Homologous recombination deficiency (HRD) score in germline BRCA2- versus ATM-altered prostate cancer

Abstract

The homologous recombination deficiency (HRD) score integrates three DNA-based measures of genomic instability, and has been understudied in prostate cancer. Given the recent FDA-approval of two PARP inhibitors for prostate cancer, HRD score analysis could help to refine treatment selection. We assessed HRD score (defined as the sum of loss-of-heterozygosity, telomeric allelic imbalance, and large-scale state transitions) in three cohorts of primary prostate cancer, including a Johns Hopkins University (JHU) cohort with germline mutations in BRCA2 , ATM or CHEK2 (n=64), the TCGA cohort (n=391), and the PROGENE cohort (n=102). In the JHU cohort, tumors with germline BRCA2 mutations had higher HRD scores (median=27) than those with germline ATM or CHEK2 mutations (median=16.5 [p=0.029] and 9 [p<0.001], respectively). For TCGA tumors without underlying HR pathway mutations, the median HRD score was 11, significantly lower than ovarian carcinoma lacking BRCA1/2 mutations (median=28). In the absence of HR gene mutations, the median HRD score was unexpectedly higher among prostate cancers with TP53 mutations versus those without (17 vs 11; p=0.015); this finding was confirmed in the PROGENE cohort (24 vs 16; p=0.001). Finally, among eight BRCA2 -altered patients who received olaparib, progression-free survival trended longer in those with HRD scores above versus below the median (14.9 vs 9.9 months). We conclude that HRD scores are low in primary prostate cancer and higher in cases with germline BRCA2 or somatic TP53 mutations. Germline BRCA2 -altered cases have significantly higher HRD scores than germline ATM -altered or CHEK2 -altered cases, consistent with the lower efficacy of PARP inhibitors among the latter.

Utility of Homologous Recombination Deficiency Biomarkers Across Cancer Types

“…Recently, in prostate cancer, TP53 mutations were reported to be associated with increased HRD scores independently of HRR pathway gene alterations. 40 This suggests that high HRD score in TP53 -mutated cases could alternatively be because of chromosomal instability caused by mechanisms other than HRD (eg, loss of cell-cycle checkpoint mechanisms).…”

Observed evidence for guideline‐recommended genes in predicting prostate cancer risk from a large population‐based cohort

“…They found HRD score was higher for tumors with germline mutations in these genes than tumors with wildtype genes. Interestingly, HRD score was highest for germline mutations in BRCA2 , followed by ATM and CHEK2 , consistent with the OR of germline mutations in these different genes 22 . For HOXB13 , the lack of deletion or protein truncating mutations suggest a gain‐of‐function may contribute to the development of PCa 23,24 …”

The utility of homologous recombination deficiency biomarkers across cancer types

“…3A). In a very recent study of prostate cancer, TP53 mutations were reported to be associated with increased HRD scores independently of HRR pathway gene alterations 57 . These observations suggest that the high HRD score in TP53 mutated cases is not necessarily due to true HRD but, rather, due to chromosomal instability caused by mechanisms other than HRD (e.g., loss of cell-cycle checkpoint mechanisms).…”