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.
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.
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.
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.
Journal of the National Cancer Institute. 2023 Sep 07 [Epub ahead of print]
Takayuki Sumiyoshi, Xiaofei Wang, Evan W Warner, Andrea Sboner, Matti Annala, Michael Sigouros, Kevin Beja, Kei Mizuno, Shengyu Ku, Ladan Fazli, James Eastham, Mary-Ellen Taplin, Jeffrey Simko, Susan Halabi, Michael J Morris, Martin E Gleave, Alexander W Wyatt, Himisha Beltran
Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, Canada., Englander Institute for Precision Medicine, Weill Cornell Medicine, New York NY, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Urology Service at the Department of Surgery, Memorial Sloan Kettering, New York, NY USA., Department of Pathology, University of California at San Francisco, San Francisco, CA, USA., Department of Biostatistics and Bioinformatics and Duke Cancer Institute-Biostatistics, Duke University, Durham, NC, USA., Department of Genitourinary Oncology, Memorial Sloan Kettering, New York, NY USA *co-senior authors.