Interrelation of Functional Homologous Recombination Deficiency and HRR Pathway Alterations in Prostate Cancer

ASCO Genitourinary Cancers Symposium 2022, Tempus-authored Presentation
Authors Jason Zhu, Sherif Mohamed El-Refai, Elizabeth Mauer, Benjamin D. Leibowitz, Landon Carter Brown, Claud Grigg, James T Kearns, Justin T. Matulay, Peter E Clark, Derek Raghavan, Earle F Burgess

Background: The use of PARP inhibitors (PARPi) may trigger synthetic lethality of tumor cells in the context of deficient homologous recombination repair (HRR). Approximately 10-20% of patients with prostate cancer harbor mutations in the HRR pathway, but HRR-associated mutations do not consistently predict the response to PARPi. Considering alternative methods to define Homologous Recombination Deficiency (HRD)—the inability to repair double strand breaks—may aid in identifying additional tumors that are sensitive to PARPi. Here, we evaluate the relationship between HRD status and HRR mutations amongst a large cohort of patients with prostate cancer.

Methods: Retrospective analysis of 1,022 de-identified patients with prostate cancer that underwent next generation sequencing (NGS) with the Tempus|xT assay (DNA-seq of 648 genes at 500x coverage, whole-exome capture RNA-seq) was performed. Comparison groups were defined based on HRR alterations—either mono- or bi-allelic alterations of BRCA1 or BRCA2 (BRCA1/2), ATM, or other HRR pathway genes. HRD status was determined via the Tempus RNA-based HRD algorithm.

Results: Among this cohort, mono (-/+) or biallelic (-/-) alterations of HRR genes were found in 432 patients: BRCA1/2 -/- (n = 31), BRCA1/2 -/+ (n = 87), ATM-/- (n = 24), ATM-/+ (n = 67), other HRR-/- (n = 54), other HRR-/+ (n = 169) or no HRR alterations (n = 590). The BRCA1/2-/- group had a higher frequency of Asians (17% vs. < 7% in all other groups) and were diagnosed at younger ages (median 62 years vs. > 65 for all other groups). We identified 130/1022 (13%) patients with prostate cancer to be HRD-positive (HRD+) and observed significant differences in HRD positivity according to the type of HRR alteration observed (Table). Notably, 54% (70/130) of HRD+ patients had no mutations in any genes associated with the HRR pathway. Conversely, 89% (278/314) of patients with non-BRCA1/2 HRR mutations were HRD negative. Amongst all individuals with biallelic loss of any HRR gene, HRD positivity was most enriched for BRCA2-/- (16/29, p < 0.001) and PALB2-/- (3/4, p = 0.082).

Conclusions: By using an RNA-based HRD algorithm, we found 13% of patients with prostate cancer are HRD+. This RNA-based HRD signature not only captures patients with HRR mutations but also identifies a substantial population of HRD+ patients who are currently undetectable by methods based solely on sequencing HRR genes. Further research is needed to assess the clinical response to PARPi in this HRD+ population, as well as the response to PARPi in the HRD negative population who harbor HRR gene alterations.