A transcriptomic model for homologous recombination deficiency in prostate cancer

Adam B. Weiner, Yang Liu, Matthew McFarlane, Pushpinder S. Bawa, Eric V. Li, Xin Zhao, Ziwen Li, Tanya Hammoud, Munna Hazime, R. Jeffrey Karnes, Elai Davicioni, Zachery R. Reichert, Arul M. Chinnaiyan, Tamara L. Lotan, Daniel E. Spratt, Edward M. Schaeffer

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Tumors with mutations associated with homologous recombination deficiency (HRD) are uncommon in prostate cancer (PCa) and variably responsive to PARP inhibition. To better identify tumors with HRD, we developed a transcriptomic signature for HRD in PCa (HRD-P). Methods: By using an established mutational signature, we created and validated HRD-P in six independent PCa cohorts (primary PCa, n = 8224; metastatic castration-resistant PCa [mCRPC], n = 328). Molecular and clinical features were compared between HRD-P+ tumors and those with single HR-gene mutations. Results: HRD-P+ tumors were more common than tumors with single HR-gene mutations in primary (201/491, 41% vs 32/491 6.5%) and mCRPC (126/328, 38% vs 82/328, 25%) cases, and HRD-P+ was more predictive of genomic instability suggestive of HRD. HRD-P+ was associated with a shorter time to recurrence following surgery and shorter overall survival in men with mCRPC. In a prospective trial of mCRPC treated with olaparib (n = 10), all three men with HRD-P+ experienced prolonged (>330 days) PSA progression-free survival. Conclusion: These results suggest transcriptomics can identify more patients that harbor phenotypic HRD than single HR-gene mutations and support further exploration of transcriptionally defined HRD tumors perhaps in conjunction with genomic markers for therapeutic application.

Original languageEnglish (US)
JournalProstate Cancer and Prostatic Diseases
DOIs
StateAccepted/In press - 2021

ASJC Scopus subject areas

  • Oncology
  • Urology
  • Cancer Research

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