Abstract P1-10-15: BRCA1 alterations with additional defects in DNA damage repair genes may confer chemoresistance to BRCA-like breast cancers treated with neoadjuvant chemotherapy

Abstract

Abstract The BRCA-like phenotype is a feature that some sporadic breast cancers share with those occurring in germinal BRCA1- or BRCA2-mutation carriers. Since tumors with the phenotype have defects in the DNA damage repair pathway, which may increase sensitivity to drugs such as DNA cross-linking agents and PARP inhibitors, a method to identify this phenotype is important. The prediction of chemoresistance, which frequently develops in these tumors, is also crucial for improving therapy. We examined genomic aberrations and BRCA1 promoter methylation in tumors of 73 breast cancer (20 HR-/HER2- and 53 HR+/HER2-) patients, who underwent diagnostic core-needle biopsy and received neoadjuvant chemotherapy with anthracycline, cyclophosphamide, and taxane, using SNP array CGH and quantitative PCR. They had a tumor size of T1, T2, T3, or T4, a lymph node status of N0, N1, N2, or N3, and no distant metastasis (M0) at diagnosis, and were enrolled as subjects in this study. The methylation and/or loss or UPD of BRCA1 (termed BRCA1 alterations) and the loss or UPD of BRCA2 (termed BRCA2 alterations) were detected in 27 (37%) and 21 (29%), respectively, out of 73 tumors. Tumors with BRCA1 or BRCA2 alterations were associated with a higher number of genomic aberrations (P<0.001 and P<0.001) and higher percentage of TP53 alterations (the loss or UPD and/or mutations) than those without (P<0.001 and P<0.001). Overall survival (OS) rates were similar between patients with or without BRCA1 or BRCA2 alterations. However, when 27 patients with BRCA1-altered tumors were classified into those with or without the loss or UPD of PALB2, PAGR1, RAD51B, FANCM, MLL4 or ERCC1/2 in tumors, patients with additional defects in DNA damage repair genes had worse OS (P=0.037, 0.045, 0.038, 0.044, 0.041, or 0.019) than those without. These defects may confer chemoresistance and predict poor outcomes in patients with BRCA1-altered breast cancer. Citation Format: Mamoru Takada, Yasuhiko Kaneko, Masayuki Haruta, Shigenori Nagai, Kenichi Inoue, Katsunori Toduka, Masafumi Kurozumi, Hiroyuki Takei, Seishi Ogawa, Takeshi Nagashima, Takafumi Sangai, Hiroshi Fujimoto, Junta Sakakibara, Ryotaro Teranaka. BRCA1 alterations with additional defects in DNA damage repair genes may confer chemoresistance to BRCA-like breast cancers treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-15.