Association between homologous recombination repair gene mutations and response to oxaliplatin in pancreatic cancer

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.

Surveillance of Individuals with a Family History of Pancreatic Cancer and Inherited Cancer Syndromes: A Strategy for Detecting Early Pancreatic Cancers

“…In cases of advanced PCs with BRCA variants, superior overall survival was recognized in the cases treated by platinum-based chemotherapies than those by non-platinum agents (22 months and 9 months, p = 0.04) [117]. A similar trend was observed in the progression-free survival after the initiation of oxaliplatin-based chemotherapy in cases with PCs; between PCs with and without somatic mutations of homologous recombination-related genes (20.8 months in mutant group vs. 1.7 months in wild-type group, p = 0.049) [118]. In a most recent study, a randomized, double-blind, phase 3 trial (Pancreas Cancer Olaparib Ongoing trial: POLO trial) for germline BRCA-variant cases with a metastatic PC, that had not progressed during first-line platinum-based chemotherapy, demonstrated a significantly longer progression-free survival in the oraparib (poly (adenosine diphosphate-ribose) polymerase inhibitor) group (7.4 months) than in the placebo group (3.8 months) (hazard ratio: 0.53, p = 0.004), although their overall survivals by an interim analysis were not different between the two groups (median: 18.9 months vs. 18.1 months; hazard ratio: 0.91, p = 0.68) [41].…”

ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications

“…In this case series, 80% of those with ATM, ATR, or CHEK2 mutations were treated with an oxaliplatin-based chemotherapy and 62.5% demonstrated partial response or stable disease on first follow-up scans (6). Another small study (N ¼ 13) demonstrated a 37.5% response rate to oxaliplatin-based chemotherapy regimens in patients with DDR-mutated tumors (69). There was also a significantly longer progressionfree survival compared with those patients whose tumors were DDR-nonmutated (20.8 months vs. (Table 1).…”

GLUT-1 as a predictor of worse prognosis in pancreatic adenocarcinoma: immunohistochemistry study showing the correlation between expression and survival

“…In recent years, new molecular prognostic markers have been investigated to optimise the reliability of prognostic information and select subgroups of patients who could benefit from specific treatment algorithms. An example of these are mutations in breast cancer genes and greater sensitivity to combinations with chemotherapy [ 7 , 8 ]. The Glucose Transporter type 1 (GLUT-1) is one of 14 in a family of facilitators of glucose transport in mammals; it is one of the most ubiquitously distributed subtypes.…”