Factors that influence genetic testing outcomes in high-risk breast/ovarian families

Abstract

9616 Background: Individuals with a family history of both breast cancer (BC) and ovarian cancer (OV) are at high risk of carrying deleterious mutations in BRCA1 and BRCA2 (BRCA1/2). As effective interventions exist to prevent OV and BC in women with BRCA1/2 mutations, genetic testing is very useful in identifying individuals appropriate for risk reduction strategies. In families with negative BRCA1/2 testing, counseling can be much more challenging. Here we report our genetic testing experience in families with both BC and OV. Methods: Charts were reviewed from 304 families with at least one case each of BC and OV in a single lineage and tested for BRCA1/2 mutations. Familial characteristics, pathology reports and BRCA1/2 mutation status were reviewed. P-values were obtained by Z-test. Results: Of the 304 families, 171 (56%) had deleterious mutations in BRCA1/2. As expected, mutations were more commonly found in the 256 families in which an affected individual (BC and/or OV) was tested, compared to the 48 families in which an unaffected individual was tested (152/256 (59%) vs. 19/48 (40%) (p=0.015)). Of the 125 families who had at least one individual with both BC and OV, affected individuals were tested in 107 (86%) –73% had BRCA1/2 mutations. Mutations were more common in women with both BC/OV (50/63, 79%); OV (95/123, 77%); BC diagnosed before age 39 (78/101, 77%) than in women with BC over age 50 (26/56, 46%), or age 40–49 (51/92, 55%) (p<0.002). Pathologic confirmation of ovarian cancer was available in 85/304 (28%) families. In 57/85 (67%) with pathological documentation of ovarian cancer, BRCA1/2 mutations were detected, vs. 114/219 (52%) of those with no pathological documentation (p=0.018). Conclusions: Genetic testing was informative for 56% of breast/ovarian families regardless of the characteristics of the individual tested but is particularly useful when an affected individual is tested and OV pathology is confirmed (72%). For families with uninformative genetic testing, possible explanations include inability to test affected individuals, phenocopy effects, incorrect ovarian cancer diagnosis in which pathological documentation is not available, in addition to the inherent limitations of current genetic testing. No significant financial relationships to disclose.