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.
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.
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.
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 inhibitors
7, 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:
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.
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.
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.
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
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.
