TY - JOUR
T1 - A transcriptomic model for homologous recombination deficiency in prostate cancer
AU - Weiner, Adam B.
AU - Liu, Yang
AU - McFarlane, Matthew
AU - Bawa, Pushpinder S.
AU - Li, Eric V.
AU - Zhao, Xin
AU - Li, Ziwen
AU - Hammoud, Tanya
AU - Hazime, Munna
AU - Karnes, R. Jeffrey
AU - Davicioni, Elai
AU - Reichert, Zachery R.
AU - Chinnaiyan, Arul M.
AU - Lotan, Tamara L.
AU - Spratt, Daniel E.
AU - Schaeffer, Edward M.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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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U2 - 10.1038/s41391-021-00416-2
DO - 10.1038/s41391-021-00416-2
M3 - Article
C2 - 34226663
AN - SCOPUS:85109752602
SN - 1365-7852
VL - 25
SP - 659
EP - 665
JO - Prostate Cancer and Prostatic Diseases
JF - Prostate Cancer and Prostatic Diseases
IS - 4
ER -