DNA damage repair (DDR) pathway defects in gastrointestinal (GI) malignancies.

Abstract

647 Background: The clinical significance of the genomic alterations associated with DDR pathway in GI tumors (besides MMR defects) is largely unknown. These patients can potentially derive benefit from targeted therapy with poly ADP ribose polymerase (PARP) inhibitors, which have already shown promising activity in ovarian, breast and prostate cancers. In this study, we investigated the frequency and clinical significance of DDR repair defects (other than MMR defects) in GI tumors. Methods: We performed a retrospective analysis of all patients who had tumor next generation sequencing performed between January 2013 and August 2017 on GI cancers harboring DDR pathway defects. Data including demographics, clinical history, and treatment were extracted from patients' records. Results: Of 299 patients with GI tumors sequenced, 35 cases (12%) were noted to have DDR defects. The most commonly mutated genes – 6 (17%) BRCA2, 5 (14%) PALB2, 4 (11%) ATM, 3 (8.6%) BRCA1, 2 (5.7%) each of NBN, MUTYH, ERCC3, PARP1 amplification and 1 (2.8%) each of ERCC2, CDK12, and PARP2 amplification. Two patients had both ATM and BRCA2 mutations. Combination of ATM and MRE11, ATM and BRCA1, BRCA1 and ERCC6, BRCA2 and CDK12 were noted in 1 patient each. Of the 23 patients with available clinical data, the median age at diagnosis was 65 (range 30–85) years with male and female prevalence rates of 60.8% and 39.2%, respectively. Stage at diagnosis was I (n = 3), II (n = 3), III (n = 8), and IV (n = 9). The primary site of tumor was found in 8 (34.8%) colon, 4 (17.4%) liver, 4 (17.4%) pancreas, 2 (8.7%) esophagus, 2 (8.7%) anus, 2 (8.7%) appendix, 1 (4.3%) rectum. Seventeen patients received platinum‐based therapy, 7 were treated with PARP inhibitors and 5 patients received both platinum and PARP inhibitor. Median overall survival from diagnosis for patients with stage I/II was 65.3 months, stage III was 23.1 months, and stage IV was 22.4 months. The median survival of patients treated with olaparib was 24.5 months. Conclusions: DDR pathway defects in GI tumors are uncommon. However, they can potentially be targeted with PARP inhibitors with durable survival. Future clinical trials are warranted to explore the role to PARP inhibitors in these unique subset of patients.