Abstract
PURPOSETo analyze the prevalence of homologous recombination deficiency (HRD) in patients with pancreatic ductal adenocarcinoma (PDAC).MATERIALS AND METHODSWe conducted a systematic review and meta-analysis of the prevalence of HRD in PDAC from PubMed, Scopus, and Cochrane Library databases, and online cancer genomic data sets. The main outcome was pooled prevalence of somatic and germline mutations in the better characterized HRD genes (BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, RAD51, and the FANC genes). The secondary outcomes were prevalence of germline mutations overall, and in sporadic and familial cases; prevalence of germline BRCA1/2 mutations in Ashkenazi Jewish (AJ); and prevalence of HRD based on other definitions (ie, alterations in other genes, genomic scars, and mutational signatures). Random-effects modeling with the Freeman-Tukey transformation was used for the analyses. PROSPERO registration number: (CRD42020190813).RESULTSSixty studies with 21,842 participants were included in the systematic review and 57 in the meta-analysis. Prevalence of germline and somatic mutations was BRCA1: 0.9%, BRCA2: 3.5%, PALB2: 0.2%, ATM: 2.2%, CHEK2: 0.3%, FANC: 0.5%, RAD51: 0.0%, and ATR: 0.1%. Prevalence of germline mutations was BRCA1: 0.9% (2.4% in AJ), BRCA2: 3.8% (8.2% in AJ), PALB2: 0.2%, ATM: 2%, CHEK2: 0.3%, and FANC: 0.4%. No significant differences between sporadic and familial cases were identified. HRD prevalence ranged between 14.5%-16.5% through targeted next-generation sequencing and 24%-44% through whole-genome or whole-exome sequencing allowing complementary genomic analysis, including genomic scars and other signatures (surrogate markers of HRD).CONCLUSIONSurrogate readouts of HRD identify a greater proportion of patients with HRD than analyses limited to gene-level approaches. There is a clear need to harmonize HRD definitions and to validate the optimal biomarker for treatment selection. Universal HRD screening including integrated somatic and germline analysis should be offered to all patients with PDAC.
Highlights
Report the relation of the genetic marker to standard prognostic variables Report on all detected genetic alterations according to the Recommendation of the Association for Molecular Pathology, ASCO, and College of American Pathologists[41]: Somatic variants: interpretation of somatic variant should follow the recommendations of the Association for Molecular Pathology, ASCO, and College of American Pathologists, which define the clinical relevance of the variants according to the four-tiered classification system.[41]
Our results showed that when these surrogate measures are used, like in studies based on whole-genome sequencing (WGS) technologies, the probability of capturing homologous recombination deficiency (HRD) rises significantly.[7,33]
This occurs in 90% or more in the case of germline BRCA1 and BRCA2,74,75 allowing the assumption that if a mutation in one allele is detected, the second is inactivated in 90%, the rate of loss of the second allele for somatic BRCA mutations is not well characterized
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the deadliest solid malignancy, with a five-year survival rate of , 10% and an increasing public health burden considering the estimated rise of its incidence and unchanging mortality over the 20 years.[1,2,3,4] Its biologic aggressiveness is compounded by the limited availability of effective therapies and a lack of prevention strategies.[5,6] Defects in DNA damage response (DDR) genes causing homologous recombination deficiency (HRD) identify a clinically relevant subgroup of patients with PDAC, with both therapeutic and preventative implications.[7,8,9,10] Accumulating evidence from nonrandomized clinical trials infers HRD as a putative biomarker of therapeutic response for platinum-based chemotherapy in patients with advanced PDAC.[11,12] Within HRD, germline variants in BRCA1 and BRCA2 are associated with improved progression-free survival in patients with platinumsensitive metastatic PDAC treated with the poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib as maintenance therapy.[13].
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