Copy number loss of chromosome 17q22 was more common among men with metastatic castration-resistant prostate cancer (mCRPC) that was resistant to enzalutamide, resulting in poorer overall survival (OS), according to a study published in Clinical Cancer Research.1

Enzalutamide is an established effective treatment for mCRPC, but “disease progression is inevitable, and little is known about mechanisms that contribute to clinical enzalutamide resistance,” the authors wrote. The purpose of this study was to characterize molecular mechanisms that may be involved with acquiring enzalutamide resistance.

The study analyzed tumor biopsy samples from 101 men with mCRPC who had never received enzalutamide or whose disease was enzalutamide resistant. Whole genome sequencing and RNA sequencing were used to identify gene mutations and copy number alterations. The clinical endpoint was OS from the time of tissue biopsy.

There were 124 protein-coding genes identified in which copy number loss occurred more frequently among the mCRPC samples with enzalutamide resistance compared with no prior enzalutamide exposure. These 124 genes comprised 9 distinct genomic regions, which included 8 putative tumor suppressor genes.


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Analysis of the 9 genomic regions demonstrated that copy number loss of 17q22 was significantly associated with enzalutamide resistance, occurring among 16% of men with enzalutamide-resistance compared with 0 among men with no prior enzalutamide exposure.

Loss of 17q22 was predictive of shorter survival after adjustment of other factors associated with survival (hazard ratio [HR], 4.634; 95% CI, 1.69-12.643; P =.0028). The median OS was 8.9 months among patients with loss of 17q22 compared with 19.3 months among patients with intact 17q22 (HR, 3.44; 95% CI, 1.338-8.867; P =.006).

There was no significant difference in gain of copy number of any gene or region between the enzalutamide-resistant and non-exposed groups.

Using the master regulator inference algorithm, loss of 17q22 was associated with activation of CDK1/2, Akt, and PLK1 “demonstrating the potential therapeutic relevance of 17q22 loss in mCRPC,” the authors wrote.

The authors concluded that these findings identify a subset of patients with mCRPC with poor prognosis. “Our results suggest that specific kinases may be activated in tumors with 17q22 loss…drugs that block these kinases are in clinical testing in CRPC and it will be important to corelate 17q22 loss with drug sensitivity,” they wrote.

Disclosures: Multiple authors declare affiliations with the pharmaceutical industry. Please refer to the reference for a complete list of authors’ disclosures.

Reference

Guan X, Sun D, Lu E, et al. Copy number loss of 17q22 is associated with enzalutamide resistance and poor prognosis in metastatic castration-resistant prostate cancer. Clin Cancer Res. Published online July 29, 2020. doi:10.1158/1078-0432.CCR-19-2303.