Liquid biopsy tumor heterogeneity test predicts resistance to targeted therapy in metastatic prostate cancer patients.
Researchers at Epic Sciences and Memorial Sloan Kettering developed and applied a ground-breaking new test for measuring the cellular diversity within tumors, or tumor heterogeneity, through the analysis of single circulating tumor cells (CTCs). To measure tumor heterogeneity, researchers analyzed protein and morphology based biomarkers in single CTCs and quantified degrees of variance among CTCs in blood samples from patients prior to receiving targeted androgen receptor signaling inhibitor (ARSi) therapies, including the blockbuster drugs Zytiga® and Xtandi®, compared to blood samples from patients prior to receiving chemotherapy. The data, released in Cancer Research highlighted that patients with higher tumor heterogeneity as measured by high CTC diversity had worse overall survival with targeted ARSi therapy compared to chemotherapy.
“A critical unmet need is to identify those patients who will not respond to targeted androgen receptor directed therapies,” said Howard Scher, M.D., chief of the genitourinary oncology service at Memorial Sloan Kettering and lead author of the study. “The measurement of tumor heterogeneity and the diversity of the cells present, linked to the response to specific drugs, is an important step forward in improving clinical decision-making.”
In recent years, tumor heterogeneity has been identified as a potential mechanism of resistance to many targeted therapies across multiple cancer types. Tumor heterogeneity has been suggested as a reason why diagnostic tests based on next generation sequencing (NGS) have struggled to predict patient outcomes on targeted therapies in clinical trials. The lack of tools to identify, characterize, and measure tumor heterogeneity has remained a hurdle to potentially understanding why many targeted cancer therapies fail.
“Many efforts to enable precision medicine through NGS-based diagnostics have failed to demonstrate clinical utility. The reason for these failures may be that the chaos of cancer is one of the most powerful predictive biomarkers of patient response to therapy,” said Ryan Dittamore, chief of medical innovation of Epic Sciences and co-author on the study.
“This study shows that using Epic Sciences’ proprietary CTC platform to measure tumor heterogeneity can help with clinical decisions between targeted therapy and chemotherapy in metastatic prostate cancer.”
In the largest cohort to date comparing survival with quantified measures of tumor heterogeneity, this study utilized two distinct approaches of imaging-based digital pathology to quantify the variance in CTC morphology in patient blood samples. The first method identified unique subtypes of CTCs and measured the population diversity of the cell types in the blood sample. The second method measured variances in digital pathology features between CTCs. Both methods demonstrated statistically significant therapy interaction with ARSi therapy but not chemotherapy. The data showed that with increasing diversity of CTCs, the patient experiences an increased risk of failure to ARSi relative to chemotherapy.
To perform both methods, the study utilized Epic Sciences “no cell left behind” platform, which analyzes every nucleated cell in a blood sample and detects CTCs without enrichment. In addition, a subset of samples was analyzed with single-cell genomic sequencing, which is impractical to perform in a diagnostic setting due to time and cost. Patients with high CTC phenotypic diversity defined by the more rapid and far less expensive imaging results from Epic’s platform all had evidence of cellular genomic diversity as well, supporting the hypothesis that resistance to a targeted therapy is mediated by the clonal diversity of disease.
“The critical tool enabling the analysis is the ability of the Epic Sciences platform to provide unbiased detection of CTCs and enable the analysis of protein expression, size, and shape to properly characterize tumor variation,” said Dr. Scher. “Utilizing an effective imaging-based approach is critical for developing a clinically-relevant product that can meet the time and price constraints of patient and healthcare needs.”
Dittamore concluded, “In this study, we have demonstrated that circulating tumor cell (CTC) diversity is a valuable tool in therapeutic selection for metastatic prostate cancer, but this clinical decision between a targeted therapy and chemotherapy is echoed in most solid tumor cancer types. As such, we are rapidly applying CTC heterogeneity algorithms across multiple academic and biopharma-led clinical trials to support therapeutic selection in other metastatic diseases, including breast and lung cancers.”
About Epic Sciences
At Epic Sciences, we develop clinically proven predictive tests to detect and monitor cancer at the individual cell level. With a proprietary rare-cell detection engine, we provide insights to clinical, biotech, pharmaceutical and academic teams on how cancer emerges, mutates and remits so they can make pivotal decisions at every point in patient treatment with greater certainty. Recognizing the unique nature of each person’s cancer, we offer truly personalized diagnostic tests, while being non-invasive for the patient.
We have developed the first clinically proven predictive test for metastatic castration-resistant prostrate cancer (mCRPC), the Epic AR-V7 test. Using the same rare-cell detection platform and Epic’s biobank of over 30,000 blood samples, each profiled with predictive biomarkers, we partner with leading pharmaceutical and biotechnology companies, major cancer centers, the National Cancer Institute (NCI), and the National Institutes of Health (NIH) to pursue additional predictive tests for breast, ovarian, colon and other cancers and diseases. Our mission is to revolutionize cancer care and therapies to make them as precise, safe and life-sustaining as humanly possible.
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