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ASCO GU 2019

ASCO GU 2019: Genomic Drivers of Poor Prognosis and Enzalutamide Resistance in Metastatic Castration-Resistant Prostate Cancer

San Francisco, CA (UroToday.com)Recent studies have identified genomic alterations in metastatic castrate resistant prostate cancer (mCRPC), but our understanding of the clinical implications is in its infancy. As part of the multi-institiutional West Coast Prostate Cancer Dream Team project, Chen et al conducted a prospective cohort study. Using whole genome sequencing (WGS), they analyzed associations between “key” gene alterations and overall survival (OS). They also performed whole-transcriptome RNA sequencing to identify genomic associations with enzalutamide resistance in mCRPC.

Metastasis biopsies were collected in 101 mCRPC patients and samples underwent WGS and RNA sequencing. Genomic events were assessed in terms of mutation, copy number, structural variation and univariate and multivariate analyses were performed to assess their prognostic significance with respect to overall survival. In a separate analysis, expression-based gene enrichment analyses then cross-sectional enrichment and survival analyses were performed on the genomic pathways to investigate enzalutamide resistance.

The median age of the cohort was 71 (±8.4), 85% of the population was white, 57 (56%) had ECOG 0 and 41 (40.6%) ECOG 1 performance scores, 65 (65%) were enzalutamide naïve, and 35 (35%) were enzalutamide resistant. The tumor biopsy sites included bone in 43 (42.6%), lymph node 39 (38.6%), liver 11 (10.9%), and other 8 (7.9%).

Sequencing analyses found that RB1 loss was associated with poor overall survival (median 14.1 vs 42.0 months, p < 0.0001) on univariate analyses. Comparing enzalutamide resistant versus naïve samples, the Wnt/beta-catenin pathway was identified as the most significantly expressed pathway in enzalutamide-resistant patients. Additionally, beta-catenin activating mutations were exclusively found in the enzalutamide resistant patients (p=0.013) and were predictive of poor overall survival (median 13.6 vs 41.7 months, p<0.001).

In conclusion, whole genome sequencing and RNA sequencing used to identify genomic alterations in mCRPC have revealed that only RB1 loss is associated with worse overall survival. Other alterations of tumor suppressor genes was not associated with shorter overall survival. In enzalutamide-resistant mCRPC, the Wnt/beta-catenin pathway is presented as an important potential therapeutic pathway.

Presented by: William S. Chen, BS

Written by: Selma Masic, MD, Urologic Oncology Fellow (SUO), Fox Chase Cancer Center, Philadelphia, PA. Twitter:@selmasic at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA