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Clinical Research

A transcriptomic model for homologous recombination deficiency in prostate cancer

Prostate Cancer and Prostatic Diseases volume 25, pages 659–665 (2022)Cite this article

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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.

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Fig. 1: Genomic and clinical characteristics of HRD-P+ tumors in TCGA.
Fig. 2: Clinical outcomes and molecular pathways in primary HRD-P+ tumors.
Fig. 3: Clinical outcomes and molecular pathways in metastatic HRD-P+ tumors.

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Funding

This work was supported in part by the National Institutes of Health grant 5U01CA196390 (EMS), the Prostate Cancer Foundation (EMS), Department of Defense grant W81XWH-15-1-0661 (EMS and TLL), the 2019 Urology Care Foundation Residency Research Award Program and the Russell Scott, Jr., MD Urology Research Fund (ABW), as well as the University of Michigan Prostate Specialized Program of Research Excellence (SPORE) P50 CA186786-05 and the Early Detection Research Network grant UO1 CA111275 (AMC). The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Author information

Authors and Affiliations

  1. Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Adam B. Weiner, Eric V. Li & Edward M. Schaeffer

  2. Decipher Biosciences, San Diego, CA, USA

    Yang Liu, Xin Zhao, Ziwen Li & Elai Davicioni

  3. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA

    Matthew McFarlane & Daniel E. Spratt

  4. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    Pushpinder S. Bawa & Arul M. Chinnaiyan

  5. University of Michigan College of Literature, Science, and the Arts, Ann Arbor, MI, USA

    Tanya Hammoud & Munna Hazime

  6. Department of Urology, Mayo Clinic Rochester, Rochester, MN, USA

    R. Jeffrey Karnes

  7. Division of Hematology/Oncology, Department of Internal Medicine, Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA

    Zachery R. Reichert

  8. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Tamara L. Lotan

Authors
  1. Adam B. Weiner
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Contributions

Conception and design: ABW, ED, AMC, TLL, DES. Acquisition of data: ABW, YL, MMcF, PSB, XZ, ZL, TH, MH, RJK, ED, AMC, TLL. Analysis and interpretation of data: ABW, YL, MMcF, XZ, ZL. Drafting of manuscript: ABW, YL, MMcF, PSB, EVL, XZ, ZL, TH, MH, DES, EMS. Critical revision of the manuscript for important intellectual content: ABW, R. JK, ED, ZRR, AMC, TLL, DES, EMS. Statistical analysis: ABW, YL. Obtaining funding: ABW, AMC, TLL, EMS. Administrative, technical, or material support: TLL, AMC, TLL, DES, EMS. Supervision: TLL, AMC, TLL, DES, EMS. Other: none.

Corresponding author

Correspondence to Edward M. Schaeffer.

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Ethics approval and consent to participate

The study was performed in accordance with the Declaration of Helsinki.

Competing interests

YL, XZ, ZL, ED are employees of Decipher Biosciences. AMC currently serves on the scientific advisory board of Tempus. The remaining authors declare no potential conflicts of interest.

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Weiner, A.B., Liu, Y., McFarlane, M. et al. A transcriptomic model for homologous recombination deficiency in prostate cancer. Prostate Cancer Prostatic Dis 25, 659–665 (2022). https://doi.org/10.1038/s41391-021-00416-2

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