Ovarian Cancer Genetic Testing: Why, When, How?
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1 Ovarian Cancer Genetic Testing: Why, When, How? Jeffrey Dungan, MD Associate Professor Division of Clinical Genetics Department of Obstetrics & Gynecology Northwestern University Feinberg School of Medicine
2 Ovarian cancer Risk factors Age Nulliparity Personal history of breast or colon cancer Family history of ovarian cancer BRCA1 or BRCA2 carrier Lynch syndrome (HNPCC) Other single gene mutations (rare)
3 Family History of Ovarian Cancer Lifetime Risk None 1.5% 1 first-degree relative 3-5% 2 first-degree relatives 7% Hereditary ovarian cancer syndrome 40% Known BRCA1 or BRCA2 mutation 15-40%
4 Inherited Cancer Earlier age of onset Higher rate of bilaterality Associated tumors Not distinguished by pathology, metastatic pattern or survival characteristics
5 Why do genetic testing for hereditary cancer syndromes? For carrier, positive status will impact surveillance recommendations For non-carriers in families with mutation, avoids unnecessary interventions Risk-reducing surgery Family members impacted Reproductive decision-making
6 When is testing done? With new diagnosis, before surgery (breast cancer cases) With known mutation in family With suspicious family history Testing in asymptomatic patient at age when surveillance should begin (usually after age 21)
7 Causes of Hereditary Susceptibility to Ovarian Cancer BRCA1 ~70% 5% 10% Other genes ~8% HNPCC BRCA2 ~2% ~20%
8 Patients with > 25% chance of being in HBOC family Personal hx of both breast and ovarian cancer Have ovarian cancer AND close relative with ovarian cancer (any age) or breast cancer (<50) Jewish women with ovarian cancer (any age) or breast cancer (<40) Have breast cancer (<50) and close relative with ovarian cancer (any age) or male with breast ca 1 or 2 relative with known BRCA1 or BRCA2 mutation SGO Committee Statement, 2007
9 Determining risk of carrying BRCA1 or BRCA2 mutation Accessed at myriadtests.com
10 Lynch (HNPCC) syndrome Cancers in colon, endometrial, small bowel, ovary, biliary, ureter, brain Lifetime cancer risk 90% (any type) Highest risk is CRC-usually right-sided: 70-85% in men, 30-50% in women Endometrial CA risk 40-60% Ovarian cancer risk 10-15%
11 Interpretation of genetic test results Normal no significant gene change identified Pathogenic (or Likely pathogenic) gene change causes disease Benign (or Likely benign) gene change does NOT causee disease Variant of undetermined significance (VUS) cannot classify risk
12 Variant of Uncertain Significance (VUS) A sequence within a gene not typically found in the general population and not consistently associated with disease VUS are found in approximately 12% of women tested for BRCA1/2 status 1 ; higher in other genes VUS should be discussed with all individuals considering cancer genetic testing 2 1. Domchek et al. J Clin Oncol Miller Samuel et al. Semin Oncol 2011
13 Drawbacks of genetic testing Will results make a difference in my care? May be inconclusive Risk for developing cancer not always established What interventions are available?
14 Management of BRCA1/BRCA2 mutation carriers Intervention Recommendation Screening Breast self exam Monthly, starting at age 18 Clinical breast exam Q 6 months, starting age 25 Mammogram Yearly, start at age 25* Breast MRI Yearly, start at age 25* Pelvic exam Q 6 12 months, start age 25 TV sono and CA 125 # Q 6 months, start 10 yr earlier than ovarian ca onset in family Chemoprevention Tamoxifen Case by case basis, mutation specific? Oral contraceptives Case by case basis Prophylactic surgery Mastectomy RRSO Case by case At age 35 40, after childbearing Based on NCCN guidelines, 2011
15 Ovarian Cancer: Risk Reduction Birth control pills 5 years of use: 27% reduction 15 years of use: 60% reduction First full-term pregnancy < age 25; number of pregnancies Breast-feeding BTL/hysterectomy RR 0.33/0.67 Prophylactic oophorectomy Risk of primary peritoneal cancer remains
16 Multi gene panels Caveats Selection of genes Accuracy of results Detection rates of mutations within the genes Rate of uncertain variants
17 Northwestern Cancer Genetics Program Ovarian cancer gene testing BRCA1, BRCA2 Lynch syndrome genes: MLH1, MSH2, MSH6, PMS2 RAD51C RAD51D BRIP1 TP53
18 New indications for BRCA testing BRCA deficient tumors demonstrate increased sensitivity to poly(adp ribose)polymerase inhibitors ( PARP inhibitors ) PARP inhibitors being investigated as followup therapy in patients with recurrent tumors, especially with initial favorable response to platinum based treatment
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