Abstract
ObjectivesWe aimed to examine the association between homologous recombination repair (HRR)-related gene mutations and efficacy of oxaliplatin-based chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC).ResultsNon-synonymous mutations in HRR-related genes were found in 13 patients and only one patient had a family history of pancreatic cancer. Eight patients with HRR-related gene mutations (group A) and nine without HRR-related gene mutations (group B) received oxaliplatin-based chemotherapy. Median progression-free survival after initiation of oxaliplatin-based chemotherapy was significantly longer in group A than in group B (20.8 months vs 1.7 months, p = 0.049). Interestingly, two patients with inactivating HRR-related gene mutations who received FOLFIRINOX as first-line treatment showed exceptional responses with respect to progression-free survival for > 24 months.Materials and MethodsComplete coding exons of 12 HRR-related genes (ATM, ATR, BAP1, BRCA1, BRCA2, BLM, CHEK1, CHEK2, FANCA, MRE11A, PALB2, and RAD51) were sequenced using a Clinical Laboratory Improvement Amendment-certified multiplex next-generation sequencing assay. Thirty consecutive PDAC patients who underwent this assay between April 2015 and July 2017 were included.ConclusionsOur results suggest that inactivating HRR-related gene mutations are predictive of response to oxaliplatin-based chemotherapy in patients with PDAC.
Highlights
BRCA1 and BRCA2 play pivotal roles in DNA homologous recombination repair (HRR), and germline BRCA1/2 mutations reportedly increase risk of pancreatic ductal adenocarcinoma (PDAC)
Our results suggest that inactivating HRR-related gene mutations are predictive of response to oxaliplatin-based chemotherapy in patients with PDAC
Supporting this idea, Waddell et al reported that four of five patients with PDAC who were deficient in BRCA1/2 or PALB2 responded to platinum-based chemotherapy [7]
Summary
BRCA1 and BRCA2 play pivotal roles in DNA homologous recombination repair (HRR), and germline BRCA1/2 mutations reportedly increase risk of pancreatic ductal adenocarcinoma (PDAC). A large clinic-based cohort study enrolling 306 patients with PDAC reported the prevalence of pathogenic BRCA1/2 germline mutations to be 4.6% [1]. Several retrospective studies have indicated that patients with PDAC harboring germline BRCA1/2 mutations are more sensitive to platinum-based chemotherapy than those without the mutations [2,3,4]. It is reasonable to speculate that patients with PDAC harboring mutations in HRR-related genes in their tumor tissues are sensitive to platinum-based chemotherapy. Supporting this idea, Waddell et al reported that four of five patients with PDAC who were deficient in BRCA1/2 or PALB2 responded to platinum-based chemotherapy [7]
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