CHICAGO (GenomeWeb) – A new study by researchers from Memorial Sloan Kettering Cancer Center has demonstrated the predictive power of an AR-V7 protein expression test using Epic Sciences' non-EPCAM-based circulating tumor cell detection platform, which could help guide treatment decisions for men with metastatic castration-resistant prostate cancer.
The results — published last weekend in JAMA Oncology — validate the assay's ability to distinguish men who might have better survival sticking with taxane chemotherapy versus anti-androgen drugs. The data also provide support for Epic to begin commercial advancement of the test, which has just been made available through the company's CLIA lab, officials told GenomeWeb at the American Society of Clinical Oncology meeting held here this week.
The same MSKCC researchers also shared other ongoing research into Epic's platform expanding on the AR-V7 results at ASCO.
In the JAMA study, a team led by MSKCC oncologist Howard Scher — who has been researching multiple aspects of the Epic CTC platform in prostate cancer precision medicine — analyzed samples from 161 MSKCC patients who were undergoing a change in therapy for progressive disease between 2012 and 2015. The patients were either initiating a new androgen receptor signaling (ARS) inhibitor or taxane chemotherapy.
AR-V7 CTC test results were not used for clinical decision making in the study. Rather, the authors set out to compare patients' test results with their ultimate outcomes on the two available therapy choices as directed by usual clinical decision making.
According to the authors, the 161 patients in the study received a total of 193 treatments between September 2012 and March 2015. Of these, 130 had a single therapy; 30 had two therapies and a single patient had three therapies.
Strikingly, the investigators found that not a single patient with CTCs positive for the AR-V7 protein responded to AR-directed therapy (defined by a greater-than 50 percent prostate-specific antigen decline). This included three patients who had AR-V7 positivity only in CK-negative CTCs — a type of circulating cell that is not detectable using other EpCAM-based methods for isolating CTCs, but is using the Epic platform.
The AR-V7-positive group also had significantly worse progression-free survival and overall survival compared with patients who had AR-V7-negative CTCs according to the Epic test.
AR-V7 positivity was not associated with any lack of response to taxane-based chemotherapy, meanwhile, suggesting that patients with AR-V7-positive CTCs would be better served by taxane therapy over the ARS inhibitors abiraterone or enzalutamide.
The MSKCC results jibe with those previously reported by researchers from Johns Hopkins University led by Emmanuel Antonorakis who have developed a different mRNA PCR-based CTC assay. In a small study they found that men who were AR-V7-positive appeared to do significantly better on chemotherapy than on hormone therapy while those who were negative did about the same on either therapy.
Ryan Dittamore, Epic's Vice President of translational research and clinical affairs told GenomeWeb at ASCO that the new MSKCC study also goes beyond those prior findings, showing more definitively that AR-V7 is not just prognostic, but predictive specifically of a failure to respond to ARS inhibition.
Based on statistical analyses, the investigators concluded that patients who had AR-V7-positive CTCs treated with taxanes had a much lower risk of death than those put on ARS inhibitors, a level of evidence they argue has not been achieved with other AR-V7 testing modalities or platforms other than Epic's.
Additionally, Scher told GenomeWeb at ASCO, the study was unique in its focus on realistic decision points in the management of patients in standard-of-care settings, analyzing the potential impact of the test in the setting of the need for a change in systemic therapy.
In their paper, Scher and colleagues said that this "enabled the assessment of clinical utility: patient benefit for test use [versus] nonuse, and separately, the harm associated with selecting an ineffective therapy with potential toxic effects. This therapy guiding approach is essential to inform when and how to use a test in practice and for proper evaluation by regulators and third-party payers."
However, Scher said, AR-V7 CTC status isn't a perfect predictor. While none of the 47 patients who responded well to ARS Inhibition had AR-V7 positive CTCs, only 16 of the 81 who were resistant to the hormonal therapies had AR-V7-positive cells, suggesting that there are other mechanisms that also predicate resistance to these drugs.
Scher and colleagues have been researching other capabilities of Epic's platform that might enable additional analysis of CTCs to help further stratify patients, including measuring the overall genomic and phenotypic heterogeneity of CTCs as a potential predictor of response to anti-ARS drugs.
In previous research he and his team found that patients whose CTC population showed a high degree of heterogeneity — either in their phenotypes or their genetic clonality — did not respond as well to hormone therapy as those with less heterogeneity.
Similar to AR-V7, heterogeneity did not have an association with chemotherapy response, suggesting that patients with low heterogeneity may be considered better candidates for hormonal therapy, while those with high or low heterogeneity can be expected to respond to chemotherapy regardless.
At ASCO this week, Scher and colleagues also presented new data demonstrating an added value when AR-V7 expression and CTC heterogeneity measures are combined.
In this study, the team analyzed the same cohort as in the AR-V7 JAMA study, and found that patients with AR-V7-positive CTCs and, separately, high phenotypic CTC heterogeneity showed improved overall survival with taxane therapy versus AR-targeted therapy.
A total of 63 patients were identified as either AR-V7-positive or having high CTC heterogeneity. Of these, 20 had both of these characteristics, and in these double-positive patients the clinical sensitivity for predicting failure of response to hormonal therapy was 85 percent better than using AR-V7 alone.
Double-positive patients had the worst outcomes with AR therapy, although patients with only AR-V7 positivity or only high heterogeneity also did worse on ARS inhibitors compared to those who were double-negative.
According to Scher, further prospective validation of both of these biomarkers is ongoing. Dittamore said that Epic's platform is currently being implemented in a handful of prospective clinical trials.
He also told GenomeWeb this week that AR-V7 CTC testing is now available through Epic's CLIA lab, but that the company intends to keep availability of the test somewhat limited at first as it works on gaining insurance reimbursement and scales its operations.
"We are expecting our first samples shortly," he said. "But since this is our first test, we really want to make a good impression for payors and with physicians, so we want to work [at first] with physicians who know the biology really well and who will use the test the right way, so they really represent the test well."