Abstract
Simple SummaryA subset of patients with pancreatic cancer demonstrate heightened response rates and prolonged survival to platinum chemotherapy and PARP inhibitors. Deficient homologous recombination (HR), a critical DNA repair program, is a major driver of this susceptibility. Furthermore, the clinical impact of mutations in distinct HR genes is variable and is modified by diverse tumor intrinsic and extrinsic factors. In this review, we discuss the determinants of homologous recombination deficiency (HRD) in pancreatic cancer. We also highlight emerging methods for identifying and inducing HRD in cancer.Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique tumor responsiveness to HR-dependent DNA damage triggered by certain treatments (platinum chemotherapy and PARP inhibitors). While pathogenic mutations in HR genes are a major driver of this sensitivity, another layer of diverse tumor intrinsic and extrinsic factors regulate the HR deficiency (HRD) phenotype. Defining the mechanisms that drive HRD may guide the development of novel strategies and therapeutics to induce treatment sensitivity in non-HRD tumors. Here, we discuss the complexity underlying HRD in pancreatic cancer and highlight implications for identifying and treating this distinct subset of patients.
Highlights
Pancreatic cancer is a therapy-resistant malignancy and a leading cause of cancerrelated mortality [1]
We suggest that the development of novel biomarkers is needed to improve identification of patients who will most benefit from platinum chemotherapy/poly (ADP-ribose) polymerase inhibitor (PARPi) treatment, with a focus on multi-feature assessment
homologous recombination deficiency (HRD) is defined by stereotyped mutations in homologous recombination (HR) genes and exquisite sensitivity to platinum chemotherapy/PARPi treatment
Summary
Pancreatic cancer is a therapy-resistant malignancy and a leading cause of cancerrelated mortality [1]. With the approval of the poly (ADP-ribose) polymerase inhibitor (PARPi) olaparib as maintenance for patients with pancreatic cancer and a germline BRCA variant, there is renewed fervor to broaden and better define homologous recombination deficiency (HRD), develop clinically usable assays to capture this population, design second-generation therapies and induce HRD in wildtype tumors. To provide an overview of the current mechanistic understanding of HRD, we will discuss relevant pre-clinical and clinical studies that define tumor intrinsic (genetic) and extrinsic (tumor microenvironment) factors that contribute to platinum chemotherapy and PARPi sensitivity. We will review current and emerging testing strategies to identify HRD Another unsolved problem is that only a minority of pancreatic cancer harbors mutations in clinically relevant HR genes [10]. Our review highlights a distinct and clinically relevant subset of patients with pancreatic cancer and provides a framework for the development of testing and treatment strategies aimed at this population
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