In a systematic review and meta-analysis reported in the Journal of Clinical Oncology, Casolino et al identified the prevalence of homologous recombination deficiency (HRD) genes in patients with pancreatic ductal adenocarcinoma and found that the reported prevalence of HRD was higher with surrogate readouts of HRD vs gene-level analysis.
Study Details
The systematic review included 59 studies and 1 cancer genomic data set (n = 21,842) identified through February 2020 that reported on the prevalence of HRD (irrespective of sequencing methodology). The meta-analysis included 56 studies and the genomic data set.
The main outcome measure was pooled prevalence of somatic and germline mutations in better characterized HRD genes—ie, BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, RAD51, and FANC. Among the 60 studies (including the data set), germline mutations were tested in 54 studies, somatic mutations in 19, and both in 13. A secondary outcome measure was the prevalence of HRD based on other definitions (ie, alterations in other genes, genomic scars, and mutational signatures).
Key Findings
The prevalence of germline and somatic mutations was 0.9% for BRCA1, 3.5% for BRCA2, 0.2% for PALB2, 2.2% for ATM, 0.3% for CHEK2, 0.5% for FANC, 0.0% for RAD51, and 0.1% for ATR. The prevalence of germline mutations was 0.9% (2.4% in Ashkenazi Jewish persons) for BRCA1, 3.8% (8.2% in Ashkenazi Jewish persons) for BRCA2, 0.2% for PALB2, 2.0% for ATM, 0.3% for CHEK2, and 0.4% for FANC. No significant differences in prevalence between sporadic and familial cases were observed.
Nine studies reported the prevalence of mutations in genes in addition to those selected for the meta-analysis, used other definitions of HRD (eg, genomic scars, mutational signatures, and structural variation patterns), or reported only the overall HRD prevalence without specifying single-gene alterations. HRD prevalence ranged from 14.5% to 16.5% when extended next-generation sequencing panels were used, and from 24% to 44% when whole-genome or whole-exome sequencing was used.
The investigators concluded, “Surrogate 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 pancreatic ductal adenocarcinoma.”
Andrew V. Biankin, MD, PhD, of the Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the Associazione Italiana Ricerca Cancro, Italian Ministry of Health, Cancer Research UK, Wellcome Trust, and others. For full disclosures of the study authors, visit ascopubs.org.
