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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.

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Fig. 1: HRD scores across prostate and ovarian tumor cohorts.

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Acknowledgements

This work was supported by the Patrick C. Walsh Prostate Cancer Research Fund (ESA, TLL), the Prostate Cancer Foundation (ESA), NIH/NCI Prostate SPORE P50 CA58236; and the NCI Cancer Center Support Grant 5P30 CA006973-52. ALR is supported by a grant from the Breast Cancer Research Foundation.

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Correspondence to Tamara L. Lotan or Emmanuel S. Antonarakis.

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TLL has received research support from Roche/Ventana Medical Systems and DeepBio for other studies. ESA has served as a paid consultant/advisor for Janssen, Pfizer, Sanofi, Dendreon, Merck, Bristol-Myers Squibb, AstraZeneca, Clovis, Eli Lilly and Amgen; has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Merck, Bristol-Myers Squibb, AstraZeneca, and Constellation; and is a co-inventor of an AR-V7 biomarker technology that has been licensed to Qiagen. JSL and KMT are employees and shareholders in Myriad Genetics. RB has received research support from Myriad Genetics and AstraZeneca.

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Lotan, T.L., Kaur, H.B., Salles, D.C. et al. Homologous recombination deficiency (HRD) score in germline BRCA2- versus ATM-altered prostate cancer. Mod Pathol (2021). https://doi.org/10.1038/s41379-020-00731-4

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