Background: Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known. Patients and methods: In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n=82) and RNA sequencing (n=75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher's exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC. Results: At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4-24.1). Genes in the Wnt/β-catenin pathway were more frequently mutated and negative regulators of Wnt/β-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥50) were associated with shorter TTTC (hazard ratio=2.11, 95% confidence interval: 1.17-3.80; P=0.01). Conclusions: Wnt/β-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.
Bibliographical noteFunding Information:
This study was funded in part by the Mayo Clinic Center for Individualized Medicine (MC1351 to MK and LW); Minnesota Partnership for Biotechnology and Medical Genomics (MNP#14.37 to MK and SMD); Department of Defense (W81XWH-15-1-0634 to SMD, MK); Prostate Cancer Foundation (2015 Prostate Cancer Foundation Challenge Award to HH, MK, and SMD); National Institute of Health-National Cancer Institute, R01 CA174777 to SMD; AT Suharya and Ghan DH.; Joseph and Gail Gassner; and Mayo Clinic Schulze Cancer for Novel Therapeutics in Cancer Research (to MK and LW). Other contributing groups include the Mayo Clinic Cancer Center (no grant numbers apply), the Pharmacogenomics Research Network (PGRN) (no grant numbers apply), and the Janssen Research & Development, LLC (no grant numbers apply), which provided partial drug support on study from April 2014 onwards for study patient number 45–92, and funding support for collaborative bioinformatics analysis).
- Abiraterone acetate
- Castrate-resistance prostate cancer
- Wnt/β-catenin signaling