In a study reported in the Journal of Clinical Oncology, Sperger et al found that use of a novel liquid biopsy technology resulted in identification of a prognostic transcriptional profile in circulating tumor cells (CTCs) from patients with metastatic prostate cancer. The profile was prognostic independent of androgen receptor splice variant (AR-V) status, an established prognostic marker.

Study Details

In the study, the multiplex liquid biopsy technology was used to collect mRNA from CTCs to measure expression of AR-Vs, AR targets, and neuroendocrine prostate cancer markers. Gene expression patterns were identified in a prospective cohort of 99 patients treated at the University of Wisconsin Carbone Cancer Center and Dana-Farber Cancer Institute. A validation cohort consisted of patients from two phase II trials assessing the AR signaling inhibitors enzalutamide (n = 21) and abiraterone (n = 27) in castration-resistant disease.

Key Findings

In the prospective cohort, hierarchical clustering of CTC transcript expression identified two distinct clusters of patients. Cluster 1 (C1, n = 73) was characterized by low to no detection of AR-regulated genes and included all patients with a histologic diagnosis of neuroendocrine prostate cancer. Cluster 2 (C2, n = 26) was enriched for patients with high expression of transcriptional targets of AR, indicating increased AR transcriptional activity. Patients in C2 were significantly more likely to have castration-resistant vs -sensitive disease, to have bone metastases, and to have received treatment with a taxane.

Median overall survival was 8.6 months in C2 vs 22.4 months in C1 (hazard ratio [HR] = 3.45, 95% confidence interval [CI] = 1.91–6.14, P < .01). Median overall survival was 8.6 months in AR-V–positive patients (AR-V7 and AR-V9, n = 24) vs 19.1 months in AR-V–negative patients (n = 75; P < .01, HR = 2.49, 95% CI = 1.39–4.47, P < .01). In multivariate analysis, C2 was prognostic for survival independent of other clinicopathologic variables (HR = 3.68, 95% CI = 1.59–8.51, P < .01), whereas AR-V status was no longer significant (HR = 0.80, 95% CI = 0.36–1.77, P = .58). C2 had a higher proportion of AR-V–positive patients (54% vs 10%, P < .0001), suggesting that AR-V status may be prognostic due to its association with the C2 profile, rather than independently prognostic.

In the pooled multicenter phase II trials, 10 (21%) of 48 patients had the C2 expression pattern. C2 was associated with worse median overall survival (15.2 months vs not reached; HR = 8.43, 95% CI = 2.74–25.92, P < .01), prostate-specific antigen progression-free survival (3.6 vs 12 months, HR = 4.64, 95% CI = 1.53–14.11, P < .01), and radiographic progression–free survival (2.7 vs 40.6 months; HR = 4.64, 95% CI = 1.82–17.41, P < .01).

The investigators concluded, “We demonstrate that a transcriptional profile detectable in CTCs obtained from liquid biopsies can serve as an independent prognostic marker beyond AR-V7 in patients with metastatic prostate cancer and can be used to identify the emergence of multiple AR signaling inhibitors resistance mechanisms. This is currently being investigated in additional prospective trials.”

Joshua M. Lang, MD, of the Carbone Cancer Center, University of Wisconsin-Madison, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by a Movember-Prostate Cancer Foundation Challenge Award, a grant from the National Institutes of Health, and Department of Defense awards. For full disclosures of the study authors, visit ascopubs.org.