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

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.

TP53 structure–function relationships in metastatic castrate‐sensitive prostate cancer and the impact of APR‐246 treatment

“…In this report, we identify TP53 mutations cluster within the DNA‐binding domain impacting protein function in patients with mCSPC. We also demonstrated TP53 DN mutations are associated with more aggressive clinical disease biology, as evidenced by enrichment in synchronous and polymetastatic disease states, which was also associated with significantly worse OS, concordant with previous characterization by Nizialek et al (2021) 21 . Furthermore, through in vitro structure–function characterization of TP53 mutant cell lines, we identified increased pro‐metastatic phenotypes as a potential mechanism for these poor clinical outcomes.…”

Management of patients with advanced prostate cancer—metastatic and/or castration-resistant prostate cancer: Report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022

“…Recent studies indicate that copy number loss or deleterious mutation(s) of one or more tumour suppressor genes (TP53, PTEN, and RB1) are associated with poor prognosis in mHSPC, while Speckle-type POZ Protein (SPOP) mutations appear to characterise a subset of patients with mHSPC that is more dependent on AR signalling, and germline inheritance of the adrenal-permissive HSD3B1 confers clinical dependence on non-gonadal androgens [18][19][20][21][22][23][24].…”

Identification of pyroptosis-related lncRNA signature and AC005253.1 as a pyroptosis-related oncogene in prostate cancer

“…TP53 mutation was the most common genetic alteration that played a major role in the pathogenesis of PCa ( 56 , 57 ). SPOP mutations were associated with improved overall survival, whereas TP53 mutations were associated with poorer survival in secondary metastatic hormone-sensitive PCa ( 58 ). These data implicated that the high-score group might have more tumorigenic gene mutations.…”