TITLE: Influence of Radiotherapy and Tamoxifen on Contralateral Cancer Risk in Women with Hereditary Breast Cancer PRINCIPAL INVESTIGATOR:

Background: The prognostic significance of germiine mutations in BRCA1 and BRCA2 In women with breast cancer remains unclear. A combined analysis was performed to address this uncertainty. Methods: Two retrospective cohorts of Ashkenazi Jewish women undergoing breast-conserving treatment for invasive cancer between 1980 and 1995 (n=584) were established. Archived tissue blocks were used as the source of DNA for Ashkenazi Jewish BRCA 1IBRCA2 founder mutation analysis. Paraffin-embedded tissue and follow-up information was available for 505 women. Results: Genotyping was successful In 496 women, of whom 56 (11.3%) were found to carry a BRCA1/BRCA2 founder mutation. After a median follow-up period of 116 months, breast cancer specific survival was worse In women with BRCA1 mutations than In those without (62% at 10 years versus 86%; P<0.0001), but not In women with the BRCA2 mutation (84% versus 86% at 10 years; P=0.76). Germiine BRCA1 mutations were an independent predictor of breast cancer mortality In multivariate analysis (hazard ratio 2.4, 95% confidence Interval 1.2-4.8; P=0.01). BRCA1 status predicted breast cancer mortality only among women who did not receive chemotherapy (hazard ratio 4.8, 95% confidence Interval 2.0-11.7; P= 0.001). The risk for metachronous Ipsilateral cancer was not greater in women with germiine BRCA1/BRCA2 founder mutations than In those without mutations (P= 0.68). Conclusion: BRCA 1 mutations, but not BRCA2 mutations, are associated with reduced survival In Ashkenazi women undergoing breast-conserving treatment for Invasive breast cancer, but the poor prognosis associated with germiine BRCA 1 mutations Is mitigated by adjuvant chemotherapy. The risk for metachronous Ipsilateral disease does not appear to be Increased for either BRCA1 or BRCA2 mutation carriers, at least up to 10 years of follow up.