A Prospective Genome-Wide Study of Prostate Cancer Metastases Reveals Association of Wnt Pathway Activation and Increased Cell Cycle Proliferation with Primary Resistance to Abiraterone Acetate-Prednisone

Abstract

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 PSA measurement, bone and CT imaging and symptom assessments. Acquired resistance was determined using the endpoint 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 (non-responders). 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 (IQR: 4.4 to 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 non-responders. Additionally, mRNA expression of cell cycle regulatory genes was increased in non-responders. In multivariate models increased cell cycle proliferation scores (≥ 50) were associated with shorter TTTC (HR = 2.11, 95% CI: 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.