Prevalence of BRCA mutations in a cohort of young high-risk breast cancer patients

Abstract

9662 Background:BRCA mutations are responsible for a modest percentage of breast cancers in young women. High risk breast cancer (HRBC), stage II disease with 10 or more positive axillary lymph nodes, stage IIIA, or IIIB inflammatory disease is associated with a poor prognosis (5-year survival of less than 50% following standard adjuvant chemotherapy). Beginning in 1989, high dose chemotherapy (HDCT) with autologous stem cell rescue was tested in clinical trials at COH for HRBC patients to improve their outcome. Recent data suggests a benefit in the inflammatory subset. The young age of the participants in HDCT trial (median age of 44 years, compared to a median age of 62 years for all new cases), suggested that many of these patients may have had inherited susceptibility mutations, since early age of onset is a typical feature of hereditary breast cancer. The influence of BRCA genotype on presentation or outcome of breast cancer treatment remains uncertain. Methods: We screened DNA samples from 120 HRBC patients, enrolled in an IRB-approved prospective registry after informed consent, by conformation sensitive gel electrophoresis to determine the proportion with an abnormal BRCA genotype. Results:We previously reported mutational analysis for BRCA1 in this high risk cohort (6 deleterious BRCA1 mutations and 13 variants of unknown significance, VUS), here we report the data for BRCA2 analysis (with complete data on 19 of 27 exons to date). All variants were confirmed by direct sequencing. Detectable BRCA2 variants were found in 9.2% of subjects (one clearly deleterious frame-shift mutation and 10 variants of unknown significance). Further characterization of each VUS indicated that 4 were suspect, while ancillary data indicated others were less likely to be pathologic. Conclusion:Overall, 25% of this HRBC cohort had BRCA variants (5.8% clearly deleterious mutations and 19% VUS) including 2 of 21 inflammatory cases. BRCA mutational analysis in this high risk cohort may expand our understanding of genetic basis of HRBC and help elucidate the prognostic implications of inherited BRCA mutations, although more BRCA carriers would be required for analysis of clinial outcome after HDCT. No significant financial relationships to disclose.