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Analysis of AR/ARV7 Expression in Isolated Circulating Tumor Cells of Patients with Metastatic Castration-Resistant Prostate Cancer (SAKK 08/14 IMPROVE Trial)


Hench, Ivana Bratic; Cathomas, Richard; Costa, Luigi; Fischer, Natalie; Gillessen, Silke; Hench, Jürgen; Hermanns, Thomas; Kremer, Eloïse; Mingrone, Walter; Mestre, Ricardo Pereira; Püschel, Heike; Rothermundt, Christian; Ruiz, Christian; Tolnay, Markus; Von Burg, Philippe; Bubendorf, Lukas; Vlajnic, Tatjana (2019). Analysis of AR/ARV7 Expression in Isolated Circulating Tumor Cells of Patients with Metastatic Castration-Resistant Prostate Cancer (SAKK 08/14 IMPROVE Trial). Cancers, 11(8):E1099.

Abstract

Despite several treatment options and an initial high response rate to androgen deprivation therapy, the majority of prostate cancers will eventually become castration-resistant in the metastatic stage (mCRPC). Androgen receptor splice variant 7 (ARV7) is one of the best-characterized androgen receptor (AR) variants whose expression in circulating tumor cells (CTCs) has been associated with enzalutamide resistance. ARV7 expression analysis before and during enzalutamide treatment could identify patients requiring alternative systemic therapies. However, a robust test for the assessment of the ARV7 status in patient samples is still missing. Here, we implemented an RT-qPCR-based assay for detection of AR full length (ARFL)/ARV7 expression in CTCs for clinical use. Additionally, as a proof-of-principle, we validated a cohort of 95 mCRPC patients initiating first line treatment with enzalutamide or enzalutamide/metformin within a clinical trial. A total of 95 mCRPC patients were analyzed at baseline of whom 27.3% (26/95) had ARFL+ARV7+, 23.1% (22/95) had ARFL+ARV7-, 23.1% (22/95) had ARFL-ARV7-, and 1.1% (1/95) had ARFL-ARV7+ CTCs. In 11.6% (11/95), no CTCs could be isolated. A total of 25/95 patients had another CTC analysis at progressive disease, of whom 48% (12/25) were ARV7+. Of those, 50% (6/12) were ARV7- and 50% (6/12) were ARV7+ at baseline. Our results show that mRNA analysis of isolated CTCs in mCRPC is feasible and allows for longitudinal endocrine agent response monitoring and hence could contribute to treatment optimization in mCRPC.

Abstract

Despite several treatment options and an initial high response rate to androgen deprivation therapy, the majority of prostate cancers will eventually become castration-resistant in the metastatic stage (mCRPC). Androgen receptor splice variant 7 (ARV7) is one of the best-characterized androgen receptor (AR) variants whose expression in circulating tumor cells (CTCs) has been associated with enzalutamide resistance. ARV7 expression analysis before and during enzalutamide treatment could identify patients requiring alternative systemic therapies. However, a robust test for the assessment of the ARV7 status in patient samples is still missing. Here, we implemented an RT-qPCR-based assay for detection of AR full length (ARFL)/ARV7 expression in CTCs for clinical use. Additionally, as a proof-of-principle, we validated a cohort of 95 mCRPC patients initiating first line treatment with enzalutamide or enzalutamide/metformin within a clinical trial. A total of 95 mCRPC patients were analyzed at baseline of whom 27.3% (26/95) had ARFL+ARV7+, 23.1% (22/95) had ARFL+ARV7-, 23.1% (22/95) had ARFL-ARV7-, and 1.1% (1/95) had ARFL-ARV7+ CTCs. In 11.6% (11/95), no CTCs could be isolated. A total of 25/95 patients had another CTC analysis at progressive disease, of whom 48% (12/25) were ARV7+. Of those, 50% (6/12) were ARV7- and 50% (6/12) were ARV7+ at baseline. Our results show that mRNA analysis of isolated CTCs in mCRPC is feasible and allows for longitudinal endocrine agent response monitoring and hence could contribute to treatment optimization in mCRPC.

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Additional indexing

Contributors:Sakk SGFCCR1
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Urological Clinic
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Oncology
Life Sciences > Cancer Research
Language:English
Date:1 August 2019
Deposited On:06 Feb 2020 08:27
Last Modified:21 Jun 2020 22:34
Publisher:MDPI Publishing
ISSN:2072-6694
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.3390/cancers11081099
PubMed ID:31374981

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