To identify molecular features associated with earlier progression to definitive therapy amongst patients with localized prostate cancer (PCa) managed on active surveillance (AS).
We performed a retrospective pilot study of seven patients with low- to intermediate-risk PCa undergoing serial multiparametric MRI (mpMRI)-targeted biopsies of the same lesion while on AS who all proceeded to definitive therapy. Time-to-treatment (TTT) was defined as years from first biopsy on AS to definitive therapy. Laser-capture microdissection was used to separate tumor epithelium, benign glands, high-grade prostatic intraepithelial neoplasia, and stroma in each biopsy specimen. DNA from tumor and matched benign tissue underwent whole-exome sequencing and RNA from all compartments underwent whole-transcriptome sequencing. Somatic mutations and copy-number alterations were compared across serial biopsies, used to reconstruct phylogenies, and quantify clonal complexity.
Tumors exhibited substantial intratumoral heterogeneity, and in three of six paired cases, serial mpMRI-targeted biopsies showed discordant somatic profiles consistent with sampling distinct major clones over time. By contrast, no single gene-level alteration, and few large-scale chromosomal events, were associated with TTT. High clonal complexity, defined as ≥3 subclones, was associated with significantly shorter TTT than low complexity (median 1.9 vs. 7.2 years; P = 0.0082). Exploratory pathway analyses of individual tissue components suggested TTT-associated differences in inflammatory signaling and stromal-epithelial cross-talk.
In this small, hypothesis-generating cohort, clonal complexity was more closely associated with earlier definitive therapy than individual genomic alterations. Larger prospective studies are needed to validate whether multiomic measures of clonal architecture can improve AS risk stratification.
Urology. 2026 Jun 24 [Epub ahead of print]
Nichelle C Whitlock, Rebecca Silver, Shana Y Trostel, Chennan Li, Rosina T Lis, Julian Custer, Nicholas T Terrigino, Ross Lake, Cathy D Vocke, Peter A Pinto, Adam G Sowalsky
Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA., Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA; Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA., Urologic Oncology Branch, National Cancer Institute, Bethesda, MD, USA., Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA., Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA. Electronic address: .