A novel liquid biopsy identified a transcription profile in the circulating tumor cells (CTCs) that was shown to be prognostic for decreased survival in patients with metastatic prostate cancer (mPC), and may have a broader ability to identify treatment resistance compared with the well-established androgen receptor (AR) splice variant 7 (AR-V7) alone. These findings were recently published in the Journal of Clinical Oncology.
Approximately 5% to 10% of men with metastatic castration-sensitive prostate cancer and castration-resistant prostate cancer who are treated with androgen receptor signaling inhibitors (ARSIs) will eventually develop resistance to ARSIs, the study authors wrote.
“Comprehensive understanding of the molecular drivers of ARSI resistance and the ability to monitor this evolution over time is critical for early detection and appropriate treatment selection to improve outcomes for these patients,” they emphasized .
To identify potential drivers of treatment resistance, the study authors developed a multiplex liquid biopsy technology capable of simultaneously measuring 3 resistance mechanisms including AR splice variants (AR-V7 and AR-V9) ), AR targets, and neuroendocrine prostate cancer markers on a single platform. Gene expression patterns were identified by using a multi-institutional prospective cohort that included a total of 99 patients.
Hierarchical cluster analysis of gene expression from RNA extracted from the CTCs of patients with mPC led to the identification of 2 distinct molecular clusters. Cluster 1 (C1; 73 patients) had low or no detectable expression of AR-regulated genes. In contrast, cluster 2 (C2; 26 patients) had an elevated expression of AR-regulated genes and was linked to worse overall survival (OS). The median OS for the C2 group was 8.6 months compared with 22.4 months for the C1 group (hazard ratio [HR], 3.45; 95% CI, 1.9-6.14; P <.01).
Multivariate survival analysis revealed that C2 was prognostic for survival independent of other clinicopathologic variables, and AR-V status was not significant when accounting for C2.
Upon further validation in pooled, multicenter phase 2 trials (ClinicalTrials.gov Identifier: NCT01942837; [enzalutamide, 21 patients] and ClinicalTrials.gov Identifier: NCT02025010 [abiraterone, 27 patients ]), 10 of 48 patients exhibited a C2 expression pattern.
Compared with C1 in patients treated with enzalutamide or abiraterone acetate, C2 was found to be associated with worse OS (15.2 months; 95% CI, 4.4-not reached) compared with C1 (HR, 8.43; 95% CI, 2.74-25.92; P <.01). Progression-free survival (PFS) for prostate-specific antigen in the C2 group was 3.6 months compared with 12 months for the C1 group (HR, 4.64; 95% CI, 1.53-14.11; P <.01). Radiographic PFS for the C2 group was 2.7 months compared with 40.6 months for the C1 group (HR, 4.64; 95% CI, 1.82-17.41, P <.01).
In their concluding remarks, the authors stated “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 [mPC] and can be used to identify the emergence of multiple ARSI resistance mechanisms.”
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Sperger JM , Emamekhoo H, McKay RR, et al. Prospective evaluation of clinical outcomes using a multiplex liquid biopsy targeting diverse resistance mechanisms in metastatic prostate cancer. J Clin Oncol. Published online July 1, 2021. doi: 10.1200/JCO.21.00169