (or an absolute DNA level > one million copies/ml). The severity of the hepatitis is graded as mild (ALT ≤2x ULN), moderate (ALT 2-5x ULN), or severe (>5xULN).4 Hepatitis flares while on chemotherapy may result in delays of chemotherapy administration, permanent discontinuation, and even fatalities.5 It is estimated that over 20-40% of patients who are HBsAg positive will have an HBV flare while on chemotherapy.4,6,7

Risk Factors for HBV Flare in HBsAg Positive Patients on Chemotherapy(8)

Detectable HBV DNA OR(odds ratio) = 8.4; use of steroids (for antiemetics or in CHOP) OR = 2.7; Lymphoma OR 5.0; Breast cancer OR = 4.2. Other series have suggested that male sex, HBeAg positivity, and pre-chemotherapy liver enzyme levels are risk factors.

Prevention of Flares

Lamivudine is a nucleoside analogue that interferes with HBV replication. In patients with detectable HBV DNA, almost 100% will have a temporary clearance of the virus after 4-12 weeks of lamivudine therapy.1 However, this results in a sustained remission in less than 20%. Initial studies showed lamivudine prophylaxis to be effective at preventing flares in HBsAg positive lymphoma patients.9 Lamivudine has also been used to successfully treat established HBV flares in patients on chemotherapy. However, treatment with lamivudine once the patient has flared is not always successful, and fatalities have been reported.5

Lamivudine prophylaxis has been studied in breast cancer patients using case-control series from Hong Kong. The largest series confined to HBsAg positive, breast cancer patients was reported in 20044 and involved 92 patients. The lamivudine (case) group received prophylactic lamivudine 100mg/d starting the week before chemotherapy and continuing for 2 months after chemotherapy ended. The control group did not receive lamivudine prophylaxis.The majority of patients were treated in the adjuvant setting, received anthracycline chemotherapy, and also received steroids as part of the anti-emetic regimen. In this series no deaths were reported. Lamivudine prophylaxis reduced the number of HBV flares from 31.1% to 6.5%, and reduced the number of delays/premature terminations of chemotherapy from 21.3% to 3.2%.
 
A second report, using an identical study design from the same Hong Kong investigators included 258 cancer patients of which 81 had breast cancer.6 In this case-control series lamivudine reduced the number of HBV flares from 24.4% to 4.6%, and reduced the number of delays/premature terminations of chemotherapy from 14.5% to 0%.

From these two reports it appears that lamivudine prophylaxis reduces the number of HBV flares on chemotherapy from 30% to 5% (24-31% to 4¨C6%). The number needed to treat to prevent one flare is between 4 and 5. The number needed to treat to avoid 1 delay/disruption in chemotherapy is approximately 6 (5.5 ¨C 7.1).

Lamivudine

The prophylactic dose is 100mg/day starting the week before chemotherapy and is continued until 8 weeks after chemotherapy finishes. Lamivudine is an expensive medication with 30 tablets costing approximately $145. It is covered by most extended health plans, but not by basic MSP until a patient reaches their deductible. A Special Access Form must be filled out so that the medication contributes to the patient's deductible (see PharmaCare).

Hepatitis C

Hepatitis C is not associated with an appreciable risk for chemotherapy related flares.10 Lamivudine is not an effective method for suppression of hepatitis C. Thus, screening for hepatitis C, and the use of lamivudine are not recommended.

Recommendations

  • Patients known to be HBsAg positive should receive lamivudine prophylaxis 100mg/day starting the week before chemotherapy and continuing until 8 weeks after the chemotherapy finishes.
  • A Special Access Form must be completed for lamivudine to contribute to a patient's deductible. This is available at PharmaCare.
  • Decisions regarding baseline screening for HBsAg carrier status should take into account the patient's risk factors and the marked regional variation in HBsAg carrier rates.
  • Patients with identifiable risk factors should be screened for HBsAg.  Screening is optional for patients from regions with low HBsAg prevalence and without known risk factors.
  • Screening and the use of lamivudine for hepatitis C is not recommended
References

  1. Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337(24):1733-45.
  2. Dawar M, Patrick DM, Bigham M, Cook D, Krajden M, Ng H. Impact of universal preadolescent vaccination against hepatitis B on antenatal seroprevalence of hepatitis B markers in British Columbia women. Cmaj 2003;168(6):703-4.
  3. BC Centre for Disease Control:  2004 British Columbia Annual Summary of Reportable Diseases.
  4. Yeo W, Ho WM, Hui P, et al. Use of lamivudine to prevent hepatitis B virus reactivation during chemotherapy in breast cancer patients. Breast Cancer Res Treat 2004;88(3):209-15.
  5. Cainelli F, Longhi MS, Concia E, Vento S. Failure of lamivudine therapy for chemotherapy-induced reactivation of hepatitis B. Am J Gastroenterol 2001;96(5):1651-2.
  6. Yeo W, Chan PK, Ho WM, et al. Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s-antigen seropositive cancer patients undergoing cytotoxic chemotherapy. J Clin Oncol 2004;22(5):927-34.
  7. Yeo W, Chan PK, Hui P, et al. Hepatitis B virus reactivation in breast cancer patients receiving cytotoxic chemotherapy: a prospective study. J Med Virol 2003;70(4):553-61.
  8. Yeo W, Zee B, Zhong S, et al. Comprehensive analysis of risk factors associating with Hepatitis  virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy. Br J Cancer 2004;90(7):1306-11.
  9. Shibolet O, Ilan Y, Gillis S, Hubert A, Shouval D, Safadi R. Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers. Blood 2002;100(2):391-6.
  10. Persico M, De Marino F, Russo GD, et al. Efficacy of lamivudine to prevent hepatitis reactivation in hepatitis B virus-infected patients treated for non-Hodgkin lymphoma. Blood 2002;99(2):724-5. 

6.4.0 Stage I or II Tumours with Muscle but Not Chest Wall Fixation

Updated February 2016

Surgery

Fixation of the tumour to underlying muscle or fascia does not carry the same poor prognosis as had been previously thought. If these patients have otherwise operable disease, they should be offered resection with an extension of the surgery to include the area of muscle involvement.

Radiation Therapy

Because of muscle involvement these patients should be offered postoperative radiation therapy.

Adjuvant Systemic Therapy

Adjuvant systemic therapy will be offered to those patients who are deemed to have risk factors for micrometastatic involvement (see Adjuvant Systemic Therapy).

6.5.0 Locally Advanced Breast Cancer (T3N1: Any T4: Any N2N3M0)

The incidence of locally advanced breast cancer (LABC) is estimated at 10% of all breast cancer diagnoses. These cancers have a higher risk of recurrence than earlier stage disease6.

The definition of LABC varies across different randomized controlled trials. The Canadian Consensus for the definition of LABC is (pan Canadian consensus, Locally Advanced Breast Cancer Network):

  • T3 or T4 tumours with any clinical N status,
  • any size tumour (T) with N2 or N3 disease
This is consistent with the MD Anderson definition of Stage IIB or Stage III disease6. Patients with a diagnosis of LABC fall into one of two categories: those who have neglected seeking medical attention for a breast tumour for some time (these tumours often have a more indolent course of slowly growing disease over many months to years with no signs of metastases), and those with rapidly growing, aggressive disease, for whom timely management and coordination of care is key (see Pathway of Care Chart under Neoadjuvant Therapy, below). Neoadjuvant therapy with chemotherapy followed by surgery and radiotherapy is standard for all patients with LABC.  

There is a wide range of response rates, pathologic complete response, and overall survival associated with LABC, depending on the underlying intrinsic subtype of the cancer (triple negative and Her2+ having higher rates of pCR than luminal A and B subtypes)7. Intrinsic subtype is not routinely ascertained at diagnosis at present, but clinical and pathological factors that predict for likelihood a higher likelihood of a pathologic complete response are young age, high grade, basal-like or Her2+ breast cancer8.

6.6.0 Inflammatory Breast Cancer

Updated: February 2016

Inflammatory breast cancer or T4d tumours present with rapid development of swelling, redness and peau d'orange (skin edema), which is often mistaken for an infection and treated with antibiotics before the correct diagnosis is made. A breast mass may or may not be apparent or the breast may be diffusely involved, but the overlying skin involvement is visible on clinical exam. The mammogram may show a discrete mass, but often there is only diffuse increase in density and skin thickening.

Inflammatory breast cancer is a clinical diagnosis. As expected, there is much controversy in the literature with regards to the "true" clinical parameters that define inflammatory breast cancer. According to international expert panel4, at a minimum, the following clinical criteria are required:

  1. Rapid onset of breast erythema, edema and/or peau d'orange, and/or warm breast, with or without an underlying palpable mass
  2. Duration of history no more than 6 months
  3. Erythema occupying at least one-third of the breast
  4. Pathologic confirmation of invasive carcinoma.
The distinctive pathological finding is the involvement of the dermal lymphatic vessels by tumour cells, which results in the skin erythema and edema. A biopsy (either core or open) to confirm the diagnosis should include skin to allow for the examination of dermal lymphatics.

This subtype of breast cancer is rare. Estimates from US datasets (SEER) suggest an incidence in the US of 1-5%5. While the incidence has increased since the early 1980s, this stage of cancer remains uncommon.

Patients with inflammatory breast cancer (IBC) should receive neoadjuvant therapy with chemotherapy and radiotherapy with the aim to render the disease operable.

Response rates and overall survival rates in this population are typically lower than for other stages of disease, with reported pathologic complete response ranging from 18-40% and 5 year OS rates ranging from 35-55%4. More intensive chemotherapy regimens are associated with higher rates of response. Treatment options are outlined in the section Neoadjuvant Therapy, below. As this subtype of breast cancer is aggressive, rapidly progressive, and associated with a high risk of recurrence/mortality, it is recommended that NAT be started in patients with IBC as soon as possible (see Pathway of Care Chart under Neoadjuvant Therapy, below).

Inflammatory breast cancer is the most aggressive form of breast cancer with a median survival of 18 to 24 months, despite intensive combined modality treatment leading to a high initial response. Prompt initial referral to BC Cancer is strongly recommended for these patients. 

Inflammatory breast cancer should be managed like other inoperable locally advanced breast cancer (stage IIIB and C) with neoadjuvant therapy, as described below.


6.7.0 Neoadjuvant Therapy

Updated January 2017

The use of systemic and or radiation therapy prior to surgery (neoadjuvant therapy or NAT) has been studied since the early 1970s. There are several potential advantages to the use of NAT1:

  • Allows for immediate assessment of tumour response
  • Allows for evaluation of new and novel agents
  • Allows for evaluation of change in biomarkers with treatment
  • May allow for earlier control of micro-metastases
The key landmark study by Wolmark et al in 2001 (NSABP B-18) demonstrated that NAT (with chemotherapy) was safe, with no difference in outcomes of disease free survival (DFS) or overall survival (OS) in patients who received either pre-operative chemotherapy or post-operative chemotherapy2. It was demonstrated, however, that patients who had a complete pathological response (pCR) to NAT had an improved OS compared to those who did not achieve a pCR with NAT.

NAT has been since studied in multiple settings, tumour subtypes, and with many different types of agents. NAT may be considered in certain patients with early stage breast cancer, and is the standard of care for patients with locally advanced breast cancer or inflammatory breast cancer. 

What are the key steps in the pathway of care for patients treated with NAT?

The neoadjuvant treatment of breast cancer requires a coordinated effort amongst surgical oncology, medical oncology, radiation oncology, nursing, pathology, radiology and clerical booking staff.3 

Who should be referred for NAT?

  1. Patients with locally advanced breast cancer (LABC)3,4,5,6,7
    • LABC is generally accepted as T3 or T4 tumours of any clinical N status or any tumour size with clinical N2 or N3 disease, operable or inoperable. Inflammatory breast cancer is included within this definition.
  2. Patients with early stage breast cancer (≥2cm) and chemo-responsive tumour markers (i.e. triple negative, Her2+), who will benefit from downsizing for breast conserving surgery (BCS)6
  3. Absolute or Relative contraindications to surgery (advanced age/multiple medical comorbidities) in the setting of estrogen receptor positive tumours (for consideration of neoadjuvant endocrine therapy)3
In general, any patient who is a candidate for adjuvant systemic therapy can be considered for neoadjuvant chemotherapy. Patients with tumours < 2cm, low grade, ER positive/Her2 negative, may not require systemic chemotherapy and should undergo surgery first.8

Referral process

  • If a patient is felt to be an appropriate candidate for NAT by a surgeon or family physician, an urgent referral should be sent to BC Cancer indicating a consultation request for NAT.
  • The patient should be seen before or at the beginning of NAT by a surgeon to determine the tentative surgical plan and to ensure all essential biopsies and imaging (e.g. axillary), and clip placement have been organized and/or completed.
  • A radiation oncologist should be consulted early in the patient's course, as the tumour can change dramatically in size and volume from initial presentation due to NAT.
Work up

Before starting NAT the following tests and procedures should be completed:4,6,7

  1. Biomarker status (estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (Her2) on core biopsy 
  2. Bilateral mammogram +/- breast ultrasound
  3. Accurate tumour measurement on clinical exam - consider breast MRI before initiation of NAT to assess tumour extent, especially if patient may be a BCS candidate
  4. Clip should be placed in tumour if patient is a candidate for, or may be considering, BCS
  5. Imaging of chest/abdomen plus bone scan to assess for distant metastases
  6. Suspicious lymph nodes on exam or imaging should undergo fine needle aspiration prior to initiation of NAT 
How should patients be followed during NAT? 

  • Patients should be assessed at each cycle of chemotherapy for clinical response with accurate clinical measurement. 
  • There are no standard recommendations for assessing radiologic response. MRI may be considered to assess radiologic response and to aid surgical planning.3,9
  • Patients should be seen by their surgeon halfway through NAT and prior to their last cycle of chemotherapy to determine final surgical plan. In addition, a more urgent assessment should be completed if the tumour is not responding to NAT. 
  • Patients on neoadjuvant endocrine therapy can be assessed  monthly.3 
Systemic Therapy

  • Options for systemic therapy are outlined in the section below. Cancers that are responding should continue the planned treatment protocol. 
  • Hormone therapy should be given after completion of NAT if cancer is ER positive (See "Early Invasive Breast Cancer". 
  • If the cancer is her2 positive, trastuzumab should be given for one year, starting during the non-anthracycline portion of the chemotherapy.
Locoregional Therapy

Following NAT, patients should undergo definitive locoregional therapy, which usually involves surgery and radiation. 

Surgery should be planned for 3-4 weeks following completion of neoadjuvant chemotherapy to allow adequate immune and general recovery first. This is consistent with timelines reported in randomized controlled trials of NAT in breast cancer patients.

Surgical considerations - Breast

  • Breast-conserving surgery can be considered for appropriate patients
  • Mastectomy should be considered for patients with contraindications to radiation therapy, multicentric disease, incomplete response of skin involvement, and large tumour to breast size ratio after NAT and potential for poor cosmesis.3.4.7
  • Mastectomy with axillary lymph node dissection is the recommended surgery for patients with inflammatory breast cancer. 
Surgical considerations - Axilla

  • Pre-NAT N0:
    • Sentinel lymph node biopsy after NAT at the time of definitive surgical management should be completed3,6,9
  • Pre-NAT N+:
    • ALND is currently recommended. 
    • SLNB after NAT remains controversial in this patient population. Ongoing studies continue to investigate SLNB after NAT in node positive patients and therefore, related literature should be reviewed and this practice re-considered in future updates9
Radiation Therapy

  • In patients with resectable disease, adjuvant locoregional radiotherapy typically starts approximately 6 weeks after surgery to allow for proper healing for patients with node positive disease 
  • In patients with disease that is still unresectable after completion of neoadjuvant chemotherapy, or who have disease that progresses on chemotherapy, locoregional radiotherapy is delivered earlier in the course of treatment 
  • Radiation therapy for N0 tumours should be routinely recommended after BCS and for select patients after mastectomy 
  • See "Radiation Therapy" section for details of radiotherapy
Reconstruction

  • If a mastectomy with autologous tissue reconstruction is planned, radiation is generally preferred prior to surgery, to minimize the negative cosmetic effect on the reconstructed breast of radiation. In other circumstances, radiation generally follows surgery. Timing of radiation should be coordinated between radiation oncology and the surgical team. 
Progression or remains inoperable on NAT

Patients with technically inoperable tumours after NAT should have radiotherapy after chemotherapy with a view to further local downstaging. If their disease becomes operable, appropriate surgery should follow.

If the tumour enlarges while on NAT, treatment should be changed. Non-cross resistant chemotherapeutic agents, salvage radiotherapy, or surgery are all appropriate options to consider in this setting. Discussion of these cases at a multi-disciplinary tumour board should be considered. Cancers showing equivocal response may benefit the most from tumour board multidisciplinary review, to explore ways to improve clinical response.

Residual disease after NAT

Pathology findings following NAT are designated with a 'y' in front of the 'p" (example ypT2N1) to reflect that the cancer has been exposed to treatment. In general, the less disease present, the better the prognosis, with a large jump (improvement) in prognosis occurring with a pathological complete response (pCR).10 The improved disease free and overall survival associated with a pCR has been shown in cancers of all biomarker profiles (triple negative, ER positive, and her2 positive).11

The definition of pathological complete response varies in clinical trials. The strictest definition allows no residual invasive disease or in situ disease in the axilla or breast. The least strict definition considers only the absence of invasive disease in the breast, allowing for residual nodal metastases. The Canadian expert consensus for the definition of pathological complete response is no evidence of invasive disease in the breast or axilla3. This definition allows for residual DCIS and is consistent with the definition most often reported in clinical trials of NAT.

There is not data to support that additional chemotherapy is of benefit in patients who have residual disease at surgery following NAT. Clinical trial options can be considered if available. Hormone therapy and trastuzumab should be given according to standard of care.

What are the options for type of NAT?

Chemotherapy

Preoperative chemotherapy (NAT) has several functions:

  • to control/ eradicate micrometastases,
  • to improve the loco-regional control
  • to render the patient operable, if they presented with inoperable disease.
In general, there is a preference for chemotherapy regimens that include an anthracycline and a taxane, either concurrently or sequentially Chemotherapy Breast Protocols, based on demonstration of improved outcome compared with anthracycline only regimens.14 Recommended regimens include BRLAACD and UBRAJACTW, but avoidance of anthracyclines or taxanes, or abbreviated courses, may be necessary for some patients with co-morbidities. Trastuzumab (BRLAACDT) should be added if the cancer is her2+. NAT is typically given for about six months (8 cycles) prior to definitive local therapy, provided there is no adverse progression of the disease on therapy.

Hormone Therapy

The likelihood of achieving a pCR with endocrine therapy is significantly lower than with chemotherapy.

Neoadjuvant endocrine therapy may be an appropriate option in patients found to have hormone receptor positive disease and who are unfit for chemotherapy. Canadian experts from the Canadian Consensus for the Treatment of Locally Advanced Breast Cancer recommend endocrine therapy for patients with ER+PR+Her2- disease and multiple co-morbidities, or who are older than 80 years. The duration of neoadjuvant hormone therapy is not well defined, but studies have been conducted using an interval of 4-8 months.12 The overall goals of care should be discussed with the patient and the duration of therapy should reflect this (ie if the goal is curative then a pre-defined duration of NAT with endocrine therapy followed by surgery; if the goal of care is control then there may be no pre-defined duration of NAT).

Aromatase inhibitors and Tamoxifen have been studied in the neoadjuvant setting.13 In serial biopsy studies, aromatase inhibitors have demonstrated a greater drop in proliferation markers (Ki67) than tamoxifen. Anastrozole, Exemestane, and Letrozole have all demonstrated similar effect on proliferation indices. One study showed better clinical response rates with letrozole than tamoxifen.14 For these reasons, aromatase inhibitors are preferred in menopausal women, although tamoxifen can be used in patients with contraindications or intolerance to AIs.

The above guideline can be summarized in the following pathway of care:

6.7 Breast section diagram.jpg

References

  1. Chia S, Swain SM, Byrd DR, et al. Locally advanced and inflammatory breast cancer. J Clin Oncol 2008: 25(5):786-90.
  2. Wolmark N, Wang J, Mamounas E, et al. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr. 2001;(30):96-102.
  3. Simmons CE, Hogeveen S, Leonard R, Rajmohan Y, Han D, Wong A, et al. A Canadian national expert consensus on neoadjuvant therapy for breast cancer: linking practice to evidence and beyond. Curr Oncol. 2015 Mar;22(Suppl 1):S43-53
  4. http://www.current-oncology.com/index.php/oncology/article/view/2328/1692 
  5. Neo-adjuvant (Pre-Operative) Therapy for Breast Cancer – General Considerations, Clinical Practice Guidelines, Alberta Health Services, Alberta, Canada. Effective: December 2014. http://www.albertahealthservices.ca/assets/info/hp/cancer/if-hp-cancer-guide-br015.pdf
  6. Brackstone M, Fletcher GG, Dayes IS, Madarnas Y, Sengupta SK, Verma S, et al. Locoregional therapy of locally advanced breast cancer: a clinical practice guideline. Curr Oncol, 2015;22(Suppl 1):S54-66. 
  7. https://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=334821 
  8. Senkus E, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rutgers E, Zackrisson S, Cardoso F.  Primary Breast Cancer: ESMO Clinical Practice Guidelines. Ann Oncol (2015) 26 (suppl 5): v8-v30. http://www.esmo.org/Guidelines/Breast-Cancer/Primary-Breast-Cancer
  9. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer (Version 2.2016). https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf 
  10. Kaufmann M, von Minckwitz G, Eleftherios P, Cameron D, Carey L, Cristofanilli M et al. Recommendations from the International Consensus Conference on the Current Status and Future of Neoadjuvant Systemic Therapy in Primary  Breast Cancer. Ann Surg Oncol (2012) 19:1508–1516 
  11. Teshome M, Hunt KK. Neoadjuvant Therapy in the Treatment of Breast Cancer. Surg Oncol Clin N Am. 2014 July ; 23(3): 505–523 
  12. Kaufmann M, von Minckwitz G, Mamounas EP,et al. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol. 2012 May;19(5):1508-16.
  13. Cortazar P, Zhang L, Untch M, et al. Meta-Analysis results form the Collaborative Trials in Neoadjuvant Breast cancer (CTNeoBC). Cancer Research 72 (24) supplement 2012: S1-11
  14. Shenkier, T., et al., Clinical practice guidelines for the care and treatment of breast cancer: 15. Treatment for women with stage III or locally advanced breast cancer. CMAJ, 2004. 170(6): 983-994.
  15. Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant Treatment of Postmenopausal Breast Cancer With Anastrozole, Tamoxifen, or Both in Combination: The Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen (IMPACT) Multicenter Double-Blind Randomized Trial. J Clin Oncol August 1, 2005 vol. 23 no. 22: 5108-5116
  16. Eiermann W, Paepke S, Appfelstaedt, J, et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study. Ann Oncol 2001;12(11):1527-32.


6.8.0 Locoregional reoccurance

Updated February 2016

Locoregional recurrence may follow modified radical mastectomy or partial mastectomy. Locoregional recurrence following modified radical mastectomy carries a poor prognosis but approximately 15% of patients will be long-term survivors after further locoregional therapy. Recurrence in the breast following partial mastectomy is curable with much greater probability. The survival of patients under these circumstances is parallel to that of patients with new tumours of similar stage.

Tumours should be carefully assessed, as some of these in-breast 'recurrences' are not recurrences but new primary breast cancers, which may require different treatment and may give a different prognosis. (e.g. the new tumour may be ER+ and the initial tumour ER-). All patients should have a biopsy to confirm recurrent disease and to assess biomarker status.

A proportion of these patients will already have demonstrable metastatic disease and a full metastatic work-up should be performed. This should include a mammogram of the contralateral breast as well as a CBC, liver enzymes, CA15-3, bone scan and chest x-ray.

The patient may be referred to BC Cancer for an opinion from the multi-disciplinary group at the Breast Conference.

1) Locoregional Recurrence Following Modified Radical Mastectomy

Surgery

If the recurrence is solitary, wide local excision is advised if possible. If the recurrence is in the axilla and the patient has not previously had an axillary node dissection, then an axillary node dissection should be considered.

Radiation Therapy

If the patient has not had previous radiation therapy, then radiation therapy should be given to the chest wall and the lymph node bearing areas with appropriate dose build-up at the site of the recurrence after it has been excised.

Chemotherapy

At present there is no defined role for chemotherapy under these circumstances, but it should be discussed in patients who have never received adjuvant systemic therapy and are otherwise well.

Hormone Therapy

Tamoxifen has been demonstrated to delay recurrence, but a statistically significant improvement in survival has not been demonstrated in randomized trials. If the initial tumour or the recurrent lesion is hormone receptor positive or unknown then an appropriate hormonal manoeuvre should be considered. This will usually be with an aromatase inhibitor or tamoxifen 20 mg po daily for five years or longer, depending on which hormone therapy was used in the initial adjuvant setting and the menopausal setting of the patient. For premenopausal women, there should be consideration of ovarian ablation by surgery or radiation therapy. Extrapolating from the adjuvant and metastatic setting, first line aromatase inhibitors are superior to tamoxifen in terms of time to disease progression and are therefore an appropriate first line option for post-menopausal patients in this setting.

2) Local Recurrence After Previous Partial Mastectomy

Surgery

Patients who did not undergo radiation to the breast after initial partial mastectomy are more likely to experience a local recurrence. If these patients are prepared to accept radiotherapy on recurrence, breast conservation is still possible and a repeat local excision can be carried out followed by radiation therapy to the residual breast tissue. Mastectomy is usually recommended for patients without demonstrable metastases if the patient has had prior breast radiotherapy. In both circumstances, the cure rate will approach that of primary surgery on a similar lesion. Axillary surgery should be performed as appropriate, based on what previous axillary surgery the patient has had and the clinical status of the axilla at the time of recurrence. 

Radiation Therapy

If the breast/chest wall has been previously irradiated, usually re-irradiation is not advised. If the breast/chest wall has not previously been irradiated, then radiotherapy should be delivered to the breast/chest wall. If the recurrence is in the axilla or supraclavicular fossa and these lymph node areas have not previously been irradiated, then radical radiation therapy should be delivered to the axilla and supraclavicular node areas. 

Chemotherapy

Data supports the use of aggressive locoregional and systemic management for the highest likelihood of cure in patients who develop an isolated in-breast, chest wall, or axillary recurrence that is resectable. Chemotherapy in this setting has been shown to increase survival and cure rates.27 The choice of chemotherapy depends on patient factors, prior therapy given, and time elapsed since prior adjuvant therapy.

If the recurrence is in the axilla, if lymphatic or vascular invasion is identified, or if the invasive tumour is > 2 cm + any grade or >1 cm + grade III, then adjuvant chemotherapy and/or hormone therapy may be considered, depending upon the patient's health status and age, history of prior adjuvant treatment, and estrogen receptor status. Referral to a medical oncologist is encouraged.


6.9.0 Metastatic Breast Cancer

Revised November 2017

6.9.1 Background

The introduction of population based screening and adjuvant treatment are important contributors to declining breast cancer mortality rates observed in western countries over the last 4 decades.1 Despite these advances, metastatic breast cancer remains one of the leading causes of cancer related mortality in women. The majority of women with metastatic breast cancer have relapsed after curative-intent therapy for early breast cancer; a smaller proportion present with distant metastases at initial diagnosis. Breast cancer is distinctly uncommon in men, however treatment principles are similar to those described below.

6.9.2 Patterns of Spread

Most patients with metastatic breast cancer have widespread disease, with bone being the commonest site. Lung, liver, and soft tissue (nodes, skin) are also commonly involved. Parenchymal brain metastases are common during the course of metastatic her2+ breast cancer and triple negative (hormone receptor and her2 negative) breast cancers, less so among ER+ cancers. Lobular histology cancers can spread to the ovaries, peritoneal cavity, and pleura.

6.9.3 Prognosis

Metastatic breast cancer is incurable with currently available therapies. The median survival is approximately 24 months. However, there is a wide range of survival, from several months in extreme cases, to 5 or more years. In general, patients with a long interval between early breast cancer diagnosis and metastatic relapse live longer than those with shorter disease free intervals. A small but significant fraction of patients achieves long-term disease control and survives more than 10 years. Survival patterns differ by type of breast cancer: patients with metastatic her2+ or metastatic ER+ cancers survive 4 to 5 years on average, while patients with metastatic ER-/her2- (triple negative cancers) typically survive a year or less.

6.9.4 Multidisciplinary Management

Assessment of the Patient

The initial investigation of a patient with metastatic disease should include:

  • Careful history with particular attention to symptoms, breast cancer history and prior treatments.
  • Complete physical examination and documentation of performance status.
  • Histological confirmation when possible and whenever the diagnosis is uncertain, with reassessment of ER/PR and HER2 status (up to 20% of cancers may change their ER,PR, and/or her2 expression at the time of metastatic recurrence, potentially opening up new treatment options).
  • Blood tests: CBC, liver and renal function, serum calcium and tumour markers CA15-3 and CEA.
  • Imaging of symptomatic sites and assessment of the extent of disease; CT Chest/Abdomen, bone scan. Brain imaging in patients with neurological symptoms.
  • PET-CT scan maybe helpful in patients when there is a high index of suspicion for metastatic disease but conventional imaging does not detect disease.
These are also useful for monitoring response to treatment and for identifying adverse disease progression and a need to change therapy.

Multidisciplinary Approach

The primary goal of treatment is to control cancer-related symptoms and to enhance survival where possible. The treatment of metastatic breast cancer requires a multidisciplinary approach (medical, radiation, surgical, specialists in pain and symptom management, and psychosocial support). Community home care and palliative support are important in later stages of the disease. There are a number of online websites, which provide a range of resources, from chat lines to information and testimonials about particular treatments for breast cancer patients. Some useful links are listed below:

Most improvements in survival and quality of life for patients with metastatic breast cancer have come from knowledge gained from successfully completed scientifically rigorous clinical trials. Patients should be given the opportunity to participate in clinical trials if available for their stage and type of breast cancer.

Radiation Therapy

Metastatic breast cancer is moderately radiosensitive and worthwhile symptomatic relief can be expected from radiation to several different types of metastases. Radiation can improve quality of life, and possibly extend life, for patients with metastatic breast cancer in the treatment of:

  • Bony metastatic lesions
  • Spinal cord compression, in conjunction with steroids with or without surgical decompression
  • Symptomatic endobronchial or parenchymal lung lesions
  • Superior vena cava obstruction
  • Cerebral metastatic disease in conjunction with steroids with or without surgery
  • Painful bulky or ulcerating soft tissue or chest wall disease
In select patients with limited metastatic disease (oligometastatic disease), high-dose radiotherapy (stereotactic radiotherapy or radiosurgery) may be considered to gain long-term control of metastatic disease. Patients should be referred to radiation oncology in such circumstances.

Surgery

There are a few well-defined indications for surgery in the palliative setting. These include investigation of a solitary lesion which may be metastatic or a new primary disease, e.g. a solitary lung lesion; treatment of pathologic fracture; prophylactic instrumentation to prevent an impending fracture; surgical decompression for spinal cord compression and/or surgical stabilization of the spine with metal rods; and surgical resection of solitary and oligo brain metastasis. Radiation following surgical intervention to bone and brain is often indicated.

Other Local Therapy

  • Ascites: Patients developing symptomatic ascites may benefit from periodic therapeutic paracentesis.
  • Pleural Effusions: Symptomatic pleural effusions may be managed with thoracentesis, PleurX catheters, or pleurodesis.
  • Leptomeningeal disease is a poor prognostic sign, and is often a terminal event. However some patients achieve moderate duration of disease control with intrathecal methotrexate or ara-C. High dose iv methotrexate can also produce temporary relief of symptoms, as can craniospinal radiation in select cases.
  • Bowel Obstruction. Bowel obstruction resulting from peritoneal metastases from breast cancer is infrequently reversible. A trial of chemotherapy with TPN support may be indicated provided there are clear expectations about when futility will be declared and TPN will be withdrawn in the absence of resolution.
  • Uveal and periorbital soft tissue metastases. These are very uncommon in breast cancer and can be treated with radiation.
Systemic Management

The systemic management of invasive metastatic breast cancer is complex. At present, invasive breast cancer can be thought of as three broad entities that influence systemic treatment decisions: hormone receptor positive/Her2 negative cancers; Her2 positive cancers (regardless of hormone receptor status); and hormone receptor negative and Her2 negative (ie, triple marker negative) cancers. Within each of these entities, treatment recommendations are also influenced by patient age and comorbidities, personal preferences, extent of disease, and other histopathologic features of the cancer. In every case, patients and physicians must always weigh the benefits of treatment, particularly chemotherapy, against the potential risks of giving it.

Hormone Receptor Positive Breast Cancer

Hormonal therapy is generally the preferred initial treatment for metastatic hormone sensitive (ER and/or PR positive) disease, which is:

  • Confined to non-visceral sites, or a low burden of visceral metastases (little/no organ dysfunction, low volume of the organ involved, minimal/no symptoms) and
  • Relatively indolent disease not likely to progress rapidly over the ensuing 3-4 months (e.g., one or two solitary pulmonary nodules or chest wall recurrence or skin involvement)
The choice of agent for optimal hormonal therapy in a given situation should reflect the best available evidence showing patient benefit, the likelihood of response and the associated side effects. One must also consider whether a patient is pre or postmenopausal, their co-morbidities and current performance status, what hormone therapies she or he was exposed to in the adjuvant setting, and whether the cancer relapsed on or sometime after they were discontinued. The probability of response is highest in patients with long disease-free interval predating relapse. Response to one hormonal agent often predicts for responses to other agents. Treatment with hormone therapy should be continued to progression unless there is significant toxicity.

Patients requiring chemotherapy as initial therapy for hormone receptor positive disease may benefit from the introduction of hormone therapy on completion of chemotherapy, as a means of maintaining longer remissions.

Hormonal therapy options in pre-menopausal women include:

  • Selective estrogen receptor modulator: BRAVTAM.
  • Ovarian suppression with LHRH agonist, bilateral oophorectomy, or bilateral ovarian radiation.
  • Ovarian suppression plus tamoxifen: BRAVLHRHT. Dual hormone inhibition may lead to longer survival than ovarian ablation alone.2,3
  • Ovarian suppression plus an aromatase inhibitor is an option for premenopausal women who have a contraindication to tamoxifen, and for premenopausal women whose disease has progressed after tamoxifen. The combination of an LHRH agonist and an aromatase inhibitor requires a CAP approval.
  • Premenopausal women who have menopause induced may benefit from the same treatment options that are recommended for menopausal women.
Hormonal therapy options in post-menopausal women include:

  • Non-steroidal aromatase inhibitors: BRAVLET, BRAVANAS
  • Steroidal aromatase inhibitor: BRAVEXE
  • Steroidal AI plus everolimus: not presently funded by BC Cancer.
  • Selective estrogen receptor modulator: BRAVTAM.
  • Selective estrogen receptor downregulator: fulvestrant: not presently funded by BC Cancer.
  • Occasional patients may still have hormone-sensitive disease after treatment with the above therapies and/or may have compelling reasons to avoid chemotherapy. In such cases older hormonal treatments such as megestrol (BRAVMEG) and testosterone enanthate (BRAVTEST) may provide some disease control.
Anastrozole and letrozole (BRAVLET, BRAVANAS) are generally the preferred first line hormone agent in menopausal metastatic breast cancer in patients who have not relapsed on either drug from the adjuvant setting. By inhibiting aromatase, they prevent peripheral conversion of androgens to estrogens, thus greatly reducing circulating estrogen levels in menopausal women. They have proven efficacy in both first and second line metastatic hormone receptor positive disease.4,5,6 They should not be used in sequence, as they have the same mechanism of action and very similar chemistry. A switch between letrozole and anastrozole can be considered if there are intolerable side effects, as sometimes there is a preference. They are not effective single agents in premenopausal women.

Tamoxifen (BRAVTAM) is a good first line choice in premenopausal women and in menopausal patients who have relapsed on an adjuvant aromatase inhibitor. It can also be used in second or third line if there was no prior tamoxifen use in the adjuvant setting, and in women with no relapse on or within one year of adjuvant Tamoxifen.

Exemestane (BRAVEXE) is an irreversible steroidal aromatase inactivator that has shown some activity after previous therapy with reversible aromatase inhibitors7, and can be given as second line or third-line, provided the duration of disease control on anastrozole or letrozole is long enough to suggest possible continued hormone responsiveness of the cancer (generally at least 4-6 months). Combination of exemestane and everolimus after exposure to a non-steroidal AI results in longer disease control than exemestane alone, and may be an option for some patients.8 It is unclear at this time whether the addition of everolimus prolongs survival, however it does add some toxicity in the form of mucositis, diarrhea, and possible interstitial pneumonitis.

Fulvestrant is a pure anti-estrogen given by monthly intramuscular injection. It provides equivalent disease control to anastrozole in the first line setting and to exemestane after a non steroidal aromatase inhibitor (second line plus). It may be particularly effective in patients with no prior hormone therapy exposure (hormone therapy naive).9,10

Hormone Refractory Disease

At some point all hormone receptor positive cancers become unresponsive to hormone therapy and chemotherapy must be considered. As well, even among those cancers felt to retain hormone sensitivity, chemotherapy is generally preferred if the disease is locally-advanced (to achieve better local control), affects the function of visceral organs, or is causing the patient a high degree of symptoms. Chemotherapy is described under the “Hormone Receptor and Her2 Negative” section below.

HER2 Positive Breast Cancer

First line therapy

The standard of care first line therapy for metastatic her2+ disease, regardless of hormone receptor status, is anti-her2 therapy combined with chemotherapy.11 Anthracyclines should not be combined with trastuzumab due to synergistic cardiotoxicity. Unless patients are too frail or have prohibitive cardiac co-morbidity, a taxane combined with trastuzumab (BRAVTRAP, BRAVTRAD, BRAVTPCARB) should be the first choice of therapy.11,12,13 The chemotherapy drug(s) may be discontinued after 6-8 cycles to minimize cumulative toxicity, however trastuzumab should be continued (BRAVTR) until disease progression or prohibitive toxicity. Vinorelbine can be substituted for a taxane combination in patients who are frail due to disease, co-morbidity, or advanced age (BRAVTRVIN).14 Some patients achieve a very long disease remission with first line therapy.

During the single agent trastuzumab phase, hormone therapy can be added if the cancer is hormone receptor positive.

All patients should have baseline left ventricular ejection fraction assessment with a MUGA scan or echocardiogram prior to initiating trastuzumab. There is no defined schedule for left ventricular ejection monitoring in the metastatic setting. Patients reporting symptoms or exhibiting signs of congestive cardiomyopathy should have anti-her2 therapy interrupted and cardiac assessment performed. Whether trastuzumab can be safely resumed later depends on the degree of recovery of cardiac function following discontinuation. Recommendations are further detailed in the BRAVTR protocol.

Relapse after adjuvant trastuzumab

A small fraction of patients receiving chemotherapy and trastuzumab for early breast cancer will experience a metastatic relapse. Patients relapsing 12 or more months after completion of adjuvant trastuzumab should be treated preferentially with chemotherapy / trastuzumab combination in first line, as described above. Patients relapsing on or within 6 months of completing trastuzumab may experience better disease control by substituting a different anti-her2 drug, such as lapatinib. It is unclear whether trastuzumab or lapatinib is better at controlling disease that recurs between 6 and 12 months after completing trastuzumab.

Concurrent ER+ disease

Patients with hormone receptor positive and her2+ disease who refuse chemotherapy may experience a period of disease control with hormone therapy alone, although this is generally of shorter duration than with chemotherapy and trastuzumab, and of shorter duration than is seen in hormone receptor positive disease that is her2 negative.15 As such, it is not the preferred option. In extenuating circumstances where chemotherapy cannot be safely given, the combination of an aromatase inhibitor and lapatinib may provide longer disease control than an aromatase inhibitor alone.16 This requires CAP approval.

Second line therapy

At the time of disease progression, continuation of anti-her2 therapy and addition of chemotherapy is associated with the longest disease control and preservation of quality of life. Options include continuing trastuzumab or switching to lapatinib, and adding either vinorelbine or capecitabine (BRAVTRVIN, UBRAVTCAP, UBRAVLCAP).14,17,18 Retreatment with a taxane/trastuzumab combination may be appropriate for patients who achieved a long period of disease control with initial treatment. After an appropriate period of combination therapy, the chemotherapy drug can be stopped to minimize toxicity, while the anti-her2 therapy is continued until disease progression.

Third line therapy and beyond

If available, continuation of anti-her2 therapy with chemotherapy in subsequent lines of therapy appears to be beneficial.19 At each time point that treatment change is required due to disease progression, consideration of whether or not to treat with further chemotherapy and which drug(s) to use must take into consideration the patient’s previous treatments, current performance status, extent of disease, likelihood of further disease control, and comorbidities. Options may include cytotoxic chemotherapy as described below, and hormonal therapy for the hormone receptor positive cancers.

Brain metastases

The majority (40-60%) of patients with metastatic her2 positive breast cancer develop brain metastases at some point in their disease course. One should maintain a low threshold for imaging the brain if a patient reports any neurologic symptoms, even if subtle. Oligometastases should be considered for surgical excision or stereotactic radiosurgery followed by whole brain radiotherapy. Retreatment of progressive brain metastases with further radiation is sometimes feasible and beneficial, if the disease was controlled for an extended period (generally at least ten months) after initial radiotherapy. Several systemic drugs have some penetration into the blood brain barrier and may enhance control of brain metastases from breast cancer. These include capecitabine, lapatinib, anthracyclines, and cisplatin. While some other drugs have been used to treat primary brain tumours, their ability to control brain metastases of breast cancer origin has been disappointing.

Occasionally the brain may be the first and only apparent site of metastatic relapse. If isolated brain metastases occur during adjuvant therapy, they should be treated as described above and trastuzumab should be continued indefinitely as the chance of systemic metastases developing is high. If isolated brain metastases develop after completion of adjuvant trastuzumab, patients should be followed closely after treating them. Systemic treatment with chemotherapy and trastuzumab should be started at the time of eventual systemic metastases detection.

Hormone Receptor and HER2 Negative (Triple Negative) Breast Cancer

Cytotoxic chemotherapy remains the standard of care for patients who have breast cancer that is negative for ER, PR, and Her2 expression. Patients with hormone receptor positive disease that is hormone refractory or who require chemotherapy, and patients with her2 positive disease that has progressed beyond available lines of anti-her2 therapy/chemotherapy combinations can be treated with chemotherapy using the same principles as for patients with triple negative disease.

There are several chemotherapeutic agents with activity against breast cancer, and choices should take into account the patient’s previous treatments, performance status, extent of disease, and other comorbidities. There is no single correct order for chemotherapy drug delivery. Unlike hormone therapy, chemotherapy has a narrow therapeutic index, requiring careful attention to toxicity. There should be a low threshold for dose modifications to minimize toxicity and patients should be advised to report side effects.

General indications for chemotherapy in patients with metastatic breast cancer:

  • Rapidly progressive metastatic disease.
  • Threatening metastatic disease e.g. involving the viscera, particularly the liver.
  • Estrogen receptor negative primary tumours with symptomatic metastasis.
  • Hormone receptor positive tumours pretreated with and failing hormonal manoeuvres.
  • Reasonable performance status (ECOG 0-2). Patients with ECOG-3-4 are unlikely to benefit and will very likely experience unacceptable toxicity.
Response to chemotherapy should be evaluated after 2 or 3 cycles, and non-responding patients should have treatment changed. In responding patients, the optimal duration of therapy varies by drug and cumulative toxicity. In general, 6-8 cycles of therapy, or treatment for two cycles beyond best response affords optimal disease control. Longer therapy is an option for patients tolerating a drug well and without evidence of progression.

In general terms, anthracyclines, taxanes, and capecitabine should be considered for the first lines of therapy:

  • Anthracyclines: there is a maximum safe lifetime cumulative dose of anthracyclines beyond which the risk of cardiac toxicity is unacceptably high.
  • Capecitabine: palmar-plantar erythrodysesthesia is a cumulative toxicity which may limit duration of therapy or require dose modification over time.
Several chemotherapy combinations have shown modest gains in response rate and overall survival duration compared with single agent therapy, however generally combining several drugs results in increased toxicity.20,21,22 Combination chemotherapy should be considered in young fit patients and in patients in whom maximal disease shrinkage is optimal for symptom resolution.

Other/subsequent chemotherapy regimens include:

  • Gemcitabine: activity of gemcitabine is modest as a single agent. Results are better in combination.
  • Vinorelbine: BRAVNAV
  • Metronomic low-dose oral cyclophosphamide and methotrexate: BRAVCMPO
  • CMF regimens: BRAVCMFPO, BRAVCMF. Survival is better with the classic version of CMF (BRAVCMFPO) however toxicity is slightly better with the iv version (BRAVCMF)
Second and subsequent lines of therapy yield less rewarding results than first-line chemotherapy both in terms of degree and duration of tumour response. Toxicity can be greater due to prior therapy and more advanced disease state. The therapeutic gain is modest in many circumstances, but chemotherapy may relieve symptoms and therefore remains an important therapeutic tool. Chemotherapy can be safely and reasonably considered in patients with a performance status of 0-2, anticipated survival >3 months, and a previous response to at least one prior chemotherapy in metastatic disease.

Targeted Therapy

There is great interest in combining classic chemotherapy with target specific drugs. To date, targeting the ER receptor and the her2 receptor has resulted in the best survival and disease control benefit for metastatic breast cancer.

  • PARP inhibitors may have a particular role in cancers with BRCA1 or 2 mutations and are being explored in triple negative disease.23
  • Targeting the EGFR and ER receptor simultaneously may result in longer disease control among cancers that are both ER and her2 positive, however this approach is not superior to the combination of anti-her2 therapy with chemotherapy.16
  • Combining more than one anti-her2 therapy with chemotherapy in early treatment of metastatic her2+ disease appears to provide longer disease control.24
  • The combination of mTOR inhibition and modulation of the ER target may restore or prolong hormone sensitivity in some ER+ cancers.
  • Although VEGF inhibition has enhanced the disease control achieved with chemotherapy for some metastatic cancers, the appropriate subtype of breast cancer to treat with this combination is not yet clear.25,26
Bone Modifying Agents

Bone modifying drugs should be considered in women with metastatic breast cancer to bone, and/or presenting with hypercalcemia of malignancy. Patients should have necessary dental work done prior to initiating bone modifying agents to minimize the risk of osteonecrosis of the jaw.

Bisphosphonates have been shown to reduce the incidence of skeletal-related events in patients with metastatic breast cancer to bone. They reduce the rate and time to pathologic fracture, palliative radiation to bone, spinal cord compression, and need for surgical intervention, however they have not been shown to increase survival.27

Oral clodronate (BRAVCLOD) and intravenous pamidronate (BRAVPAM) are funded by BC Cancer for bone metastases. For hypercalcemia, iv pamidronate is recommended, with zoledronic acid as a second line agent if hypercalcemia is resistant to pamidronate. Zoledronic acid and denosumab (a RANK-ligand inhibitor) are also active in slowing the development of skeletal related events.28,29 The optimal duration of bisphosphonate therapy is not well defined30, but the Breast Tumour Group recommends a treatment period of two to three years.

Acute pain syndrome

IV pamidronate 90-120 mg iv over 2-4 hours can also provide dramatic pain relief in cases of acute pain syndrome.31 It should be followed by appropriately dosed narcotic analgesics and treatment of underlying disease if possible. Repeat use of pamidronate may be considered if after 1 week there is clear but only partial relief of the pain despite aggressive analgesics.

References

  1. Chu KC, Tarone RE, Kessler LG, et al. Recent trends in US breast cancer incidence, survival, and mortality rates. J Natl Cancer Inst 1996;21:1571-1579
  2. Klijn JG, Beex LV, Mauriac L, et al. Combined treatment with buserelin and tamoixfen in premenopausal metastatic breast cancer: a randomized study. J Natl Cancer Inst 2000; 92(11):903-11
  3. Klijn JGM, Blamey RW, Boccardo F, et al. Combined Tamoxifen and Luteinizing Hormone-Releasing Hormone (LHRH) Agonist versus LHRH Agonist alone in Premenopausal Advanced Breast Cancer: A Meta-Analysis of Four Randomized Trials. J Clin Onco 2001; 19 (2):343-53
  4. Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is Superior to Tamoxifen as First-Line Therapy for Advanced Breast Cancer in Postmenopausal Women: Results of a North American Multicenter Randomized Trial. J Clin Oncol 2000; 18:3758-3767
  5. Mourisden H, Gershanovich M, Sun Y, et al. Superior Efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001;19:2596-2606
  6. Paridaens RJ, Dirix LY, Beex LV et al. Phase III Study Comparing Exemestane With Tamoxifen As First-Line Hormonal Treatment of Metastatic Breast Cancer in Postmenopausal Women : The European Organisation of Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol 2008;26:1-8
  7. Lonning PE, Bajetta E, Murray R, et al. Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: A phase II trial. J Clin Oncol 2000; 18:2234-2244
  8. Baselga J, Campone M, Piccart M, et al. Everolimus in Postmenopausal Hormone-receptor-positive Advanced Breast Cancer. NEJM 2012;366:520-9
  9. Chia S, Gradishar W, Mauriac L, et al. Double-Blind, Randomized Placebo Controlled Trial of Fulvestrant Compared With Exemestane After Prior Nonsteroidal Aromatase Inhibitor Therapy in Postmenopausal Women with Hormone receptor-Positive, Advanced Breast Cancer: Results From EFECT. J Clin Oncol 2008;26:1664-1670
  10. Robertson JFR, Llombart-Cussac A, Rolski J, et al. Activity of Fulvestrant 500mg versus Anastrozole 1mg as the first line treatment of Advanced Breast Cancer: Results from the FIRST trial. J Clin Oncol 2009;27: 4530-4535
  11. Slamon D, Leyland-Jones B, Shak S, et al. Use of Chemotherapy plus a Monoclonal Antibody for Metastatic Breast Cancer That Overexpresses HER2. NEJM 2001;344:783-92
  12. Marty M, Cognetti F, Maraninchi D et al. Efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2 – positive metastatic breast cancer administered as first-line treatment: results of a randomized phase II trial by the M77001 study group. J Clin Oncol 2005;23:1-10
  13. Robert N, Leyland-Jones B, Asmar L, et al. Phase III comparative study of paclitaxel, trastuzumab and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 2006;24:2786-92
  14. Anderson M, Lidbink E, Bjerre K, et al. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol 2011;29: 264-271
  15. Kaufman B, Mackey JR, Clemens M, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast caner: results from the randomized phase III TAnDEM study. J Clin Onco 2009;27:5529-5537
  16. Johnston S, Pippen Jr J, Pivot X, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 2009;27:5538-5546
  17. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer : a German Breast Group 26/Breast International Groups 03-05 study. J Clin Oncol 2009;27:1999-2006
  18. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733-43
  19. Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 study. J Clin Oncol 2012;30:2585-92
  20. O’Shaughnessy J, Miles D, Vukekja S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002;20:2812-2823
  21. Chan S, Romieu G, Huober J, et al. Phase III study of gemcitabine plus docetaxel compared with capecitabine plus docetaxel for anthracycline-pretreated patients with metastatic breast cancer. J Clin Oncol 2009;27:1753-1760
  22. Albain KS, Nag SM, Calderillo-Ruiz G, et al. Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol 2006;25:3950-3957
  23. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer : a proof of concept trial. The Lancet 2010;376:235-244
  24. Baselga J, Cortes J, Kim S, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366:109-19
  25. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357:2666-2676
  26. Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor 2-negative metastatic breast cancer. J Clin Oncol 2010;28:3239-3247
  27. Pavlakis N, Schmidt RL, Stocker MR. Bisphosphonates for breast cancer. Cochrane Library online publication 16 Jul 2008
  28. Rosen LS, Gordon DH, Dugan Jr W, et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004;100:36-43
  29. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized double-blind study. J Clin Oncol 2010;28:5132-5139
  30. Van Poznak CH, Temin S, Yee GC, et al. American Society of Clinical Oncology Executive Summary of the Clinical Practice Guideline Update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol 2011;29:1221-7
  31. Portenoy RK, Lesage P. Management of cancer pain. The Lancet 1999;353:1695-1700


6.10. Radiation Therapy

Updated May 2022

6.10.1 Contraindications to Radiation Therapy

Radiation Therapy may be relatively or absolutely contraindicated in the following circumstances:

  1. Pregnancy
  2. Connective tissue disorders (systemic lupus erythematosus, scleroderma, etc.) with significant vasculitis. The use of radiation may not be contraindicated with all connective tissue disorders. 
  3. Significant pre-existing lung disease  if the diffusing capacity is severely reduced
  4. Prior radiation therapy to the same part
  5. Pacemaker in the radiotherapy field

6.10.2 Radiotherapy Planning and Prescription

Radiation Therapy Planning for Breast only radiotherapy:

  1. Indications: Patients with DCIS or node-negative (low-moderate risk) invasive breast cancer, treated with breast-conserving surgery, patients with locally recurrent node-negative disease who have not previously had radiotherapy (RT).
  2. Clinical Target Volume: For whole breast RT, the entire ipsilateral breast tissue should be included in the field. The lower axilla may be included if the patient has high-risk features, particularly if an axillary node dissection has not been done.  For external-beam PBI, a tumour bed to CTV expansion of 1 cm is recommended for cases with clear margins (> 2 mm) and cases with close or positive anterior margins (at skin) and/or posterior margins (at pectoralis fascia) that cannot be rendered negative with further surgery. For other cases with a boost indication, a tumour bed to CTV expansion of 1.5 cm is recommended.
  3. Dose: Fractionation:
    1. Standard whole breast RT prescription is 40 Gy in 15 daily fractions.
    2. Some patients may be eligible for whole breast short-course RT (refer to section 6.3.1.2) using 26 Gy in 5 daily fractions over 1 week.
    3. Certain patients are at risk for inferior cosmetic outcome. Extended fractionation could be considered for patients with very large breast size, and those with significant post-operative induration, edema, erythema, hematoma or infection. Patients with indications for extended fractionation could consider 50 Gy in 25 daily fractions or 50.4 Gy in 28 daily fractions.
    4. Patients eligible for partial breast RT (refer to section 6.3.1.2) can be treated using standard external beam radiotherapy (EBRT) dose of 40 Gy in 15 fractions, 26 Gy in 5 fractions, or with brachytherapy seed implants.
    5. If a boost is used, an additional dose of 10 Gy in 4 or 5 fractions or 16 Gy in 8 fractions is recommended.
  4. Technique: For whole breast RT, ordinarily a tangential pair of fields to encompass the anatomic extent of the breast is used.  Patients may be positioned in the supine or prone position.  Forward or inverse-planned tangential IMRT (sometimes referred to as multi-leaf collimator compensation) to improve dose homogeneity is recommended. For partial breast radiotherapy, EBRT using short tangents, 3D conformal radiotherapy, IMRT, or brachytherapy using seed implants can be used. 
  5. Overall treatment time: For EBRT, patients should be treated daily, Monday to Friday, for an interval of one to six weeks depending on the treatment recommended by the radiation oncologist.  If a 5-fraction course is used, no more than 3 days between fractions is recommended.  Breast brachytherapy is a one-day out-patient surgical procedure.
  6. Boost technique: The location of the boost may be guided by the presence of clips placed at the time of surgery or the post-operative seroma as contoured on the RT-planning CT scan.  Boost may be treated with a direct electron field or conformal/mini-tangent photon fields.
Radiation Therapy Planning for Breast/Chest wall + nodal radiotherapy:

  1. Indications: Patients with node-positive or high-risk node-negative invasive breast cancer
  2. Clinical Target Volume: Entire chest wall or ipsilateral breast and regional nodes. The regional nodal volume should include the supraclavicular and level 3 axillary nodes medial to the coracoid process. The axillary contents lateral to the coracoid process should be included if fewer than 10 nodes were recovered, or if there are bulky or N2-3 disease or significant extranodal spread in the fat of the axilla.  Treatment of the ipsilateral internal mammary chain (IMC) nodal region including the first three inter-costal spaces should be considered when the supraclavicular or axillary nodes are to be treated, and for those with inner quadrant or central tumours.  Studies demonstrating a survival impact from regional RT consistently included the IMC lymph node region in the treatment volume. Doing so increases the lung volume treated and for left-sided breast cancer, cardiac exposure.
  3. Dose: Fractionation:
    1. Standard whole breast dose is 40Gy in 15 daily fractions, chest wall dose is 40 Gy in 15 fractions, nodal dose is 37.5-40 Gy/15 fractions.
    2. After breast conserving surgery, extended fractionation should be considered for patients with very large breast size, and those with significant post-operative induration, edema, erythema, hematoma or infection. Recommended extended fractionation dose: 50 Gy in 25 daily fractions or 50.4 Gy in 28 daily fractions to the breast and 45 Gy in 25 fractions to the supraclavicular nodal region.
    3. After mastectomy, patients with significant postoperative infection, very large chest wall separation, and those undergoing reconstruction could also be considered for extended fractionation. Recommended extended fractionation dose: 50Gy in 25 daily fractions or 50.4 Gy in 28 daily fractions to the chest wall and 45 Gy in 25 fractions to the supraclavicular nodal region.
    4. For those with close or positive margins post-mastectomy, a higher chest wall dose (e.g. 42.5 Gy in 16 fractions) may be used, or a boost dose of 10Gy in 4 or 5 fractions or 16Gy in 8 fractions may be considered, if the anatomic area requiring the boost dose can be accurately delineated.
    5. For patients post-breast conserving surgery with close or positive margins, or young age, supplemental boost is recommended as described above in the T1T2 N0 Post "Breast Conserving Surgery" section.
  4. Technique: Ordinarily a mono isocentric 4-field technique to encompass the anatomic extent of the breast/chest wall and regional nodes will be used. Forward or inverse-planned tangential IMRT (sometimes referred to as multi-leaf collimator (MLC) compensation) to improve dose homogeneity is recommended. Inclusion of the IMC nodes may be achieved using a modified-wide tangent pair in addition to the nodal fields. Specialized techniques, such as multi-field IMRT and Deep Inspiration Breath Hold techniques may be necessary to minimize dose to normal tissues in certain patients.
  5. Overall treatment time: Patients should be treated daily, Monday to Friday, for an interval of three to six weeks.
  6. Boost technique post-BCS: The location of the boost may be guided by the presence of clips placed at the time of surgery or the post-operative seroma as contoured on the RT-planning CT scan. Boost may be treated with a direct electron field or conformal/mini-tangent photon fields.

6.10.3 Side Effects of Radiation Therapy

Updated: May 2022

Side effects of curative intent, adjuvant radiation therapy are directly proportional to the volume of the irradiated tissues. Since radiation therapy (except whole body radiation) is essentially a localized treatment, the side effects depend also on the anatomic location irradiated. The severity of side effects is directly related to the dose of radiation delivered and the time over which it is delivered.

  1. Skin - Mild to moderate erythema generally develops through the course of treatment but for the 5-fraction course of breast radiotherapy, the skin reaction is expected to occur after the completion of radiotherapy.   The skin reaction can continue to progress for eight to fourteen days following treatment after which it will subside quickly.  Dry desquamation or moist desquamation may occur in the axilla or in the inframammary fold, particularly in large breasted women.  Commonly, there may be late changes in the appearance or texture of the skin or soft tissue within the radiotherapy field, e.g. hyperpigmentation (tanned appearance), telangiectasias, or fibrosis. For acute skin reaction we recommend that patients use a water-based moisturizer regularly on the irradiated areas.  A steroid cream may be used over small areas where the reaction is particularly itchy, but without moist desquamation. Saline soaks may be used over areas of moist desquamation.  Read more about the care of radiation skin reactions here.
  2. Esophagitis - Patients undergoing nodal radiotherapy may experience mild esophagitis, typically described by patients as mild difficulty swallowing or a feeling of a "lump in the throat.  Medication is occasionally required for symptom relief. 
  3. Fatigue - A variable amount of generalized tiredness may begin after the first one to two weeks of treatment and last for several months thereafter. The cause is not known. Resting appropriately, reducing stress, and doing moderate exercise (e.g. a daily walk) can also improve fatigue.
  4. Lung - Some part of the lung is always irradiated in patients undergoing breast/chest wall/nodal radiotherapy. The amount of irradiated lung is the least in the "breast only" tangent pair technique and is maximal when nodal areas are irradiated.  Subacute pneumonitis is uncommon. Patients with subacute pneumonitis will typically present with dry cough or shortness of breath, often with accompanying radiologic changes, 6 weeks to 6 months after the completion of radiotherapy. Patients who are symptomatic may need treatment with steroids (prednisone 30-50 mg daily for two weeks and then very slowly tapered over the next few weeks). Late radiologic changes of radiation fibrosis are common but symptoms from this are rare.
  5. Heart - Symptomatic cardiac toxicity with current techniques is rare, but patients treated with left-sided regional radiation, especially those treated using older techniques, have a slightly increased risk of coronary artery disease. There is also a small risk of acute or subacute pericarditis.
  6. Musculoskeletal - Occasionally, radiotherapy may cause mild pain or discomfort in the breast/chest wall or shoulder. Radiotherapy to the breast/chest wall is associated with a 1% risk of a rib fracture. Radiotherapy to the axilla increases the risk of lymphedema in the ipsilateral arm. There is also a very small risk of brachial plexopathy secondary to radiotherapy to the axilla.
  7. Second Malignancy – There is a very small risk of second malignancy after radiotherapy. These tumours are typically soft-tissue sarcomas or lung cancer, and usually will occur 7-10 years after radiotherapy.
  8. Radiation Recall – Radiation recall is a rare phenomenon where patients who have received radiation therapy and subsequently need certain types of chemotherapy (for example Adriamycin) may have a "recall" of the radiation reaction

6.11. Special Circumstances

6.11.1 Breast Cancer in Pregnancy

Updated November 2004
Since breast cancer is the most common tumour occurring in women during the reproductive years, carcinoma of the breast in pregnancy does occur and presents special management problems. It is, fortunately, relatively unusual and each case deserves consideration on its own merits with referral to multidisciplinary conference. It is extremely important to assess the potential for cure in an individual patient. The welfare of the patient and the fetus needs to be evaluated. 

New suspicious localized breast masses should undergo evaluation with mammography and ultrasound. Core biopsy should be carried out if indicated.  Mammography can be performed utilizing abdominal and pelvic shielding. Breast MRI cannot be carried out due to the need for gadolinium. If metastatic staging is indicated, consideration should be given for chest radiograph with fetal protection, ultrasound assessment for liver lesions, and non-contrast MRI of the thoracic and lumbar spine.

1) Stage I or II

First Twelve Weeks

Surgery can be carried out safely during pregnancy. However, consideration may be given for therapeutic abortion to allow for timely treatment and should be considered on an individual basis. In this scenario, the treatment of the malignancy will then proceed as in the non-pregnant state. Patients who continue with the pregnancy commonly undergo mastectomy. Breast conserving therapy is possible if radiation therapy can safely be deferred to the post-partum period.  Axillary staging should be carried out (see below) in accordance with recommendations in the non-pregnant state.

No adjuvant radiation therapy should be given during pregnancy. Chemotherapy with AC chemo has been given in this situation, but is avoided if possible, unless the risks of withholding chemo outweighed the risks to the fetus. Referral is recommended to assess the need for further treatment after the baby has been delivered.

Twelve to Twenty-eight Weeks

During this interval the breast cancer can be adequately treated surgically without terminating pregnancy. Patients may undergo breast conserving surgery or mastectomy. Axillary staging should be carried out. (see below). Adjuvant radiotherapy is contraindicated during pregnancy. The risk of recurrence should be estimated based on the pathology of the tumour. If the risk of relapse is high then adjuvant chemotherapy may be given. Cyclophosphamide and doxorubicin with or without 5-fluorouracil is the preferred combination during pregnancy. Epirubicin and taxanes should be avoided. Tamoxifen exposure in the first and second trimesters may be associated with genitourinary abnormalities and therefore should be avoided. Referral of these patients for assessment is recommended.

Twenty-eight Weeks to Term

Maturity of the fetus should be assessed. Consideration should be given to inducing labour as soon as obstetric advice indicates that the fetus is viable.  Surgical treatment (breast conserving surgery or mastectomy +/- axillary staging, see below) should be carried out. As soon as the fetus has been delivered the patient should receive additional treatment as for the non-pregnant state. Chemotherapy may be given during pregnancy (see above), but in most circumstances is delayed until after delivery.

Axillary Staging in Pregnancy

Radiolabelled technetium colloid appear to be safe in pregnancy and sentinel lymph node biopsy may be carried out using technetium-99 with avoidance of blue dye. However, breast lymphatic drainage may be altered in pregnancy and the sensitivity and specificity of SLNB have not been established in this setting. Safety data were derived from limited case reports and series.  Thus, there is insufficient data for a strong recommendation for its use during pregnancy and should be discussed on an individual basis.

Lactation

When a carcinoma arises during lactation, lactation should be terminated and therapy appropriate for the treatment of the malignancy instituted.

2) Locally Advanced or Inflammatory Breast Cancer

Patients with advanced disease pose a special problem. In the early weeks of pregnancy, consideration has to be given to termination of the pregnancy. If the patient is in the second trimester and is still hoping to deliver a viable child then chemotherapy with drugs least likely to harm the fetus may be considered (see above). Referral to BC Cancer is recommended. Radiotherapy is contra-indicated except in exceptional circumstances.

6.11.2 Cancer of the Male Breast

Updated: February 2016

Cancer of the male breast is uncommon, about one percent of all breast cancers. Investigation of breast cancer in the male is identical to that of the female patient, including mammography as an initial investigation.

Because the male breast is very small, mastectomy has commonly been carried out. Recommendations for axillary staging in the male remain the same as that for female patients. Pathologic assessment for tumour characteristics and hormone receptor status is identical to that in females. Local resection (i.e. lumpectomy) combined with radiation may be possible and should be discussed at multidisciplinary conference. The indications for post mastectomy radiation for males are the same as those for females (i.e. in those with T3/T4 or node-positive disease).

There are no series of male patients, which have been adequately studied in regard to adjuvant systemic therapy. However, experience demonstrates that the clinical behaviour of male and female breast cancers are very similar. Because of this, adjuvant hormonal or chemotherapeutic recommendations are the same, stage-for-stage, as for a woman of the same age. The role of aromatase inhibitors and fulvestrant in males has not been established. Orchiectomy or LHRH may provide a response after progression on tamoxifen in the metastatic setting.

6.11.3 Considerations for Young Women with Breast Cancer  

Breast cancer in young women (less than 40 years of age) requires additional consideration for issues specific to this patient population. Multidisciplinary care is strongly recommended. 

In general, overall management should not significantly differ in terms of surgical options and adjuvant treatment recommendations when compared to women > 40 years of age. Of note, neoadjuvant endocrine therapy is typically not recommended for young women and aromatase inhibitors are not recommended in pre-menopausal women. 

Specific considerations:

  1. Pregnancy-associated breast cancer
    • a. See specific section
  2. Fertility Preservation
    • a. All young women with a breast cancer diagnosis and the desire for future children should be referred to a fertility specialist prior to the initiation of any therapies
    • b. Options for fertility preservation include:
      • i. GnRH analogues during chemotherapy
      • ii. Oocyte/embryo cryopreservation
      • iii. Ovarian tissue freezing 
  3. Pregnancy after Breast Cancer 
    • a. Women should complete the recommended length of their treatments before trying to conceive
    • b. The risk of relapse due to stopping treatment prematurely should be discussed and weighed against patient’s desire for children and risk of delaying pregnancy. 
    • c. A treatment free interval after chemotherapy and/or endocrine therapy should be recommended to allow for potentially harmful agents to be eliminated from the system before pregnancy. Patients should communicate with their physicians early on if they are planning to get pregnant to allow for a coordinated plan. 
    • d. This issue is discussed more fully in section 7.2.5 (LINK to this section)
  4. Contraception before, during and after treatment
    • a. Contraception is strongly recommended during treatment for all young women with breast cancer, as amenorrheic women may still be fertile, and pregnancy is generally a contraindication to adjuvant treatment. 
  5. Effect of Surgery and Adjuvant therapies on Lactation and Breast-feeding
    • a. Breast-feeding after treatment can still be completed
    • b. Milk production may be reduced from a breast that has undergone surgery and radiation. Feeding from the opposite breast should be encouraged. Breast-feeding after bilateral mastectomies will not be possible. 
    • c. Women should be off any chemotherapy or endocrine medications during breast-feeding. 
  6. Desire for Breast Reconstruction
    • a. A higher proportion of young women opt for breast reconstruction if they are undergoing mastectomy. Referral to a plastic surgeon is recommended for either immediate or delayed reconstruction. 
  7. Side effects of adjuvant therapies to address:
    • a. Pre-mature menopause
    • b. Lymphedema
    • c. Bone Health
    • d. Sexual function and identity
    • e. Cognitive impairment
  8. Genetics
    • a. A majority of young women with breast cancer qualify for genetic counselling and subsequent genetic testing. Referral is recommended. 
  9. Psychosocial support
    • a. Additional supports may be required in terms of financial support due to inability to work, counselling for relationships with spouse and children and community supports for childcare, etc. Referral to a counsellor or support group is recommended. 
  10. Clinical trials/Research Studies
    • a. An increasing number of studies are being completed for young women with breast cancer. Identification of appropriate trials or studies for patients should be attempted
References

  1. Cardoso F, Loibl S, Pagani O, Graziottin A, Panizza P, Martincich L, Gentilini O, Peccatori F, Fourquet A, Delaloge S, Marotti L, Penault-Llorca F, Kotti-Kitromilidou A, Rodger A, Harbeck N. The European Society of Breast Cancer Specialists recommendations for the management of young women with breast cancer. 2012 October 2012. 
    https://www.eusoma.org/en/recommendations/other-guidelines/the-european-society-of-breast-cancer-specialists-recommendations-for-the-management-of-young-women-with-breast-cancer/1-396-1-
  2. Partridge AH, Pagani O, Abulkhair O, Aebi S, Amant F, Azim HA Jr, Costa A, Delaloge S, Freilich G, Gentilini OD, Harbeck N, Kelly CM, Loibl S, Meirow D, Peccatori F, Kaufmann B, Cardoso F. First international consensus guidelines for breast cancer in young women (BCY1). Breast. 2014 Jun;23(3):209-20. doi: 10.1016/j.breast.2014.03.011. Epub 2014 Apr 24. http://www.thebreastonline.com/article/S0960-9776(14)00055-1/pdf 

6.11.5 Consideration in the management of the Elderly

6.11.4 Older Patients 

There are additional considerations when managing older patients. Many older patients have comorbidities that increase their risk from surgical procedures or from systemic therapy,and may have contraindications to radiotherapy. As a result of these factors, older patients are less likely to be offered standard treatment for breast cancer, which may negatively affect survival.1 

Randomised trials of adjuvant radiotherapy after lumpectomy in older women with Stage 1 (T1N0M0), ER + breast cancer undergoing a 5-year course of tamoxifen have shown that radiation therapy is associated with the same relative reduction in local recurrence as in younger women, reducing the risk of local recurrence by 2/3 – ¾. In this population, however, the baseline local recurrence risk is significantly lower, e.g. 6-10% at 10 years, resulting in a much lower absolute benefit. In this cohort, in women with very low-risk tumours, breast conserving surgery and hormonal therapy, without adjuvant radiotherapy, is a viable option that likely has similar survival.2,3,4,5

Many randomized chemotherapy studies excluded older patients, which makes it difficult to extrapolate what the benefit is in this cohort. Given that older patients may not tolerate chemotherapy as well as younger patients due to limited bone marrow reserve and comorbidities, careful consideration must be given to weigh the risks and benefits of chemotherapy. Hormonal therapy alone often provides excellent results in this cohort. 

Multidisciplinary discussion for the management of these patients is encouraged.  

References

  1. Hans Wildiers, Ian Kunkler, Laura Biganzoli, et al.  Management of breast cancer in elderly individuals:  recommendations of the International Society of Geriatric Oncology.  Lancet Oncology Vol 8 December 2007
  2. Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 2004;351: 971–77.
  3. Hughes, Kevin S.; Schnaper, Lauren A.; Bellon, Jennifer R.; Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343.  Journal of Clinical Oncology (2013), 31(19), 2382-2387
  4. Fyles AW, McCready DR, Manchul LA, Trudeau ME, Merante P, Pintilie M, et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med. 2004 Sep 2;351(10):963-70.
  5. Kunkler IH, Williams LJ, Jack WJ, Cameron DA, Dixon JM; PRIME II investigators. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol. 2015 Mar;16(3):266-73. doi: 10.1016/S1470-2045(14)71221-5. Epub 2015 Jan 28

6.11.5 Unusual Histologies

Paget’s Disease of the Breast

Management of Paget disease of the breast is discussed in Section 6.2 "In Situ Disease". In summary, women with Paget’s disease of the nipple-areolar complex should be thoroughly investigated as the majority of patients have an associated in situ or invasive breast cancer that is managed in accordance to the in situ/invasive breast cancer component, as well as therapy directed for the treatment of Paget disease. 

Variants of Invasive Breast Cancer

There are a number of pathologic variants of invasive breast cancer that are treated the same way as described above for more common invasive ductal or lobular breast cancer, not otherwise specified (NOS).

Tubular, mucinous (colloid), cribriform, and medullary carcinomas are all variants of invasive ductal carcinoma, that generally hold a more favourable prognosis. Micropapillary carcinomas tend to be more aggressive, and are more frequently associated with axillary nodal metastases. As with more common invasive ductal carcinomas NOS, patients with any of these pathologies should be managed initially surgically, with appropriate nodal staging and adjuvant therapy as described above.

Metaplastic tumours

Metaplastic tumours are tumours that are comprised of more than one histology, specifically high-grade invasive ductal adenocarcinoma plus either sarcomatous and/or non-glandular epithelial components (e.g. squamous cell carcinoma). These tumours may metastasize through the lymphatic system, and therefore require axillary sampling (e.g. with sentinel node biopsy). These tumours are typically estrogen and progesterone receptor negative and her-2-neu negative, and appear to be more aggressive than common invasive ductal carcinomas. It is possible that they do not respond as well as typical invasive ductal carcinomas to standard adjuvant therapy. In spite of this, patients with this histology should be managed with mastectomy or breast conserving surgery with axillary staging, plus adjuvant radiation and systemic therapy as described above for more common invasive ductal carcinomas, NOS. 

Phyllodes Tumours of Breast (Cystosarcoma Phyllodes)

Updated February 2017

These uncommon sarcomas of the female breast arise from the stromal elements. Clinically and on imaging, they may appear very similar to fibroadenomas, although large size and rapid development or growth of the lesion should raise clinical suspicion. Histologically they may be categorized as benign, borderline, or malignant. Adenocarcinoma may co-exist and therefore pathology review of these tumours is recommended. A phyllodes tumour should be suspected if a fibroadenoma is "recurrent."

The mainstay of treatment of Phyllodes tumours is surgical excision.1,2,3,4  Specimens should be inked so their margins can be assessed for involvement by tumour. If the lesion is deep in the breast, the excision must include fascia. NCCN currently recommends a surgical procedure with the intention of obtaining a 1 cm margin.  

More recent studies4,5,6,7 are showing little difference between closer margins and widely clear margins for malignant, borderline, and benign tumours and this has also been found when reviewing provincial data.8 Factors that suggest an increased recurrence rate in recent studies include tumour on inked margin, size of tumour, grade of tumour, stromal overgrowth, infiltrating borders, heterologous sarcomatous differentiation, malignant epithelial transformation and increased mitoses.4,5,6,7,8 All of these factors should be considered in assessment of adequate margins. A pathology review and referral to BC Cancer may be helpful. 

As lymph node metastases are rare, in the absence of adenocarcinoma elements, axillary node dissection is not recommended. Local recurrences may predict for development of metastases even in patients with "benign" disease. Metastases are generally to lung, although bone and liver involvement may occur. 

Patients with more aggressive histology may be offered radiation therapy to improve local control rates. There is no known role for chemotherapy in the adjuvant setting.

References

  1. Barrio A, Clark B, Goldberg J, et al. Clinicopathologic features and long term outcomes of 293 phyllodes tumors of the breast.  Ann Surg Oncol 2007;14:2961-2970.
  2. Guillot E, Couturanud B, Reyal F et al. Management of Phyllodes breast tumors. Breast J 2011;17:129-137.
  3. Kim S, Kim Y, Kim d, et al. Analysis of phyllodes tumor recurrence according to the histologic grade. Breast Cancer Res Treat. 2013;14:353-63.
  4. Onkendi E, Jimenez R, Spears G, et al.  Surgical Treatment of borderline and malignant phyllodes tumors:  the effect of the extent of resection and tumor characteristics on patient outcome.  Ann Surg Oncol  2014; 21:3304-3309.
  5. Jang J, Choi M, Lee S, et al. Clinicopathologic Risk Factors for the local recurrence of Phyllodes tumor of the breast. Ann Surg Oncol 2012; 19: 2612-2617
  6. Kaveh  Borhani-Khomani   MS, Maj-Lis Møller Talman MD, Niels Kroman MD, DMSc, Tove Filtenborg Tvedskov MD, PhD Risk of Local Recurrence of Benign and Borderline Phyllodes Tumors: A Danish Population-Based Retrospective Study. Breast Oncology Volume 23, Issue 5 / May , 2016
  7. Yom C, Han W, Kim S et al   Reappraisal of Conventional Risk Stratification for Local Recurrence Based on Clinical Outcomes in 285 resected Phyllodes Tumors of the breast.  Ann Surg Oncol (201) 22:2912-2918.
  8. Rodrigues MF, Truong PT, McKevitt EC, Weir LM, Knowling MA, Wai ES. Phyllodes tumours of the breast: the British Columbia Cancer Agency experience. In Press, Cancer Radiotherapie


7.1 Follow-up Care

Updated October 2015

The follow-up of patients who have been treated with curative intent for breast cancer has four main goals:

  1. Detection of local, regional, or distant recurrence
  2. Screening for a new breast cancer
  3. Enhancing adherence to hormone therapy (if applicable)
  4. Monitoring for and treating late or residual side effects of therapy
All patients who have undergone curative treatment for breast cancer should be seen by a physician every 6 months until 5 years from diagnosis, then annually for a careful history and physical examination including examination of the nodal regions of the head, neck and axilla, breast/chest wall, heart, lung, spine, and abdomen.1 Patients with residual breast tissue should have annual diagnostic mammography to facilitate early detection of any subsequent new ipsilateral or contralateral breast cancer or recurrence.

1. Detecting Recurrences

Regular history and physical examination plus annual mammography should aid in early detection of local, regional, or distant metastases. In addition to regular follow-up, patients are encouraged to seek medical attention between scheduled visits if they develop unexplained and new, persistent symptoms. In the absence of concerning signs or symptoms, no lab or imaging tests, other than annual mammography, are recommended to monitor for recurrence. Detection of asymptomatic metastases by periodic scheduled investigations has not been shown to increase survival or quality of life.2 Instead, clinicians should maintain a low threshold for promptly investigating any new concerning sign or symptom, even if the likelihood that breast cancer has recurred is low. Patients who have been discharged to their primary care physician for follow up can/should be referred back to their oncologist if concern or confirmation of recurrence arises.

Recurrences of triple negative cancer occur most frequently within the first five years following diagnosis and plateau at about 7 years. Hormone receptor breast cancers continue to recur over time, out to and beyond ten years. Her2 positive cancers that are hormone receptor negative appear to have a relapse pattern similar to triple negative cancers, and those that are hormone receptor positive behave more like their her2 negative, hormone receptor positive counterparts. 

Location of Recurrence

Selected recurrences have the potential to be cured with appropriate therapy. These include:

  • Local recurrence in a breast, which was previously treated by partial mastectomy and axillary node dissection [with or without radiation therapy].
  • Local recurrence on the chest wall (and occasionally in the regional nodes) following mastectomy.
  • Limited regional recurrence, particularly if resectable and no prior history of nodal radiotherapy 
  • Isolated solitary or oligo brain metastases following adjuvant therapy of her2+ breast cancer.
Ideally, patients with these types of recurrences should be assessed by a multidisciplinary team to determine curability and plan overall management. If thought to be curable, patients should be treated with surgical excision and radiotherapy (if applicable) for curative intent. A recent study suggests that chemotherapy following local management of local and regional recurrences may improve overall survival and cure rate.3 

The most common sites of distant metastases are bone, brain, liver, or lung. These are generally treatable but not curable. Aggressive local therapy may improve long-term survival in select cases with limited burden of metastases. Initial assessment and management by a multidisciplinary team, including the palliative care team as appropriate, is ideal for patients with metastatic disease. 

2. Screening for Contralateral Breast Cancer

A new primary malignancy in the contralateral breast occurs at a rate of approximately 0.5% to 1% per year. The average 50 year old woman who has had breast cancer once carries approximately a 10-15% risk of a second contralateral breast cancer (invasive or DCIS) over the next 25 years.4 Adjuvant hormone therapy will reduce this risk.

Women who have confirmed BRCA2 and BRCA1 mutations and a prior breast cancer carry approximately 35% and 45% risk of a second breast cancer over 25 years respectively, if they do not have bilateral mastectomies or oophorectomy.5 They are also at increased risk of ovarian cancer. Women with confirmed BRCA1 and/or 2 mutations should be referred to the high-risk hereditary cancer surveillance program for breast cancer screening with annual MRI followed every six months by mammography.

3. Hormone Therapy Compliance

Patients taking hormone therapy are typically advised to take hormone therapy for 5-10 years after initial treatment. Numerous population-based studies report poor long-term compliance with hormone therapy following early breast cancer, even when a patient does not have to pay for the drug.6 Lack of adherence is associated with poorer survival.6 Physicians should take the opportunity at each visit with a breast cancer patient to ask about adherence to hormone therapy, and explore reasons behind non-compliance. Patients should be reminded of the benefits of adherence in terms of risk reduction for recurrence and contralateral new disease. Means to reduce side effects should be explored when they are a hindrance to adherence.

4. Long Term Side Effects

Long-term side effects may occur as a result of any part of management of breast cancer. Life-threatening late side effects are extremely rare, but many survivors of breast cancer experience side effects that can significantly affect their quality of life, both in the short and long-term. The type and severity of these side effects vary according, in part, to the type of therapy that have been given.

A number of late or chronic side effects are possible from chemotherapy, including early menopause, bone loss, chronic neuropathy, cognitive changes, congestive cardiomyopathy, and secondary leukemia. As a consequence of surgery and radiation, patients may experience long-term intermittent breast or chest wall pain, shoulder pain and reduced range of motion, lymphedema, lung fibrosis, rib fracture, second malignancy of the irradiated area and chest wall/axillary dysesthesia. Hormone therapy can be associated with hot flashes, vaginal dryness or atrophy, depression, postmenopausal bone loss, joint pain, and hyperlipidemia. 

There can be great value to detecting these side effects, as some may be amenable to therapeutic intervention if particularly symptomatic. Discussion of management of post-menopausal symptoms, lymphedema, and osteoporosis are discussed below. 

References

  1. Smith TJ, Davidson NE, Schapira DV, et al. American Society of Clinical Oncology 1998 update of recommended breast cancer surveillance guidelines. J Clin Oncol 1999; 17:1080-1082
  2. Grunefeld E, Mant D, Yudkin P, et al. Routine follow-up of breast cancer in primary care: randomized trial. BMJ 1996: 313: 665-669
  3. Aebi S, Gelber S, Lang I, et al. Chemotherapy prolongs survival for isolated local or regional recurrence of breast cancer: the CALOR trial (chemotherapy as adjuvant for locally recurrent breast cancer; IBCSG 27-02, NSABP B-37, BIG 1-02). Cancer Treatment 2012: 24 suppl 3: abstract S3-3
  4. Gao X, Fisher SG, and Emami B. Risk of second primary cancer in the contralateral breast in women treated for early stage breast cancer: a population based study. Int J Radiat Oncol Biol Phys 2003; 56:1038-45
  5. Metcalfe K, Lynch HT, Ghadirian P, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2004; 22:2328-2335
  6. Hershman DL, Shao T, Kushi LH, et al. Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Breast Cancer Res Treat 2011; 126:529-537
  7. Partridge AH, LaFountain A, Mayer E, Taylor S, Winer E, Asnis-Alibozek A. Adherence to initial adjuvant anastrozole therapy among women with early-stage breast cancer. J Clin Oncol 2008; 26: 556-562

7.2 Other Post-treatment Issues

7.2.1 Second Cancers

In addition to the recognized increase in risk of developing a carcinoma of the contralateral breast, patients who have had breast cancer have a statistical increase in their risk of developing sarcoma of the breast/chest wall if treated with radiotherapy, carcinoma of the colon, carcinoma of the endometrium, and carcinoma of the ovary. The family physician should be aware of these possibilities in the follow-up of patients with breast cancer and should ask about corresponding signs or symptoms during the annual history.

7.2.2 Contraception

Ideally, patients who have been treated for breast cancer should avoid contraception that includes a hormonal manoeuvre. If a patient with a history of breast cancer requires contraception, then tubal ligation could be considered. Other options include non-hormonal contraception, such as a barrier techniques or an IUD.

7.2.3 Hormone Replacement Therapy After a Diagnosis of Breast Cancer

The Breast Tumour Group of BC Cancer has had a number of discussions regarding the use of hormone replacement therapy (HRT) after a diagnosis of breast cancer. The traditional dogma has been that any use of hormones in patients with a personal history is contraindicated. This is based on the epidemiology of primary breast cancer, which reports an increased incidence of breast cancer in postmenopausal women exposed to long-term estrogen replacement therapy.1 As well, a recent study has confirmed that HRT using a combination of progesterone and estrogen is also associated with an increased risk of developing breast cancer.2

There is no direct evidence that estrogen causes recurrence in women with a previous history of cancer, but there is evidence of a decreased recurrence rate when women with a history of breast cancer are treated with Tamoxifen or after oophorectomy. Concerns about doing harm and contributing to incurable breast cancer recurrences have limited the use of estrogen replacement in these women. However, we are seeing an increased number of young women with early breast cancer and a relatively good prognosis, who are experiencing early menopause after adjuvant chemotherapy. As well, through screening mammography, we are identifying large numbers of older women with highly curable breast cancer.

At this time, there is no good information on the risks of giving hormone replacement therapy to women after a diagnosis of breast cancer. There are a number of series reported in the literature, which are not helpful because the studies are too small and have very short follow-up.3,4,5,6 Although there are plans for large randomized studies of women with a history of breast cancer to assess the risks and benefits of hormone replacement therapy, this data will not be available for many years.

Without evidence of safety our general policy has been to do no harm and therefore to not risk prescribing HRT to women with a previous history of any breast malignancy if there are other therapeutic options that can result in similar outcomes. Although there is evidence that HRT can improve bone health and conflicting evidence for cardiac health, there are often other therapies and lifestyle changes that can also be of benefit and should be considered as the first options in women with a history of breast cancer. 

Non-hormonal Therapies

  1. Hot Flushes: Hot flushes may be particularly noticeable in the first few months after cessation of chemotherapy or the start of hormonal therapy.  These hot flushes may decrease over time, and patients may consider avoiding other therapy, at least initially. Avoidance of triggers for hot flushes may be helpful, including avoidance of caffeine (coffee or tea), chocolate, alcohol, colas, stress, hot weather. Medications that have been shown to be effective for some women include venlafaxine (Effexor) (lowest effective dose of 37.5 mg/day), clonidine (Dixarit) (0.05 mg bid), and gabapentin (Neurontin) (900 mg/day). 
  2. Vaginal Irritation/Dyspareunia: Non-hormonal, water-soluble moisturizers or lubricants applied directly to the vagina (e.g. Replens vaginal suppositories, or introitus, and/or penis, e.g. KY Jelly, may improve daily irritation or dyspareunia). 
  3. Heart disease: There is controversy over the role of hormone replacement and the prevention of heart disease. Maintenance of appropriate weight through diet and exercise, avoidance of smoking and management of hypertension and cholesterol may be of major benefit.
In situations where there is a greater health risk from the non-breast cancer disease and there are no other options, the woman should be informed of the situation clearly and an individual decision to use HRT may be appropriate. Similarly, if there are symptoms that interfere significantly with a woman's quality of life (i.e. troublesome hot flashes, vaginal dryness, vaginal atrophy, dyspareunia, sleep disturbances, depression) and there are no other therapeutic options, HRT can be considered. For vaginal complaints, topical estrogens using as low a dose as possible, may be considered. In all situations the woman must be fully informed about the risks, benefits, and areas where we are lacking in clear information, and the use of HRT monitored and for a limited duration.

The role of HRT in women with a known genetic mutation in BRCA1 or BRCA2 causing an increased risk of breast or ovarian cancer is also unknown. There is evidence that oral contraceptives may be of value in decreasing the incidence of ovarian cancer.7 It is not clear if either oral contraceptives or HRT affects the incidence of breast cancer in carriers of BRCA1 or BRCA2 mutations. Women with BRCA1 or BRCA2 mutations should be assessed by the Hereditary Cancer Program to discuss these issues.

In summary, the role of HRT in women with a history of breast cancer is unknown. If there are options for other therapies they should be used. Research may give us new insights in the next few years. If there are patients that need further assessment, please consult their oncologist. If HRT is used, it is advisable to prescribe the lowest dose of estrogen to relieve symptoms, to monitor the patient carefully and to consider short-term use until long-term data is available.

References

  1. Collaborative Group on Hormonal Factors in Breast Cancer. Breast Cancer and hormone replacement therapy: collaborative re-analysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997; 350: 1047-1058.
  2. Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000; 283: 485-491.
  3. Powles TJ, Hickish T, Casey S; Hormone replacement after breast cancer. Lancet: 1993; 342: 60-61.
  4. Stoll BA. Hormone replacement therapy in women treated for breast cancer. Eur J Cancer 1995; 25: 1909-1913.
  5. Disaia PJ. Estrogen replacement therapy for the breast cancer survivor; A reappraisal. J Surg Oncol 1997: 64; 175-80.
  6. Eden JA. A case controlled study of combined continuous estrogen-progestin replacement therapy among women with a personal history of breast cancer. Menopause 1995; 2: 67-72.
  7. Narod SA, Risch H, Moslehi R et al Oral contraceptives and the risk of hereditary ovarian cancer. NEJM 1998; 339: 424-427.

7.2.4 Patient Guidelines for the Prevention of Osteoporosis in Women

Revised 9 March 2011

Postmenopausal women have an increased risk of osteoporosis. As well, this risk can be increased further by factors such as family history, smoking, diet, early menopause, chemotherapy, long term corticosteroids and some hormonal therapies that lower estrogen.

The following guidelines are provided to patients to reduce the risk of bone loss during and after treatment. If a patient’s bone density scan at the start of treatment indicates that she or he are at increased risk of osteoporosis, medications such as bisphosphonates (eg. alendronate (Fosamax®) should be considered.  In addition, the following guidelines regarding management/prevention of osteoporosis, including information about optimal consumption of Calcium and Vitamin D, encouragement of weight-bearing exercise, avoidance of excessive caffeine and salt, and smoking cessation should be given to the patient. 

Calcium & Vitamin D

Calcium and vitamin D are essential for strong bones. A daily dose is the sum of what you consume from food sources and from supplements. The recommended daily intake for calcium is 1200 mg. A daily supplement of 1000 IU of vitamin D is recommended for bone health and the prevention of cancer, in all women.

Food Sources of Calcium

Food SourcePortion Size
Calcium (mg)
Cheese (Swiss)
50 g (2 oz)
440
Cheese (Cheddar/Mozzarella)
50 g (2 oz)
390
Milk (skim, 1 or 2% MF or whole)
250 mg (1 cup)
300
Buttermilk, or Chocolate milk
250 ml (1 cup)
300
Yogurt, plain
175 ml (3/4 cup)
300
Milk powder, dry
45 ml (3 Tbsp)
280
Fortified Beverages (soy, rice, orange juice)
250 ml (1 cup)
300
Blackstrap Molasses
15 ml (1 Tbsp)
180
Parmesan Cheese
15 ml (1 Tbsp)
90
Sardines, with edible bones
24 mg
90
Cottage cheese, 2% MF
125 ml (1/2 cup)
80
Figs, dried, uncooked
3
80
Orange, raw
1 medium
50
Broccoli, frozen, boiled, drained
250 ml (1 cup)
50

Adapted from the Manual of Clinical Dietetics, 6th Edition (p.746-747), by American Dietetic Association et al, 2000.

Calcium intake from all sources should not exceed 2000 mg per day.

Food Sources of Vitamin D

Food SourcePortion Size
Vitamin D (IU)
Fish, herring
100 gm (3 oz)
900
Fish, mackerel or salmon
100 gm (3 oz)
650
Fish, sardines or tuna
100 gm (3 oz)
250
Milk or Soy Beverage, fortified
250 ml (1 cup)
90
Margarine, fortified
5 ml (1 tsp)
55
Egg
1 large
25

Adapted from the Manual of Clinical Dietetics, 6th Edition (p.746-747), by American Dietetic Association et al, 2000.

Vitamin D intake from all sources should not exceed 4000 IU per day.

Vitamin and Mineral Supplements

If you can't meet the recommended amounts with food alone, consider a supplement. Calcium carbonate is the least expensive calcium supplement and is well tolerated by most people when taken with food. The absorption of calcium from supplements is most efficient at doses of 500 mg or less. Some calcium supplements also include vitamin D (check the label for the exact amount). A standard multivitamin and mineral supplement provides approximately 175 mg of calcium and 400 IU of vitamin D and other nutrients.

Protein

Adequate protein is required to maintain bone health. Include one of the following protein rich foods at each meal: meat, fish, poultry, beans, lentils, nuts, eggs, milk, yogurt and cheese.

Caffeine and Salt

Excess caffeine and salt can have a negative effect on bone. Caffeine is found in coffee and also tea, chocolate (cocoa) and some soft drinks. For optimal bone health, limit coffee to less than 4 cups per day.

Foods high in salt generally include processed foods such as canned soups, snack foods, crackers, pastas and sauces. Check the nutrition label on processed foods and limit salt to less than 2100 mg per day.

Physical Activity

Being physically active maintains optimal bone health and decreases the risk of a bone fracture by improving bone mass and increasing muscular strength, coordination and balance and thereby reducing falls. Physical activity that is weight bearing is best, examples include walking, dancing, aerobics, skating and weight lifting.

Smoking

Smoking is related to poor bone and general health. If you smoke, ask your doctor for assistance to stop smoking.

Developed by BC Cancer Breast Tumour Group, 14 Oct. 2004; Revised March 2011

7.2.5 Pregnancy Following Breast Cancer

The literature suggests that pregnancy after a carcinoma of the breast is not hazardous. It is however recommended that patients be advised to delay pregnancy. The length of the delay depends upon two factors, the initial stage of the disease and thus the probability of the development of metastatic disease and the age of the patient at the time of diagnosis.

The greatest incidence of both locoregional recurrence and distant metastases occurs within the first two years following diagnosis and treatment. It would appear that for women in their thirties desirous of a subsequent pregnancy a delay of two years should be recommended. For very young women with breast cancer a delay of five years may be more appropriate since the chance of developing metastatic disease is much reduced after such an interval and child bearing potential is probably not significantly adversely affected. As well, pregnancy while on Tamoxifen is contraindicated.  Survivor preferences and medical indications must be balanced for individualized decisions regarding the optimal time to become pregnant after treatment of breast cancer. 

7.2.6 Lymphedema

Updated 5 March 2007

These guidelines are based on a review of published data and expert opinion from the Cancerlit and Medline databases (1966-2000) and from recent breast cancer textbooks.  The guidelines largely reflect evidence at Levels III-V and sometimes rely on consensus and common sense, due to limited clinical research in this area. 

Limitation of shoulder mobility may occur in as little as two weeks following immobilization. Post-operative physiotherapy is useful for most patients.

This guideline applies to the provision of upper extremity rehabilitation, as well as hand and arm care, to prevent/manage symptoms of the upper extremity including decreased range of motion, pain and lymphedema in people who have received axillary surgery as part of the management of breast cancer. Because breast cancer occurs predominantly in women, the remainder of the text addresses women with breast cancer, but recommendations are largely applicable to men as well.

Recommendations

Upper Extremity Rehabilitation

  • Pre-operative, bilateral upper extremity function, e.g. active range of motion (ROM), strength, sensation, and limb circumference, should be assessed by the surgeon, family physician, or a physical therapist to provide a baseline prior to treatments.1,2,3
  • Post-operative physical therapy should begin the first day following surgery. Gentle ROM exercises should be encouraged in the first week after surgery.1,2,4
  • Active stretching exercises can begin 1 week after surgery, or when the drain is removed, and should be continued for 6-8 weeks or until full ROM is achieved in the affected upper extremity. Women should be instructed in scar tissue massage.1,2,3,5
  • Post-operative assessments following surgery to include ROM, strength, sensation, limb circumference, and scar and chest wall tissue mobility.1,3,6
  • Progressive resistive exercises, i.e. strengthening, can begin with light weights (1-2 lbs.) within 4-6 weeks after surgery. A compression sleeve should be worn during any resistive exercises or strenuous upper body athletic activity.2,3,4,5,6,7
Hand and Arm Care

  • Careful hand and arm care, e.g. proper hygiene and avoiding trauma to the arm can minimize risks for infection and lymphedema.8,9,10
  • Minimizing the extent of axillary dissection, preventing infection, and avoiding obesity may help prevent the development of lymphedema.9,11,12,13
  • Generally, injections, vaccinations, venipuncture, and intravenous access in the axillary-dissected arms and shoulder have been contra-indicated.14,15,16 There is some evidence (Level V) that these restrictions can be relaxed.17
  • Many suggestions regarding proper hygiene and trauma avoidance for the axillary-dissected upper extremity are sensible but there is little scientific literature to support these restrictions.
Electrotherapy Modalities

Laser treatment, electrical stimulation, microwave, and thermal therapy are not recommended at this time due to insufficient evidence to support their use as well as published precautions and contra-indications for their use in persons with neoplasms.18,19,20

Therapeutic ultrasound is contra-indicated over sites of possible metastasis in women with a history of breast cancer.19,21,22,23

Exercise for Cardiovascular Fitness

Although these guidelines focus on upper extremity rehabilitation, women who have had breast cancer should be encouraged to engage in an ongoing, regular program of moderate, aerobic exercise.24,25 In a study published in 2005, women who exercised 3-5 hours per week (at an aerobic level equivalent to walking a 20-30 minute mile) significantly reduced their risk of recurrence as well as their risk of dying from breast cancer when compared to women who exercised less than 3 hours per week.26

Benefits, Risks, and Costs

Benefits include functional and timely recovery of the upper extremity and avoidance of lymphedema and/or cellulitis. There may be increased wound drainage if exercises are initiated too early post-operatively (Day 1). However a number of recent studies (Evidence Levels I-II) have supported both the safety and effectiveness of early post-operative exercise. Stretching exercises during the early post-operative period may assist in breaking up of sclerosed lymphatic vessels (which appear as fine, cord-like structures along the medial surface of the upper arm and forearm). Exercises should provide slow, prolonged stretches, particularly to the shoulder abductors and flexors, with minimal pain or discomfort.

To locate a physical therapist in your area who has special expertise in working with women facing breast cancer surgery or recovering from surgery, ask your doctors or women who had breast cancer, or check with the Physiotherapy Association of BC. You do not need a doctor's referral to access physical therapy private clinics. The Medical Services Plan of BC no longer covers the cost of private physiotherapy treatments unless you meet low-income criteria. Prior to scheduling your first appointment, discuss the costs for the initial assessment, follow-up appointments and cancellation policy.

Recommendations included in these guidelines, for standard pre- and post-operative assessments and treatments under the direction of a physical therapist would likely require fewer than 12 visits. In cases where complications arise (e.g. post-treatment lymphedema) additional physical therapy visits would be necessary. There may also be costs of compression sleeves, compression pumps, and antibiotic therapy in cases of infection. Many of these costs are covered, at least in part, through extended health plans.

References

  1. Gerber L. Rehabilitation management for women with breast cancer: Maximizing functional outcomes. In Harris JR, Lippman ME, Morrow M, Hellman S (eds):Diseases of the Breast, Lippincott-Raven, Philadelphia, 1996: 939-947.
  2. Wingate L, Croghan I, Natarajan N, Michalek AM, Jordan C. Rehabilitation of the mastectomy patient: A randomized, blind, prospective study. Arch Phys Med Rehab 1989; 70: 21-24.
  3. 3Hladiuk M, Huchcroft S, Temple W, Schnurr BE. Arm function after axillary dissection for breast cancer: A pilot study to provide parameter estimates. J Surg Oncol 1992; 50: 57-52.
  4. Konecne SM. Post-surgery breast cancer inpatient program. Clinical Management 1992; 12: 42-49. 
  5. Miller LT. Post-surgery breast cancer outpatient program. Clinical Management 1992; 12: 50-56.
  6. Maunsell E, Brisson J, Deschenes L. Arm problems and psychological distress after surgery for breast cancer. Can J Surg 1993; 36: 315-320.
  7. Stumm D. Recovering from Breast Surgery: Exercises to Strengthen your Body and Relieve Pain, Hunter House, Alameda, CA, 1995.
  8. Spratt JS, Donegan WL. Surgical management. In Donegan WL, Spratt JS (eds.), Cancer of the Breast, ed. 4, W.B. Saunders, Philadelphia, PA, 1995: 443-504.
  9. Petrek J, Lerner R. Lymphedema. In Harris JR, Lippman ME, et al (eds): Diseases of the Breast., Lippincott-Raven, Philadelphia New York, 1996; 896-903.
  10. Brennan MJ, DePompolo RW, Garden FH. Focused review: Post mastectomy lymphedema. Arch Phys Med Rehabil. 1996; 77: S74 - S80.
  11. Segerstrom K, Byerle P, Graffman S, Nystrom A: Factors that influence the incidence of brachial edema after treatment of breast cancer. Scand J Plast Reconstr Hand Surg 1992; 26: 223-227.
  12. Aitken D. Complications associated with mastectomy. Surg Clin N Am 1983; 63(6): 1331 - 1351
  13. Werner RS, McCormick B, Petrek J, et al. Arm edema in conservatively managed breast cancer: Obesity is a major predictive factor. Therapeutic Radiology 1991; 180: 177 - 184.
  14. Centers for Disease Control and Prevention: General recommendations on immunization: Recommendations of the Advisory Committee on Immunization Practices(ACIP). Morbidity and Mortality Weekly Report 1994; 43 (RR-1): 6.
  15. Procedures for the Collection of Diagnostic Blood Specimens by Venipuncture, ed 3. National Committee for Clinical Laboratory Standards (NCCLS). Villanova, PA, 1991: H3-A3.
  16. Koepke JA. Phlebotomy after mastectomy (Letter). Medical Laboratory Observer. 1992; 12-14.
  17. Dawson WJ, Elenz DR, Winchester DP, Feldman JL. Elective hand surgery in the breast cancer patient with prior ipsilateral axillary dissection. Ann Surg Oncol 1995; 2(2): 132 - 137.
  18. Lehmann JF, de Lateur BJ. Therapeutic heat. In Lehmann JF (ed.), Therapeutic Heat and Cold, 4th ed., Williams & Wilkins, Baltimore, MD, 1990: 417-581.
  19. The Chartered Society of Physiotherapy. Safety of Electrotherapy Working Group. Guidelines for the safe use of lasers in physiotherapy. Physiotherapy 1991; 77: 169-170.
  20. Snyder-Mackler L, Collender SL. Therapeutic uses of light in rehabilitation. In Michlovitz SL (ed.): Thermal Agents in Rehabilitation, 3rd ed., F.A. Davis, Philadelphia, PA, 1996: 255-277.
  21. Hogan RD, Burke KM, Franklin TD. The effect of ultrasound on microvascular hemodynamics in skeletal muscle: Effects during ischemia. Microvascular Res 1982; 23: 370-379.22.
  22. Basford JR. Physical agents and biofeedback. In DeLisa JA (ed.), Rehabilitation Medicine: Principles and Practice, Philadelphia, PA, J.B. Lippincott, 1988: 261-263.
  23. Friedenreich CM, Courneya KS. Exercise as rehabilitation for cancer patients. Clin J Sport Med 1996; 6: 237-244.
  24. American College of Sports Medicine. The recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness in healthy adults. Med Sci Sports Exer 1990; 22: 265-274.
  25. Thune I, Brenn T, Lund E, Gaard M. Physical activity and the risk of breast cancer. New Eng J Med 1997; 336: 1269-1275.
  26. Holmes MD, Chen WY, Feskanich D, Kroenke CH, Colditz GA. Physical activity and survival after breast cancer diagnosis. JAMA. 2005;293:2479-2486.
  27. Sackett DL. Rules of evidence and clinical recommendations on the use of anti-thrombotic agents. Chest 1989;95:2S-4S.
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