Serial blood-based analysis of AR-V7 in men with advanced prostate cancer

Abstract

Background: We previously showed that pretreatment detection of androgen receptor splice variant-7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer is associated with resistance to abiraterone and enzalutamide, but not to taxane chemotherapies. Here, we conducted serial measurements of AR-V7 and evaluated patterns of longitudinal AR-V7 dynamics over the course of multiple sequential therapies.

Patients and methods: Metastatic prostate cancer patients treated at Johns Hopkins with AR-directed therapies or taxane chemotherapies underwent serial liquid biopsies for CTC-based AR-V7 analysis at baseline, during therapy, and at progression. We used a CTC enrichment platform followed by multiplexed reverse-transcription polymerase chain reaction analysis to detect full-length androgen receptor and AR-V7 transcripts. Patients selected for inclusion in this report were those who provided ≥4 CTC samples, at least one of which was AR-V7 positive, over the course of ≥2 consecutive therapies.

Results: We identified 14 patients who received a total of 37 therapies and contributed 70 CTC samples for AR-V7 analysis during a median follow-up period of 11 months. Three patients remained AR-V7 positive during the entire course of therapy. The remainder underwent transitions in AR-V7 status: there were eight instances of 'conversions' from AR-V7-negative to -positive status (during treatment with first-line androgen deprivation therapy, abiraterone, enzalutamide, and docetaxel), and six instances of 'reversions' from AR-V7-positive to -negative status (during treatment with docetaxel and cabazitaxel).

Conclusions: AR-V7 is a dynamic marker, and transitions in AR-V7 status may reflect selective pressures on the tumor exerted by therapeutic interventions. While 'conversions' to AR-V7-positive status were observed with both AR-directed therapies and taxane chemotherapies, 'reversions' to AR-V7-negative status only occurred during taxane therapies. Serial blood-based AR-V7 testing is feasible in routine clinical practice, and may provide insights into temporal changes in tumor evolution.

Keywords: AR-V7; androgen receptor; circulating tumor cell; prostate cancer; splice variant.

© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Swimmer plot indicating treatments that patients received, along with timing (and AR-V7 status) of CTC sampling, and whether or not PSA responses occurred during each therapy. Shaded boxes indicate failure to achieve PSA response; unshaded boxes indicate achievement of 50% PSA reduction on therapy. Percentage values indicate best PSA response. Daggers indicate deceased patient. Thirteen of 14 patients have previously been included in our prior publications, but only in the context of a single therapy.

Figure 2.

Quantification of AR-V7/AR-FL ratios in patients with conversions and reversions in AR-V7 status with AR-directed therapies or taxane chemotherapies. (A) Patients undergoing conversions from AR-V7-negative to -positive status during treatment with AR-directed therapies (ADT, abiraterone, and enzalutamide) as well as docetaxel chemotherapy. Percentage values indicate ratio of AR-V7 to AR-FL transcripts. Note that positive AR-FL values may not appear due to Log conversion of AR-FL transcript copy numbers. (B) Patients undergoing reversions from AR-V7-positive to -negative status during treatment with taxane chemotherapy (docetaxel or cabazitaxel). Percentage values indicate ratio of AR-V7 to AR-FL transcripts. Note that positive AR-FL values may not appear due to Log conversion of AR-FL transcript copy numbers.