AR-V7 Androgen Receptor Variant as a Predictor of Response to Androgen-receptor Targeting Agents Used to Treat Castration-refractory Metastatic Prostate Cancer
Authors:
Büchler Tomáš 1; Bobek Vladimír 2,3; Kološtová Katarína 2
Authors‘ workplace:
Onkologická klinika 1. LF UK a Thomayerovy nemocnice, Praha
1; Ústav laboratorní diagnostiky, FN Královské Vinohrady, Praha
2; III. chirurgická klinika 1. LF UK a FN Motol, Praha
3
Published in:
Klin Onkol 2018; 31(1): 9-14
Category:
Review
doi:
https://doi.org/10.14735/amko20189
Overview
Background:
Several systemic treatment options are currently available for patients with metastatic castration-refractory prostate cancer (mCRPC), including the androgen-receptor targeting agents (ARTA) enzalutamide and abiraterone, the taxanes docetaxel and cabazitaxel, and the radioisotope drug 223-radium dichloride. In some patients with mCRCP, alternative splicing of androgen receptor (AR) mRNA occurs, resulting in the formation of a truncated AR lacking the androgen-binding domain. These receptors activate downstream signalling pathways even without the ligand. Recent studies show that the presence of the AR-V7 (ARV – AR variants) splicing variant is associated with resistance to ARTA. Bec>ause the presence of AR-V7 does not affect the efficacy of other systemic therapies used in mCRCPs, particularly taxanes, AR-V7 is a candidate predictive biomarker for the individualisation of mCRCP treatment. Two types of assays based on mRNA or abnormal protein detection are used to detect AR-V7 in circulating tumour cells.
Aim:
To describe the current status of AR-V7 testing in mCRPC and possible applications of this method for predicting outcomes of ARTA therapy.
Conclusion:
The percentage of CTC AR-V7+ in ARTA-naive men is relatively low at baseline, but in patients pretreated with ARTA, the prevalence of AR-V7 increases to 19–34%. Given the relatively high expected prevalence, AR-V7 testing may be economically feasible in this population. The proportion of AR-V7+ patients responding to ARTA retreatment appears to be very low, at only 4.8%. AR-V7 testing could thus be useful if an ARTA switch is considered in a patient progressing onto an ARTA drug. Both protein-based tests and mRNA-based tests are currently undergoing clinical validation in prospective studies, with results expected within a year.
Key words:
prostate cancer – abiraterone – enzalutamide – alternative splicing – drug resistance
Submitted:
30. 8. 2017
Accepted:
5. 11. 2017
doc. MUDr. Tomáš Büchler, Ph.D. received honorary lectures and publications from Astellas and Janssen and a travel grant from Janssen.
Supported by Ministry of Health, Czech Republic – conceptual development of research organization Thomayer Hospital – TN 0064190.
The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.
Sources
1. Richter I, Dvořák J, Hejzlarová V et al. Enzalutamid a abirateron v léčbě metastatického kastračně refrakterního karcinomu prostaty po předchozí chemoterapii. Klin Onkol 2016; 29 (2): 127–132. doi: 10.14735/amko2016127.
2. Liu LL, Xie N, Sun S et al. Mechanisms of the androgen receptor splicing in prostate cancer cells. Oncogene 2014; 33 (24): 3140–3150. doi: 10.1038/onc.2013.284.
3. Watson PA, Chen YF, Balbas MD et al. Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci U S A 2010; 107 (39): 16759–16765. doi: 10.1073/pnas.1012443107.
4. Wadosky KM, Koochekpour S. Androgen receptor splice variants and prostate cancer: From bench to bedside. Oncotarget 2017; 8 (11): 18550–18576. doi: 10.18632/oncotarget.14537.
5. Antonarakis ES, Armstrong AJ, Dehm SM et al. Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting. Prostate Cancer Prostatic Dis 2016; 19 (3): 231–241. doi: 10.1038/pcan.2016.17.
6. Richter I, Dvořák J, Bartoš J. Možnosti chemoterapie v léčbě karcinomu prostaty. Klin Onkol 2017; 30 (1): 28–33. doi: 10.14735/amko201728.
7. Richter I, Dvořák J, Bartoš J. Sekvence docetaxel–kabazitaxel–enzalutamid ve srovnání se sekvencí docetaxel–enzalutamid u pacientů s metastatickým kastračně rezistentním karcinomem prostaty. Klin Onkol 2017; 30 (4): 289–293. doi: 10.14735/amko2017289.
8. Antonarakis ES, Lu C, Wang H et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371 (11): 1028–1038. doi: 10.1056/NEJMoa1315815.
9. Antonarakis ES, Lu C, Luber B et al. Androgen receptor splice variant/ 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer. JAMA Oncol 2015; 1 (5): 582–591. doi: 10.1001/jamaoncol.2015.1341.
10. Nakazawa M, Lu C, Chen Y et al. Serial blood-based analysis of AR-V7 in men with advanced prostate cancer. Ann Oncol 2015; 26 (9): 1859–1865. doi: 10.1093/annonc/mdv282.
11. Antonarakis ES, Lu C, Luber B et al. Clinical significance of androgen receptor splice variant-7 mrna detection in circulating tumor cells of men with metastatic castration-resistant prostate cancer treated with first-and second-line abiraterone and enzalutamide. J Clin Oncol 2017; 35 (19): 2149–2156. doi: 10.1200/JCO.2016.70.1961.
12. Scher HI, Lu D, Schreiber NA et al. Association of AR-V7 on circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate Cancer. JAMA Oncol 2016; 2 (11): 1441–1449. doi: 10.1001/jamaoncol.2016.1828.
13. Scher HI, Graf RP, Schreiber NA et al. Nuclear-specific AR-V7 protein localization is necessary to guide treatment selection in metastatic castration-resistant prostate cancer. Eur Urol 2017; 71 (6): 874–882. doi: 10.1016/j.eururo.2016.11.024.
14. Bernemann C, Schnoeller TJ, Luedeke M et al. Expression of AR-V7 in circulating tumour cells does not preclude response to next generation androgen deprivation therapy in patients with castration resistant prostate cancer. Eur Urol 2017; 71 (1): 1–3. doi: 10.1016/j.eururo.2016.07.021.
15. Efstathiou E, Titus M, Wen S et al. Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer. Eur Urol 2015; 67 (1): 53–60. doi: 10.1016/j.eururo.2014.05.005.
16. NCCN Clinical Practice Guidelines in Oncology. Prostate cancer Version 2.2017. National Comprehensive Cancer Network. [online]. Available from: https: //www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
17. Parker C, Gillessen S, Heidenreich A et al. Cancer of the prostate: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015; 26 (Suppl 5): v69–v77. doi: 10.1093/annonc/mdv222.
18. Mottet (Chair) N, Bellmunt J, Briers E. Prostate Cancer 2017 Guidelines. European Association of Urology. [online]. Available from: http: //uroweb.org/guideline/prostate-cancer/.
19. Markowski MC, Frick KD, Eshleman JR et al. Cost-savings analysis of AR-V7 testing in patients with metastatic castration-resistant prostate cancer eligible for treatment with abiraterone or enzalutamide. Prostate 2016; 76 (16): 1484–1490. doi: 10.1002/pros.23232.
20. Antonarakis ES, Lu C, Chen Y et al. AR splice variant 7 (AR-V7) and response to taxanes in men with metastatic castration-resistant prostate cancer (mCRPC). JAMA Oncol 2015; 582–591. doi: 10.1001/jamaoncol.2015.1341.
21. van Soest RJ, de Morree ES, Kweldam CF et al. Targeting the androgen receptor confers in vivo cross-resistance between enzalutamide and docetaxel, but not cabazitaxel, in castration-resistant prostate cancer. Eur Urol 2014; 67 (6): 981–985. doi: 10.1016/j.eururo.2014.11. 033.
22. van Soest RJ, van Royen ME, de Morree ES et al. Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer. Eur J Cancer 2013; 49 (18): 3821–3830. doi: 10.1016/j.ejca.2013.09.026.
23. Farrell J, Petrovics G, McLeod DG et al. Genetic and molecular differences in prostate carcinogenesis between African American and Caucasian American men. Int J Mol Sci 2013; 14 (8): 15510–15531. doi: 10.3390/ijms140815 510.
24. Lokhandwala PM, Riel SL, Haley L et al. Analytical validation of androgen receptor splice variant 7 detection in a Clinical Laboratory Improvement Amendments (CLIA) laboratory setting. J Mol Diagn 2017; 19 (1): 115–125. doi: 10.1016/j.jmoldx.2016.08.003.
Labels
Paediatric clinical oncology Surgery Clinical oncologyArticle was published in
Clinical Oncology
2018 Issue 1
Most read in this issue
- Surgical Treatment of Ampullary Adenocarcinoma – Single Center Experience and a Review of Literature
- Curcumine (Turmeric – Curcuma longa) as a Supportive Phytotherapeutic Treatment in Oncology
- Pedicled Flaps for Reconstruction of Head and Neck Region
- Current Status of Checkpoint Inhibitors in the Treatment of Esophageal and Gastric Tumors – Overview of Studies