Epic Sciences said today its researchers have partnered with investigators at Memorial Sloan Kettering Cancer Center (MSK) to develop and apply a new liquid biopsy blood test shown to measure resistance to targeted therapies in metastatic castration-resistant prostate cancer (mCRPC) patients.
The test—which measures tumor heterogeneity through analysis of single circulating tumor cells (CTCs)—has found that patients with higher tumor heterogeneity as measured by high CTC diversity had worse overall survival with targeted androgen receptor signaling inhibitor (ARSi) therapies compared to chemotherapy, according to a study published by the researchers.
The discovery offers the potential to guide treatment choices in prostate cancer and multiple solid tumor cancers, the researchers added.
The study, “Phenotypic Heterogeneity of Circulating Tumor Cells Informs Clinical Decisions between AR Signaling Inhibitors and Taxanes in Metastatic Prostate Cancer,” has been published in the journal Cancer Research.
“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,” Howard Scher, M.D., chief of the genitourinary oncology service at MSK and lead author of the study, said in a statement. “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.”
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—and has been identified as a potential mechanism of resistance to many of those targeted therapies across multiple cancer types.
In their study, researchers measured tumor heterogeneity by analyzing protein- and morphology-based biomarkers in single CTCs and quantified degrees of variance among CTCs in blood samples from patients before treatment with targeted ARSi therapies—including Zytiga® (abiraterone acetate) and Xtandi® (enzalutamide)—compared to blood samples from patients before receiving chemotherapy.
Zytiga is marketed by Johnson & Johnson’s Janssen Biotech; Xtandi, by Astellas Pharma and Medivation, a wholly-owned subsidiary of Pfizer.
The study quantified the variance in CTC morphology in patient blood samples by applying two methods. One method identified unique subtypes of CTCs and measured the population diversity of the cell types in the blood sample. The other method measured variances in digital pathology features between CTCs.
For both methods, the study used Epic Sciences’ No Cell Left Behind® platform, designed to analyze every nucleated cell in a blood sample and detect CTCs without enrichment. The study also analyzed a subset of samples with single-cell genomic sequencing that is impractical for a diagnostic setting due to time and cost.
Both methods showed statistically significant therapy interaction with ARSi therapy but not chemotherapy. Data from the study showed patients to experience an increased risk of failure to ARSi relative to chemotherapy with increasing diversity of CTCs.
Heterogeneity was quantified based on the diversity of cell types in individual patient samples using the Shannon index and associated with overall survival in 145 specimens collected before initiation of second or later lines of therapy. Patients with high CTC phenotypic diversity, defined by the faster and less costly imaging results from Epic's platform all had evidence of cellular genomic diversity as well—results that the company said supported the hypothesis that resistance to a targeted therapy is mediated by the clonal diversity of disease.
The study quantified digital pathology features on 9,225 individual CTCs from 179 mCRPC patients to define phenotypically distinct cell types—the largest cohort to date designed to compare survival with quantified measures of tumor heterogeneity, the researchers added.
“We have demonstrated that 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,” added Ryan Dittamore, chief of medical innovation of Epic Sciences and co-author on the study. “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.”