Molecular features of prostate cancer post-neoadjuvant therapy in the Phase 3 CALGB 90203 trial.
Academic Article
Overview
abstract
PURPOSE: The phase 3 CALGB 90203 (Alliance) trial evaluated neoadjuvant chemohormonal therapy (CHT) for high-risk localized PCa before radical prostatectomy (RP). We dissect the molecular features of post-treated PCa along with long-term clinical outcomes to explore mechanisms of response and resistance to CHT. PATIENTS AND METHODS: We evaluated 471 RP tumors, including 294 samples from 166 patients treated with 6 cycles of docetaxel plus androgen deprivation therapy prior to RP, and 177 samples from 97 patients in the control arm of RP alone. Targeted DNA sequencing and mRNA expression of tumor foci and adjacent non-cancer regions were analyzed in conjunction with pathologic changes and clinical outcomes. RESULTS: Tumor fraction estimated from DNA sequencing was significantly lower in CHT-exposed tissues compared to control. Higher tumor fraction after CHT was associated with aggressive pathologic features and poor outcomes including PSA progression-free survival. SPOP mutations were infrequently detected after CHT, while TP53 mutations were enriched and associated with shorter overall survival. Residual tumor fraction post-CHT was linked with higher expression of androgen receptor-regulated, cell cycle, and neuroendocrine genes, suggesting persistent populations of active PCa cells. Supervised clustering of post-CHT high tumor fraction tissues identified a group of patients with elevated cell cycle-related gene expression and poor clinical outcomes. CONCLUSIONS: Distinct recurrent PCa genomic and transcriptomic features are observed after CHT exposure. Tumor fraction assessed by DNA sequencing quantifies pathologic response and could be a useful trial endpoint or prognostic biomarker. TP53 mutations and high cell cycle transcriptomic activity are linked with aggressive residual disease despite potent CHT.
