An international collaborative study between Lawson Health Research Institute, Memorial Sloan Kettering Cancer Centre, the Royal Marsden Hospital and Epic Sciences is one of the first to demonstrate that a blood test can predict how patients with advanced prostate cancer will respond to specific treatments, leading to improved survival.
The study used a liquid biopsy test developed by molecular diagnostics company Epic Sciences that examines circulating tumour cells (CTCs) in blood samples from patients with advanced prostate cancer who are deciding whether to switch from hormone-targeting therapy to chemotherapy. CTCs are cancer cells that leave a tumour, enter the blood stream and invade other parts of the body, causing the spread of cancer.
The test identifies whether or not a patient's CTCs contain a protein called AR-V7 in the cell's nucleus. The research team set out to determine whether the presence of this protein predicted which treatment would best prolong a patient's life. They found that patients who tested positive for the protein responded best to taxane-based chemotherapy while those who tested negative for the protein responded best to hormone-targeting therapy with drugs called androgen-receptor signaling (ARS) inhibitors. These are the two most widely used drug classes to treat advanced prostate cancer.
"The study focused on a critical decision point when patients and their oncologists are choosing what therapy to pursue next," says Dr Alison Allan, a scientist at Lawson and chair, department of anatomy & cell biology at Western University's Schulich School of Medicine & Dentistry. "We are addressing a critical unmet need by validating that a blood test or liquid biopsy can be used to select a therapy most likely to extend a patient's life."
Research participants included 142 patients with advanced prostate cancer from the London Regional Cancer Programme at London Health Sciences Centre (LHSC) in London, Ontario; Memorial Sloan Kettering Cancer Centre in New York; and the Royal Marsden in London, England. The patients had already undergone at least one round of hormone-targeting therapy without success and were working with their oncologist to decide whether to switch to a different hormone-targeting therapy or to chemotherapy as their next line of treatment.
Hormone-targeting therapies like ARS inhibitors work by slowing or stopping the growth of cancers that use hormones to grow. Prostate cancer growth relies on hormones called androgens, which include testosterone. Androgen deprivation therapy like ARS inhibitors blocks the production of male hormones to treat the recurrence or spread of prostate cancer.
"ARS inhibitors are the preferred first line of treatment because they target the hormones that provide the fuel for prostate cancer cells to grow," explains Allan. "However, at some point, cancer cells can figure out a way to survive without this fuel and become resistant to ARS inhibitors, in many cases through production of the AR-V7 protein. That's why chemotherapy is sometimes used a second line therapy."
While this study looked at predicting the best treatment for patients who had already undergone at least one round of hormone-targeting therapy, a future goal of the team is to assess the use of this test or similar CTC blood tests in determining optimal therapy at earlier decision points in advanced prostate cancer care. The team also plans to collaborate further with Epic Sciences to evaluate different versions of the CTC blood test for other types of cancer, such as lung cancer.
Through Epic Sciences' partnership with Genomic Health, the CTC blood test is now commercially available in the US as the Oncotype DX AR-V7 Nucleus Detect.
Importance: A blood test to determine whether to treat patients with metastatic castration-resistant prostate cancer (mCRPC) with an androgen receptor signaling (ARS) inhibitor or taxane is an unmet medical need.
Objective: To determine whether a validated assay for the nuclear-localized androgen receptor splice variant 7 (AR-V7) protein in circulating tumor cells can determine differential overall survival among patients with mCRPC treated with taxanes vs ARS inhibitors.
Design, Setting, and Participants: This blinded correlative study conducted from December 31, 2012, to September 1, 2016, included 142 patients with histologically confirmed mCRPC and who were treated at Memorial Sloan Kettering Cancer Center, The Royal Marsden, or the London Health Sciences Centre. Blood samples were obtained prior to administration of ARS inhibitors or taxanes as a second-line or greater systemic therapy for progressing mCRPC.
Main Outcomes and Measures: Overall survival after treatment with an ARS inhibitor or taxane in relation to pretherapy AR-V7 status.
Results: Among the 142 patients in the study (mean [SD] age, 69.5 [9.6] years), 70 were designated as high risk by conventional prognostic factors. In this high-risk group, patients positive for AR-V7 who were treated with taxanes had superior overall survival relative to those treated with ARS inhibitors (median overall survival, 14.3 vs 7.3 months; hazard ratio, 0.62; 95% CI, 0.28-1.39; P = .25). Patients negative for AR-V7 who were treated with ARS inhibitors had superior overall survival relative to those treated with taxanes (median overall survival, 19.8 vs 12.8 months; hazard ratio, 1.67; 95% CI, 1.00-2.81; P = .05).
Conclusions and Relevance: This study suggests that nuclear-localized AR-V7 protein in circulating tumor cells can identify patients who may live longer with taxane chemotherapy vs ARS inhibitor treatment.
Howard I Scher, Ryon P Graf, Nicole A Schreiber, Anuradha Jayaram, Eric Winquist, Brigit McLaughlin, David Lu, Martin Fleisher, Sarah Orr, Lori Lowes, Amanda Anderson, Yipeng Wang, Ryan Dittamore, Alison L Allan, Gerhardt Attard, Glenn Heller
[link url="https://www.sciencedaily.com/releases/2018/07/180724174332.htm"]Lawson Health Research Institute material[/link]
[link url="https://jamanetwork.com/journals/jamaoncology/fullarticle/2686031"]JAMA Oncology abstract[/link]