Genomic profiles and clinical outcomes in primary versus secondary metastatic hormone-sensitive prostate cancer

Emily Nizialek, Su Jin Lim, Hao Wang, Pedro Isaacsson Velho, Srinivasan Yegnasubramanian, Emmanuel S. Antonarakis

Research output: Contribution to journalArticlepeer-review

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, 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.

Original languageEnglish (US)
Pages (from-to)572-579
Number of pages8
JournalProstate
Volume81
Issue number9
DOIs
StatePublished - May 2021
Externally publishedYes

Bibliographical note

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

Keywords

  • de novo metastatic prostate cancer
  • metastatic hormone-sensitive prostate cancer
  • TP53 dominant-negative mutation

PubMed: MeSH publication types

  • Journal Article

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