To determine the performance of a multi-gene copy number variation (MG-CNV) risk score in metastatic tissue and plasma biospecimens from treatment-naïve metastatic castrate-resistant prostate cancer (mCRPC) patients for prediction of clinical outcomes.
mCRPC tissue and plasma cell-free DNA (cfDNA) biospecimen sequencing results obtained from publicly accessed cohorts in dbGaP, cBioPortal, and an institutional mCRPC cohort were used to develop a MG-CNV risk score derived from gains in AR, MYC, COL22A1, PIK3CA, PIK3CB, NOTCH1 and losses in TMPRSS2, NCOR1, ZBTB16, TP53, NKX3-1 in independent cohorts for determining overall survival (OS), progression free survival (PFS) to first-line Androgen Receptor Pathway Inhibitors (ARPIs). The range of the risk scores for each cohort was dichotomized into "high-risk" group and "low-risk" groups and association with OS/PFS determined. Univariate and multi-variate Cox Proportional Hazard Regressions were applied for survival analyses (P < .05 for statistical significance).
Of 1,137 metastatic tissue-plasma biospecimens across all cohorts, 699/1137 were treatment-naive mCRPC (235/699 metastatic tissue; 464/699 plasma-cfDNA) and 311/1137 were matched tissue-cfDNA pairs. In multivariate analysis the MG-CNV risk score derived from metastatic tissue or in cfDNA was statistically significantly associated with OS with high score associated with short survival, Hazard Ratio (HR) 2.65 (CI: 1.99- 3.51; P = 1.35-11) and shorter PFS to ARPIs (median PFS of 7.8 months) compared to 14 months in patients with low-risk score.
A molecular risk score in treatment-naïve mCRPC state obtained either in metastatic tissue or cfDNA predicts clinical survival outcomes and offers a tumor biology-based tool to design biomarker -based enrichment clinical trials.
JNCI cancer spectrum. 2025 Feb 28 [Epub ahead of print]
Muhammad Zaki Hidayatullah Fadlullah, David Nix, Cameron Herberts, Corinne Maurice-Dror, Alexander W Wyatt, Bogdana Schmidt, Brayden Fairbourn, Aik-Choon Tan, Liang Wang, Manish Kohli
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, US., Department of Biomedical Informatics, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, US., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada., Division of Urology, Department of Surgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, US., Department of Internal Medicine, Spencer Fox Eccles School of Medicine., Department of Tumor Biology, H. Lee Moffitt Cancer Center, Tampa, 33612, FL, USA., Division of Oncology, Department of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, US.