Abstract P6-03-03: The Q-CROC-3 project reveals novel genomic alterations in triple negative breast cancers in residual tumors after neoadjuvant chemotherapy

Abstract

Abstract The prognosis of triple negative breast cancer that shows resistance and/or incomplete response to cytotoxic chemotherapy is poor. In order to understand the mechanisms of resistance to chemotherapy and the genomic evolution of TNBCs treated with chemotherapy, an international multi-center biopsy-driven clinical trial was created for the collection and study of drug-resistant primary and metastatic freshly frozen tumors (Q-CROC-03: NCT01276899). We consented 60 patients with operable TNBC undergoing neoadjuvant Anthracycline/Taxane-based chemotherapy for pre and post-treatment biopsies as well as collection of residual tumor at the time of surgery and serial blood sampling. In 12-15 patients, adequate residual tumor material was available for genomic studies, which included whole exome sequencing, array CGH, gene expression microarray profiling and RNAseq of paired tumors. Whole exome sequencing revealed clonal shifts as well as the relatively infrequent appearance of novel mutations in individual tumors, without any recurrently detected variants. Array CGH revealed a remarkable stability in the number of DNA copy number alterations with a few functional alterations enriched for in the residual tumor, including an amplicon involving the NFIB gene. Finally, gene expression profiling showed shifts towards the immune-modulatory and basal TNBC subtypes after chemotherapy as well as an increase in the expression of several targetable genes, including DUSP1, a dual specificity phosphatase. In the 4 cases of primary and matching metastatic tumors, the post-NAC residual tumor had acquired changes many of which persisted in the metastatic sites, indicating that the analysis of the residual tumors can provide a partial picture of genomic changes present in metastases but not in the primary tumor. In summary, the genomic characterization of residual post-NAC tumor tissue provides important information for the development of novel therapeutic strategies for drug-resistant TNBCs as well as a portrait of genomic evolution of TNBCs subjected to chemotherapy. Citation Format: Basik M, Aguilar-Mahecha A, Lafleur J, Bareke E, Przybytkowski E, Alirezaie N, Discepola F, Légaré S, Kovacina B, Lan C, Mihalcioiu CL, Robidoux A, Marcus E, Roy J-A, Pelmus M, Aleynikova O, Nabavi S, Tonellato P, Majewski J. The Q-CROC-3 project reveals novel genomic alterations in triple negative breast cancers in residual tumors after neoadjuvant chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-03-03.