By Dr. Anna Tinker (biography and disclosures)
What I did before
Before, I used to painstakingly take a detailed family history from every woman diagnosed with ovarian cancer. Family history was the only method of identifying patients and families at risk of harboring a germline, i.e. heritable, BRCA mutation. The type of cancer, the number of affected individuals, and the age of cancer diagnosis help identify at risk patients and families. In BC patients with one of the following family histories are eligible for referral to the Hereditary Cancer Program (HCP) at the BC Cancer Agency to be counseled about BRCA mutation testings: patients with close relatives (close relatives being defined as children, siblings, parents, aunts and uncles , grandparents and grandchildren), the finding of 1 breast and 1 ovarian cancer, or 1 case of male breast cancer along with 1 breast or ovarian cancer, or 2 close relatives with breast cancer both diagnosed under the age of 50, or 2 close relatives with ovarian cancer, or 3 cases of breast cancer with one being diagnosed before 50 years of age. More information about the HCP can be found at http://www.screeningbc.ca/Hereditary/ForHealthProfessionals/Default.
Historically, it was believed that germline mutations in the BRCA1 and BRCA2 genes accounted for 5-10% of all cases of ovarian cancer . In my practice the identification of BRCA mutation carriers starts with the index case; the woman diagnosed with ovarian cancer. Patients would be asked their family history in an attempt to identify one of the above concerning family histories. The sensitivity of family history in identifying at risk individuals and families is influenced by many factors : 1) the skill of the history taker with genetic counselors out performing most physicians, 2) small families have few individuals at risk, 3) early deaths from non-cancer causes can obscure the disease prevalence in a family, 4) family events can be poorly recalled, or unknown, 5) adopted patients are always at a disadvantage.
What changed my practice
Ovarian cancer, is a highly lethal malignancy affecting approximately 1/60 women over the course of their lifetime. While most cases of ovarian cancer are sporadic, the majority of familial breast and ovarian cancers are due to mutations in the BRCA1/2 genes. Individuals with confirmed BRCA mutations are eligible for breast cancer screening interventions and for risk reducing prophylactic mastectomies, which can reduce the risk of breast cancer by > 90%. Unfortunately, there are no effective screening strategies for ovarian cancer: neither blood tests looking for the CA125 tumour marker, pelvic ultrasounds nor a combination or both testing modalities have ever demonstrated an improved survival when tested in screening for ovarian cancer. The BC Cancer Agency, and most cancer institutes do not offer ovarian cancer screening programs as a result. However, risk-reducing surgery, entailing the removal of both ovaries and fallopian tubes (bilateral salpingo-oopherectomy) can lower the risk of developing ovarian cancer by approximately 80%, and also further contributes to reducing the risk of breast cancer by 30-75%. This underscores the need for identifying BRCA mutation carriers, such that they can be informed of these important breast cancer screening and risk reducing strategies.
Ovarian cancer is a complicated disease. There are multiple histological subtypes, with different clinical behaviors, different prognoses, and molecular signatures . New data have demonstrated that it is High Grade Serous Carcinoma (HGSC) of the ovary (and of the peritoneum and the fallopian tubes) that is associated with BRCA1 or BRCA2 mutations . Patients diagnosed with HGSC of the ovary, fallopian tube or the peritoneum have approximately a 20% risk of harboring a BRCA mutation [3,4], a much higher rate than previously appreciated. First degree relatives of BRCA mutation carriers have a 50% risk of having the same mutation.
What I do now
I refer all women diagnosed with a HGSC of the ovary, fallopian tube or the peritoneum, irrespective of age, to the HCP for genetic counseling and for BRCA mutation testing. This approach has led to an increase in the detection of BRCA mutations over family history alone, giving family members an opportunity to make informed decisions about their own risk, genetic testing, cancer screening and risk reduction strategies. Access to the HCP is available province-wide, with consultations being conducted by video-conferencing to may remote centres. When needed, urgent consultations, for example, for very ill patients, can be arranged. The referral form for the HCP can be found at: http://www.screeningbc.ca/Hereditary/ForHealthProfessionals/Default.
While family history remains important, it no longer forms the sole basis for genetic testing referral. Tumor characteristics, histologic and molecular, are increasingly improving our ability to identify hereditary cases of cancer. Other programs in BC include reflex screening of colon cancers in patients diagnosed under the age of 50, by IHC for the absence of mismatch repair proteins (MLH1, MSH2, MSH6 , PMS2 .).
All women diagnosed with a high grade serous cancer of the ovary, fallopian tube or the peritoneum, irrespective of age, are now eligible for referral to the HCP for genetic counseling and for BRCA mutation testing.
BC Cancer Agency: Hereditary Cancer Program: http://www.screeningbc.ca/Hereditary/ForHealthProfessionals/Default
- Malander S, Ridderheim M, Masback A, Loman N, Kristoffersson U, Olsson H, et al. One in 10 ovarian cancer patients carry germ line BRCA1 or BRCA2 mutations: results of a prospective study in Southern Sweden. Eur J Cancer 2004 Feb;40(3):422-428. (View with CPSBC or UBC)
- Kobel M, Kalloger SE, Boyd N, McKinney S, Mehl E, Palmer C, et al. Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med 2008 Dec 2;5(12):e232. (View)
- Schrader KA, Hurlburt J, Kalloger SE, Hansford S, Young S, Huntsman DG, et al. Germline BRCA1 and BRCA2 mutations in ovarian cancer: utility of a histology-based referral strategy. Obstet Gynecol 2012 Aug;120(2 Pt 1):235-240. (Request from CPSBC or view with UBC)
- Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol 2012 Jul 20;30(21):2654-2663. (View)