July 10, 2016
“Liquid biopsies are the way to go,” said Srinivas Pentyala, PhD, director of translational research at the Stony Brook School of Medicine in New York. Blood tests are easier to perform, and are less invasive and more convenient for patients, he said.
“I think CTCs and cell-free DNA will be very helpful in the future to identify men with prostate cancer who are more or less likely to benefit from a range of therapies, including docetaxel, PARP inhibitors, immunotherapies, and [androgen receptor]-directed therapies,” said Andrew J. Armstrong, MD, FACP, associate director for clinical research in genitourinary oncology at the Duke Cancer Institute in Durham, North Carolina.
There is growing demand for such tools in the clinic. Only skin cancer is more frequently diagnosed among men in the United States. More than 2.8 million US men are living with prostate cancer, and an estimated 180,890 men will be newly diagnosed in 2016, according to the National Cancer Institute (NCI).2 Currently, it is unclear which men with castration-resistant prostate cancer (CRPC) will benefit from taxane therapy and which will do better with the androgen-receptor signaling (ARS) inhibitors abiraterone and enzalutamide.3
But CRPC resistance involves AR signaling reactivation through 1 of several molecular pathways, making gene mutations in these pathways attractive targets for developing predictive biomarkers.
A recent cross-sectional study of men treated for metastatic CRPC (mCRPC) at the Memorial Sloan Kettering Cancer Center in New York, New York, strengthened the case that androgen-receptor splice variant 7 (AR-V7) plays a role in tumors’ ARS inhibitor drug resistance and is a promising biomarker for informing treatment selection decisions. The findings, published inJAMA Oncology, show that CTC expression of AR-V7 protein predicts ARS inhibitor therapy failure. Furthermore, CTC AR-V7 is associated with longer survival times among patients who were treated with taxane-based chemotherapy (overall survival [OS]: 8.9 months versus 4.6 months; P = .035).
The study utilized immunofluorescence protein assay, whereas previous work with CTC AR-V7 has used immunohistochemical (IHC) testing. While the findings are exciting, they must now be validated in prospective trials.
“There is mounting evidence on the role of AR-Vs as drivers of castration-resistance,” said William Douglas Figg, Sr, PharmD, head of the Molecular Pharmacology Section and deputy branch chief in the Genitourinary Malignancies Branch at the NCI’s Center for Cancer Research in Bethesda, Maryland, in an e-mail to Cancer Therapy Advisor. “Preclinical studies in 22RV1 cells that express both the full-length androgen receptor (AR-FL) and variant (AR-V7) suggest that inhibiting both AR-FLs and variant is necessary to inhibit tumor growth.”
- Beltran H, Antonarakis ES, Morris MJ, Attard G. Emerging molecular biomarkers in advanced prostate cancer: translation to the clinic. Am Soc Clin Oncol Educ Book. 2016;35:131-141.
- SEER Stat Fact Sheets: Prostate Cancer. US National Cancer Institute (NCI). http://seer.cancer.gov/statfacts/html/prost.html. Accessed June 22, 2016.
- Scher HI, Lu D, Schreiber NA, et al. Association of AR-V7 in circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer. JAMA Oncol.4 Jun 2016. doi:10.1001/jamaoncol.2016.1828 [Epub ahead of print]
- Leibrand CR, Price DK, Figg WD. Androgen receptor splice variant 7 (AR-V7) and drug efficacy in castration-resistant prostate cancer: biomarker for treatment selection exclusion or inclusion?Cancer Biol Ther. 2016;17(5):467-469.
- Pentyala S, Whyard T, Pentyala S, et al. Prostate cancer markers: an update. Biomed Rep.2016;4(3):263–268.