Homologous recombination deficiency in patients with pancreatic ductal adenocarcinoma and response to chemotherapy

Safi Shahda, Kirsten M. Timms, Ashley A. Ibrahim, Julia E. Reid, Harvey M. Cramer, Milan Radovich, Sulfikar Ibrahim, Brian Allen, Bert H. O'Neil

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Purpose Mutations or copy number abnormalities of genes involved in homologous recombination (HR) occur in pancreatic ductal adenocarcinoma (PDAC). DNA-basedmeasures of HRdeficiency (HRD)have been developed and mayhelp identify tumors with better response to DNA-damaging agents. This study aimed to describe the HR pathway mutations and HRD status and determine their association with treatment response and outcome in patients with PDAC. Patients and Methods We performed a retrospective analysis of tumor samples from patients treated at Indiana University for locally advanced or metastatic PDAC. Patients were included if they received gemcitabine plus nanoparticle albumin-bound paclitaxel (control) or fluorouracil, oxaliplatin, leucovorin, and irinotecan (FOLFIRINOX) and had adequate follow-up to assess survival and response to therapy. Tumor analysis generated a three-biomarker HRD score and mutation data for 44 genes. Results Ninety-one samples met inclusion criteria, and 78 samples (formalin-fixed paraffinembedded, n = 15; fine-needle aspiration, n = 63) generated mutation data. HRD analysis wassuccessful for57samples(HRDscore: median, 18; range,5to61); the primary cause of failure was low tumor cellularity. Six BRCA1/2 mutations were detected, four with HRD scores in the top decile (P = .011). There was no statistically significant correlation between HRD score and radiographic response (odds ratio per interquartile range, 1.40; P = .32 adjusted for treatment) in either treatment group. In patients treated withFOLFIRINOX,HRDscore dichotomized at the median was not associated with progression-free survival (median, 5.3 v 9.4months for low v high HRDscore, respectively; P = .083) or overall survival (median, 11.9 v 10.7 months for low v high HRD score, respectively; P = .76). Conclusion Mutations inDNArepair genes occur inPDAC,andHRDscores can be generated in the majority of patients. The HRD score was not significantly associated with higher response rate or prolonged survival in patients treated with FOLFIRINOX.

Original languageEnglish (US)
JournalJCO Precision Oncology
Volume2
DOIs
StatePublished - Jan 1 2018

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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