We recommend that all women with non-mucinous EOC have testing for high-risk hereditary cancer genes predisposition genes (e.g. germline BRCA1/2)
BRCA1 and BRCA2 are tumour suppressor genes important for DNA repair (through the homologous recombination repair pathway). Less commonly, patients with hereditary ovarian carcinoma may carry germline mutations in genes other than BRCA1 or BRCA2 that are also involved in DNA repair (e.g., PALB2, RAD51C, BRIP1).
Individuals with mutations in these genes are at increased risk for cancers, particularly breast and ovarian cancers. In British Columbia, all women with ovarian cancer (except for mucinous histology) are eligible for BRCA mutation testing, and should be referred to the Hereditary Cancer Program for counseling and genetic testing by their clinical care team. In women with BRCA mutations who do not have cancer, and have finished childbearing, prophylactic BSO (removal of both tubes and ovaries) has been shown to reduce risk of EOC cancer by 80%.
In patients with known BRCA1/BRCA2 mutations (or other rarer germline mutations which can occur in hereditary breast and ovarian cancer syndrome, e.g., BRIP1, PALB2, etc.) who undergo prophylactic BSO, the ovaries and fallopian tubes should be immediately fixed in formalin and submitted in entirety for histologic examination. The fallopian tubes are examined by SEE-FIM (Sectioning and Extensively Examining the Fimbriated End of the Fallopian Tube) protocol (www.cap.org). This protocol increases the detection of early serous carcinoma precursor lesions (serous tubal intraepithelial carcinoma, STIC) by 4-fold.
Key Message:
In the first 5 years following treatment for advanced (stage 3 and 4) ovarian cancer, intensive screening with breast MRI and risk-reducing mastectomy are not routinely recommended in BRCA1/2 carriers.
BRCA1/2 mutation carriers have an increased risk of developing breast cancer. In BRCA1/2 carriers who have been treated for high-grade serous carcinoma of the ovary (or fallopian tube/primary peritoneum), the risk of developing a subsequent breast cancer is lower than in unaffected BRCA carriers [56-61].
For these patients, overall survival is largely dictated by their ovarian cancer risk, as the 10-year breast cancer incidence following an ovarian cancer diagnosis is less than 10%. In one retrospective cohort of 184 BRCA1/2 carriers with epithelial ovarian cancer, only 16 (8%) developed breast cancer at a median of 7 years’ follow-up. Another multi-institutional cohort of 164 patients with BRCA-associated ovarian cancer demonstrated a 10-year breast cancer-free survival of 91%, with no deaths due to breast cancer [58]. A third review of 232 women with BRCA1/2 related ovarian cancer, 33 were diagnosed with breast cancer (14%), with the majority (30/33, or 91%) having stage I or II disease [61]. The median interval to breast cancer diagnosis was 80 months (6.6 years) from the time of ovarian cancer diagnosis, with only 4/33 (12%) being diagnosed within 2 years. Possible explanations for these findings include the putative preventive effect of platinum-based chemotherapy for ovarian cancer on the subsequent breast cancer incidence.
Early-stage ovarian cancer: For patients who were treated for early stage (stage I or II) ovarian cancer, intensified breast cancer screening using MRI and mammography may be considered. Risk-reducing mastectomies (RRM) have not been demonstrated to improve survival, and are not routinely recommended, but can be considered on a case-by-case basis after treatment for ovarian cancer has been completed.
Advanced stage ovarian cancer: Given the low breast cancer risk in the first 5 years following treatment for ovarian cancer, intensive screening with breast MRI is not routinely considered in patients with advanced stage (stages III and IV) ovarian cancers, regardless of patient age and factors like breast density. Likewise, RRM is not routinely considered in BRCA carriers treated for stage III or IV ovarian cancer. In this patient group, annual mammography is sufficient for the first 5-8 years after ovarian cancer therapy has been completed, and if there is no evidence of ovarian cancer recurrence.
Survival following ovarian cancer typically plateaus beyond 8–10 years, after which RRM may be considered on a case-by-case basis in ovarian cancer survivors. The impact of 2–3 years of adjuvant PARP inhibitors on subsequent breast cancer risk remains an area of ongoing investigation in this select patient population.
Recurrent ovarian cancer: There is no role for breast cancer screening of any form or RRM in patients who have experienced a recurrence of their ovarian cancer.
BRCA mutation carriers diagnosed with ovarian cancer, particularly those with stage I or II ovarian cancer, and those who have completed follow up at BC Cancer and have not experienced a recurrence of ovarian cancer, can be referred to the BC Cancer High Risk Clinic to discuss the best management of their risk of breast cancer.
http://www.bccancer.bc.ca/our-services/services/hereditary-cancer/high-risk-clinic [with modifications, from Wong SM et al. [62]]
We recommend that all endometrioid and clear cell ovarian carcinomas undergo immunohistochemical testing for mismatch repair (MMR) proteins (MSH6 and PMS2, and if abnormal, then MSH2 or MLH1). Immunohistochemistry is the preferred method of screening (over MSI assay) due to its widespread availability. When abnormal MMR immunohistochemical results are found, a reflex statement is issued in the pathology report recommending referral to the Hereditary Cancer Program, and the referral is made by the submitting clinician/surgeon. If a patient then undergoes germline testing after genetic counseling and is confirmed to have LS, they can consider additional early detection interventions against colorectal cancer.
DNA mismatch repair (MMR) genes can be impaired by methylation events (epigenetic mechanisms), acquired (somatic) mutations or inherited (germline) mutations. Screening for defective/loss of MMR proteins can be done using 1) immunohistochemistry or 2) microsatellite instability (MSI) assays. MLH1 hypermethylation testing, if available, can be done to determine if loss of MLH1 detected by immunohistochemistry is sporadic or not. Confirmation of LS requires direct sequencing of the MMR gene, which requires both tumor tissue and patient blood samples.
Patients with LS have an inherited mutation in an MMR gene. The major MMR genes in humans are MLH1, PMS2, MSH2 and MSH6. Patients with LS have a 40-60% lifetime risk of colorectal and endometrial carcinoma, 6-12% lifetime risk of ovarian carcinoma and increased lifetime risks of many other cancer types (stomach, hepatobiliary, urinary, etc.)
LS-associated ovarian cancers present differently than typical ovarian cancer. Generally, women with LS-associated ovarian cancers are younger (median 43 years of age) and develop early stage endometrioid or clear cell histology.
Cascade testing of family members should ensue if a patient is found to carry a hereditary cancer syndrome. There are published guidelines on screening and interventions for carries of hereditary cancer mutations, developed in a syndrome specific fashion. For example, individuals with Lynch syndrome need to have increased screening for colorectal carcinoma. Women should be counseled about considering risk reducing surgery (hysterectomy and BSO) after childbearing. Female family members with BRCA1/2 mutations should be counseled about risk-reducing interventions against breast cancer (mammography +/- breast MRI if premenopausal, and bilateral mastectomy), as well as ovarian cancer (BSO). Age of penetrance varies by affected gene and can be part of the discussion regarding timing of procedures. More information is available from the BC Cancer Hereditary Cancer Program.
56. Gangi A., Cass I., Paik D., Barmparas G., Karlan B., Dang C., Li A., Walsh C., Rimel B.J., Amersi F.F. Breast cancer following ovarian cancer in BRCA mutation carriers. JAMA Surg. 2014;149:1306–1313. doi: 10.1001/jamasurg.2014.1081.
57. Nanez A., Stram D.A., Bethan Powell C., Garcia C. Breast cancer risk in BRCA mutation carriers after diagnosis of epithelial ovarian cancer is lower than in carriers without ovarian cancer. Gynecol. Oncol. Rep. 2022;39:100899. doi: 10.1016/j.gore.2021.100899.
58. Domchek S.M., Jhaveri K., Patil S., Stopfer J.E., Hudis C., Powers J., Stadler Z., Goldstein L., Kauff N., Khasraw M., et al. Risk of metachronous breast cancer after BRCA mutation-associated ovarian cancer. Cancer. 2013;119:1344–1348. doi: 10.1002/cncr.27842.
59. Vencken P.M., Kriege M., Hooning M., Menke-Pluymers M.B., Heemskerk-Gerritsen B.A., van Doorn L.C., Collee M.M., Jager A., van Montfort C., Burger C.W., et al. The risk of primary and contralateral breast cancer after ovarian cancer in BRCA1/BRCA2 mutation carriers: Implications for counseling. Cancer. 2013;119:955–962. doi: 10.1002/cncr.27839.
60. McGee J., Giannakeas V., Karlan B., Lubinski J., Gronwald J., Rosen B., McLaughlin J., Risch H., Sun P., Foulkes W.D., et al. Risk of breast cancer after a diagnosis of ovarian cancer in BRCA mutation carriers: Is preventive mastectomy warranted? Gynecol. Oncol. 2017;145:346–351. doi: 10.1016/j.ygyno.2017.02.032.
61. Nañez A, Stram DA, Bethan Powell C, Garcia C. Breast cancer risk in BRCA mutation carriers after diagnosis of epithelial ovarian cancer is lower than in carriers without ovarian cancer. Gynecol Oncol Rep. 2021 Dec 4;39:100899. doi: 10.1016/j.gore.2021.100899. PMID: 34917730; PMCID: PMC8666339.
62. Wong SM, Apostolova C, Eisenberg E, Foulkes WD. Counselling Framework for Germline BRCA1/2 and PALB2 Carriers Considering Risk-Reducing Mastectomy. Curr Oncol. 2024 Jan 9;31(1):350-365. doi: 10.3390/curroncol31010023. PMID: 38248108; PMCID: PMC10814079.
