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Genomic profiles and clinical outcomes in primary versus secondary metastatic hormone‐sensitive prostate cancer
Author(s) -
Nizialek Emily,
Lim Su Jin,
Wang Hao,
Isaacsson Velho Pedro,
Yegnasubramanian Srinivasan,
Antonarakis Emmanuel S.
Publication year - 2021
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.24135
Subject(s) - oncology , medicine , hazard ratio , pten , univariate analysis , prostate cancer , proportional hazards model , confidence interval , multivariate analysis , cancer , biology , genetics , apoptosis , pi3k/akt/mtor pathway
Abstract 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, TP5 3 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.