Predicting therapeutic benefit

Nuclear localization of protein can change course of prostate cancer therapy

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NEW YORK—In the United States alone, more than 50,000 patients per year are facing the decision about how to treat metastatic prostate cancer. According to the National Cancer Institute, prostate cancer is the most common cancer in men in the United States, after skin cancer, and is the second leading cause of death from cancer in men. A highly specific and accurate test may be able to extend their lives while saving costs when switching treatment from expensive proprietary drugs to generic chemotherapy.
According to a recent article in European Urology, only nuclear localization of AR-V7 protein in circulating tumor cells (CTCs) from metastatic castration-resistant prostate cancer (mCRPC) patient blood samples can predict therapeutic benefit. The investigators—from Memorial Sloan Kettering Cancer Center (MSK) and Epic Sciences—had previously published work reported in JAMA Oncology in 2016, demonstrating that nuclear localized AR-V7 protein in CTCs could predict a 76-percent reduction of risk of death for mCRPC patients who received taxane chemotherapy versus androgen receptor signaling inhibitors (ARSi), Zytiga and Xtandi. 
The European Urology article describes the comparison of clinical utility of detecting any AR-V7 protein in CTCs versus the previously described nuclear AR-V7 scoring criteria. The study, which analyzed 191 mCRPC patient samples, determined that patients with a less restrictive scoring criteria using any AR-V7 expression detected in CTCs exhibited generally poor outcomes on ARSi, Zytiga and Xtandi. Nonetheless, about 13 percent of the positive patients still responded to ARSi.
Conversely, none of the patients with nuclear localized AR-V7 protein expression in CTCs exhibited a response to ARSi, demonstrating superior performance of the nuclear localized approach. The difference between the scoring criteria also made significant differences in the prediction of therapeutic benefit of switching from commonly utilized ARSi to taxane chemotherapy, with only the nuclear scoring criteria demonstrating extension of life through switching therapies.
“We previously looked at all the AR-V7 protein that was positive,” explained Ryan Dittamore, co-author on the studies and Epic’s vice president of translational research and clinical affairs. “Now we know that it has to be localized in the nucleus. If not, we could be misidentifying patients who need a change in therapy.”
He added, “We know that when AR-V7 protein is detected in the nucleus of the tumor cell, those patients demonstrate high specificity to ARSi resistance. This study shows that using Epic Sciences’ proprietary CTC platform to determine whether AR-V7 protein is sequestered in the cytoplasm or translocated to the nucleus can provide an important clinical difference compared to other technologies with less specific AR-V7 detection techniques.”
According to Dr. Howard Scher, chief of the genitourinary oncology service at MSK and lead author of the study, “The results highlight the importance of robust analytic and clinical validation of predictive cancer biomarker tests at key clinical decision points in patient management. The decision to prescribe intravenous treatment with a taxane over an oral ARSi needs to be based on a thoroughly evaluated technology in order to ensure patient outcomes are improved. Our work demonstrates the importance of the rigorous validation of the AR-V7 assay to guide the choice of systemic therapy in patients with metastatic disease.”
In 2016, Epic Sciences partnered with Genomic Health Inc., to offer the highly specific nuclear AR-V7 liquid biopsy test later this year. It will be provided through Genomic Health’s world-class Oncotype IQ Genomic Intelligence Platform and performed at the Epic Sciences CAP/CLIA-certified laboratory.
Epic Sciences, which has been working on the AR-V7 liquid biopsy for three years, attempts to enable the rapid and noninvasive detection of genetic and molecular changes in cancer throughout a patient’s journey, according to Dittamore. Its technology is designed to match patients to targeted therapies and monitor for drug resistance, so that the best treatment path can be chosen at every clinical decision point. The company is working on 12 different cancer types and is partnering with 40 biopharmaceutical companies and 25 academic institutions.
“First we focus on the clinical decisions of importance that oncologists and patients have identified, and then we try to find the biomarker that is most relevant, “ Dittamore summarized.

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