Abstract 68: Evaluation of BRCA1 mutations in patients with triple negative breast cancer
Authors: Ellsworth Rachel E. , Rummel Seth , Varner Erika , Shriver Craig D. 
Published: August 2012

Abstract
Background: Triple negative (TN) breast cancer is characterized by aggressive behavior and poor prognosis and until recently targeted treatments were not available. Ongoing trials of PARP inhibitors, which exploit defects in the DNA repair pathway caused by mutations in BRCA1, may offer the first tailored treatment for patients with TN disease, however, whether PARP inhibitors in both patients with and without BRCA1 mutations, remains to be determined. The prevalence and nature of BRCA1 mutations in a population of women with TN breast cancer with and without significant family history was thus evaluated. Methods: The Clinical Breast Care Project database was queried to identify all female patients with TN tumors with and without significant family histories defined as being diagnosed &lt;35 years, diagnosed &lt;50 years with at least one primary family member with breast and/or ovarian cancer, or diagnosed &lt;50 years with at least two secondary family members from the same parental branch from two generations diagnosed with breast and/or ovarian cancer. Genomic DNA was isolated from blood and exonic regions of the BRCA1 genes were amplified and sequenced on an ABI3730xl. Sequence data was analyzed using Sequencher 4.10.1. Results: Of the 162 women with TN tumors, genomic DNA was available for 154. Twenty-seven of these women had a significant family history of breast cancer, of which nine had clinically relevant mutations, including the C61G mutation in two Caucasian women, and the 943ins10 West African founder mutation in one African American woman. An additional two African American women with family histories harbored the 2090A/G and R841W variants of unknown clinical significance, while in the remaining 14 (52%) of women with significant family histories of breast cancer BRCA1 mutations were not detected. Of the 128 women without significant family history, five had clinically relevant mutations, including one Caucasian woman with the C61G mutation diagnosed at age 57, 15 had variants of unknown significance and 107 (84%) had no detectable mutations. Of the women without BRCA1 mutations, intrinsic subtype was determined for 37; 33 of which were basal-like. Conclusion: The majority of TN tumors are not driven by germline BRCA1 mutations with only 9% and 11% of the overall TN population harboring clinically relevant mutations and variants of unknown significance, respectively. In addition, given the different genetic backgrounds of heritable compared to sporadic TN tumors not all TN tumors may respond in the same way to PARP inhibitors. Finally, the presence of BRCA1 mutations in TN patients without significant family histories and/or diagnosed at a later age and absence in patients with significant family histories suggests that current criteria for identifying patients likely to harbor BRCA1 mutations may need to be reevaluated in the triple negative patient populations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 68. doi:1538-7445.AM2012-68