Abstract A81: Identification of reversion mutation by next-generation sequencing in PARP-inhibitor resistant BRCA2 associated breast cancer: Defects in mis-match repair and acquired chemoresistance in breast cancer

Women harboring germline mutations in BRCA2 have an increased risk of developing breast and ovarian cancers. The cancers that arise have undergone loss of the wildtype BRCA2 allele, consistent with BRCA2 functioning as a tumor suppressor. The DNA repair defect present in BRCA2-associated cancers renders them highly sensitive to certain classes of DNA damaging agents including platinum agents and PARP inhibitors. BRCA2-mutant cancers have shown acquired resistance to platinum agents through reversion mutations, in which a second mutation in BRCA2 restores an open reading frame that can partially or completely restore functional protein. This kind of functional restoration is often achieved by genomic deletions that excise the exon containing the deleterious germline mutation and place the gene back in frame. Here we report a case of a BRCA2-mutation associated breast cancer that progressed after a prolonged response to PARP inhibitor- based therapy and became chemoresistant. The patient was positive for germline BRCA2 Q2899 * mutation. Next-generation sequencing of the chemoresistant tumor revealed a secondary mutation in BRCA2 that altered BRCA2 Q2899* to Q2899L_converting a non-sense mutation into a missense mutation. In addition to BRCA2 mutation, the tumor had a deletion in MLH1, suggesting that an acquired defect in mis-match repair may have allowed reversion of BRCA2 Q2899* by a point-mutation in this tumor. Analysis of serial specimens from this patient allows reconstruction of the evolution of this tumor, and points to a novel mechanism of reversion mutation due to defects in mismatch repair. This finding suggest how mismatch repair defects can functionally affect BRCA2 mutant cancers, and raise possible therapeutic strategies. Citation Format: JINESH S. GHEEYA, Jeremy Tang, Joseph Ho, Serena Wong, Deborah Toppmeyer, Kim HIrshfield, Lorna Rodriguez, Shridar Ganesan. Identification of reversion mutation by next-generation sequencing in PARP-inhibitor resistant BRCA2 associated breast cancer: Defects in mis-match repair and acquired chemoresistance in breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A81.