TY - JOUR
T1 - Genomic profiles and clinical outcomes in primary versus secondary metastatic hormone-sensitive prostate cancer
AU - Nizialek, Emily
AU - Lim, Su Jin
AU - Wang, Hao
AU - Isaacsson Velho, Pedro
AU - Yegnasubramanian, Srinivasan
AU - Antonarakis, Emmanuel S.
N1 - Funding Information:
Dr. Antonarakis reports grants and personal fees from Janssen, personal fees from Astellas, grants and personal fees from Sanofi, grants and personal fees from Dendreon, personal fees from Pfizer, personal fees from Invitae, grants and personal fees from AstraZeneca, grants and personal fees from Clovis, grants and personal fees from Merck, grants from Johnson & Johnson, grants from Genentech, grants from Novartis, grants from Bristol Myers‐Squibb; and also has a patent (PCT/US2015/046806; US20170275673A1) on an AR‐V7 biomarker technology, licensed to Qiagen. Dr. Isaacsson Velho reports honoraria from Bayer, Astellas Pharma, and AstraZeneca, and on the speakers' bureau for AstraZeneca, Pfizer, Bristol‐Myers Squibb, and Bayer, and research funding from Bristol‐Myers Squibb, Bayer, and Pfizer, and expert testimony for Bayer, and travel, accommodations, expenses from AstraZeneca, Astellas Pharma, Pfizer, Merck Serono, and Merck. No disclosures to report for authors Emily Nizialek, Su Jin Lim, Hao Wang, and Srinivasan Yegnasubramanian.
Publisher Copyright:
© 2021 The Authors. The Prostate published by Wiley Periodicals LLC
PY - 2021/6/15
Y1 - 2021/6/15
N2 - Background: Clinical outcomes may differ among patients presenting with primary (de novo) metastatic hormone-sensitive prostate cancer (mHSPC) versus secondary (metachronous) mHSPC occurring after local therapy. It is unknown what molecular features distinguish these potentially distinct presentations. Methods: A single-center retrospective study of mHSPC patients classified as primary mHSPC (n = 121) or secondary mHSPC (n = 106). A targeted set of genes was analyzed: BRCA2, PTEN, RB1, TP53, SPOP, CDK12, any two out of PTEN/RB1/TP53 alterations, and homologous recombination deficiency mutations. TP53 mutations were categorized as loss-of-function (LOF) versus dominant-negative (DN). The impacts of genetic features on progression-free survival (PFS) and overall survival (OS) were assessed using univariate and multivariate Cox proportional hazards regression. Results: Median PFS was 15 and 30 months for men with primary and secondary mHSPC, respectively (hazard ratio: 0.57, 95% confidence interval: 0.41–0.78; p <.01). OS did not show a significant difference between groups. There were more men with Gleason 8–10 disease in the primary versus secondary mHSPC groups (83% vs. 68%; p <.01). In univariate and multivariate analyses, TP53 DN mutations showed a statistically significant association with OS for the entire mHSPC population. Conversely, SPOP mutations were associated with improved OS. Additionally, TP53 mutations (DN and LOF) were associated with worse OS for secondary mHSPC. A combination of PTEN/RB1/TP53 mutations was associated with worse OS and PFS for secondary mHSPC, while no genomic alteration affected outcomes for primary mHSPC. Conclusions: TP53 DN mutations, but not all TP53 alterations, were the strongest predictor of negative outcomes in men with mHSPC, while SPOP mutations were associated with improved outcomes. In subgroup analyses, specific alterations were prognostic of outcomes in secondary, but not primary, mHSPC.
AB - Background: Clinical outcomes may differ among patients presenting with primary (de novo) metastatic hormone-sensitive prostate cancer (mHSPC) versus secondary (metachronous) mHSPC occurring after local therapy. It is unknown what molecular features distinguish these potentially distinct presentations. Methods: A single-center retrospective study of mHSPC patients classified as primary mHSPC (n = 121) or secondary mHSPC (n = 106). A targeted set of genes was analyzed: BRCA2, PTEN, RB1, TP53, SPOP, CDK12, any two out of PTEN/RB1/TP53 alterations, and homologous recombination deficiency mutations. TP53 mutations were categorized as loss-of-function (LOF) versus dominant-negative (DN). The impacts of genetic features on progression-free survival (PFS) and overall survival (OS) were assessed using univariate and multivariate Cox proportional hazards regression. Results: Median PFS was 15 and 30 months for men with primary and secondary mHSPC, respectively (hazard ratio: 0.57, 95% confidence interval: 0.41–0.78; p <.01). OS did not show a significant difference between groups. There were more men with Gleason 8–10 disease in the primary versus secondary mHSPC groups (83% vs. 68%; p <.01). In univariate and multivariate analyses, TP53 DN mutations showed a statistically significant association with OS for the entire mHSPC population. Conversely, SPOP mutations were associated with improved OS. Additionally, TP53 mutations (DN and LOF) were associated with worse OS for secondary mHSPC. A combination of PTEN/RB1/TP53 mutations was associated with worse OS and PFS for secondary mHSPC, while no genomic alteration affected outcomes for primary mHSPC. Conclusions: TP53 DN mutations, but not all TP53 alterations, were the strongest predictor of negative outcomes in men with mHSPC, while SPOP mutations were associated with improved outcomes. In subgroup analyses, specific alterations were prognostic of outcomes in secondary, but not primary, mHSPC.
KW - TP53 dominant-negative mutation
KW - de novo metastatic prostate cancer
KW - metastatic hormone-sensitive prostate cancer
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U2 - 10.1002/pros.24135
DO - 10.1002/pros.24135
M3 - Article
C2 - 33955569
AN - SCOPUS:85105174023
SN - 0270-4137
VL - 81
SP - 572
EP - 579
JO - Prostate
JF - Prostate
IS - 9
ER -