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  • Pancreatic Cancer and DNA Damage Repair Deficiency: Mechanisms, Biomarkers, and Therapeutic Implications

  • Shaghayegh Ghorbani Neshlandeh,1,*
    1. Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University


  • Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer mortality; more than 50% of patients are diagnosed with locally advanced or metastatic disease. It has a median survival of 6 months and a 5-year survival that remains less than 5% despite 50 years of research and therapeutic development. The defective repair of DNA damage is a hallmark of cancer. The DNA damage response (DDR) is a signal transduction pathway that senses DNA damage and replication stress and sets in motion a choreographed response to protect the cell. TP53 is the most frequently mutated gene in human cancer. At least four independent pathways can repair DSBs: HR, NHEJ, alternative-NHEJ, and single-strand annealing. ATM and ATR are protein kinases that are recruited to and activated by DSBs and RPA-coated ssDNA, respectively. CHK1 and CHK2 together with ATM and ATR act to reduce cyclin-dependent kinase (CDK) activity by various mechanisms, some of which are mediated by activation of the p53 transcription factor. Mutations in BRCA1/2 and PALB2 genes are present in approximately 5% to 9% of patients with PDAC; these genes code for proteins critical for homologous recombination repair of DNA. Cancers arising in the setting of a BRCA mutation are associated with increased sensitivity to platinum agents because of ineffective DNA repair, and they also demonstrate a synthetically lethal interaction with poly(ADP-ribose) polymerase inhibitors. The prevalence of somatic and germline variants in DDR pathways in metastatic PDAC is reported to be approximately 15 - 25%. HRD tumor cells are defined by genomic instability, which facilitates mutagenesis and tumorigenesis. Germline BRCA mutations occur in approximately 4-7% of pancreatic cancer. HRD extends beyond BRCA mutations; approximately 24% of PDAC patients express putative biomarkers of DDR deficiency. Three major types of chromosomal aberrations are characteristic of HRD, including telomeric allelic imbalance (TAI), loss of heterozygosity (LOH) and large-scale transitions (LSTs). HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.
  • Methods: A systematic review and meta-analysis of the prevalence of HRD in PDAC was conducted according to Preferred Reporting Items for Systematic reviews and MetaAnalyses guidelines. PubMed, Scopus, and the Cochrane Library databases, and online cancer genomic data sets were queried. Specific HRD genes were selected: BRCA1, BRCA2, PALB2, ATR, ATM, CHEK2, and RAD51 (including -B, C, D), and the Fanconi-Anemia (FANC) genes. Eligible patients were at least 18 years old; had locally advanced or metastatic PC; and had a confirmed pathogenic or likely pathogenic germline or somatic PV in BRCA1, BRCA2, or PALB2.
  • Results: Fifty patients with a median age of 64 years (range, 37 to 82 years) and of whom 28 (56%) were female were included in the final analysis. The pooled proportion of germline and somatic mutations in all included studies was BRCA1: 0.9%, BRCA2: 3.5%, PALB2: 0.2%, ATM: 2.2%, CHEK2: 0.3%, FANC: 0.5%. HRD prevalence ranged between 14.5% - 16.5% through targeted next-generation sequencing and 24% - 44% through whole-genome or whole-exome sequencing. The POLO trial demonstrated that maintenance olaparib provided a significant progression-free survival benefit to patients with a germline BRCA mutation and metastatic pancreatic cancer that had not progressed during platinum-based chemotherapy, with median progression-free survival significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months).
  • Conclusion: HRD constitutes a prevalent and clinically relevant pathway in PDAC, and every patient with newly diagnosed PDAC should be tested for HRD and ideally enrolled in biomarker-enriched clinical trials. Based on our study and available literature, integrated HRD assessment, including germline and somatic analysis, represents the current ideal approach, with the highest potential to drive therapeutic choices not only in metastatic but also in early-stage disease. Treatment with platinum chemotherapy in the first-line setting for patients with HR-deficient PDAC has been demonstrated to impact survival. Maintenance therapy with olaparib following induction chemotherapy in patients with germline BRCA1/2 mutations has yielded promising results. In BRCA1/2 mutated tumors, the most common mechanism of resistance to PARP inhibitors is achieved through intragenic secondary mutations. Germline and somatic genomic testing are standard of care for all patients with PDAC. Major efforts are necessary to harmonize HRD definition and to find the optimal biomarker for treatment selection.
  • Keywords: Homologous Recombination Deficiency, PDAC, DNA Damage Repair, BRCA Mutations, Precision Medicine

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