San Francisco, CA USA (UroToday.com) Dr. Howard Scher of Memorial Sloan Kettering Cancer Center presented work evaluating circulating tumor cells (CTCs) of patients with mCRPC during treatment with abiraterone, enzalutamide, or docetaxel. The investigators assessed the degree of genomic heterogeneity and phenotypic alterations of the patient cells at various decision points during clinical care, and used the Epic Sciences CTC
isolation platform to perform this work. This unique method allowed investigators to perform a “liquid biopsy” of each patient in which CTCs could be assessed on a cell-by-cell basis, capturing a heterogeneous population of all cells, including CK-, small, apoptotic, and CTC clusters, rather than sorting by various criteria prior to evaluation. The investigators sought to perform assessments of CTCs at treatment decision points to ensure the clinical utility of their findings.
After collecting CTCs at baseline, the investigators analyzed cell morphology and protein chemistry. They measured various features of each cell, with features falling into protein biomarker, digital pathology, or additional categorical variable categories. The team then followed patients over a series of lines of therapy, collecting CTCs at each change in treatment. Treatment was delivered per standard of care, with therapy decisions made by the treating physician.
By analyzing 9225 cells, the team identified 15 distinct CTC phenotypes at baseline. With each subsequent line of therapy, there was a trend toward increasing genetic heterogeneity within each patient sample as measured by the Shannon Index. There were no cells with low heterogeneity by the third and fourth lines of treatment. The investigators demonstrated that high heterogeneity was associated with decreased progression free and overall survival when compared with low heterogeneity among patients treated with AR directed treatments (median survival 9 months vs not reached in high heterogeneity vs low heterogeneity groups, respectively, p<0.001). This difference was not evident among men treated with taxane therapy (HR for survival 1.6, p=0.182). In a multivariable model, patients with high heterogeneity fared better with taxane based therapy relative to AR directed therapy (HR 0.32 (0.12-0.86).
Next the team assessed genomic variation by evaluating copy number variation of CTCs within single patients, allowing them to identify distinct clones that might not be detectable with other CTC platforms. They then assessed the relationship between phenotypic and genomic heterogeneity and found that high phenotypic heterogeneity was associated with high genomic heterogeneity. Additionally the investigators identified a CTC subtype, type K, which is associated with poor outcomes for patients treated with both AR directed therapies and taxane based therapy (HR during AR directed therapy 6.4, p<0.001; HR during taxane therapy 2.3, p=0.0152).
Dr. Scher concluded his discussion by noting that assessing tumor phenotypic and genomic heterogeneity could be evaluated in single CTCs using the Epic Sciences platform. Patients with high phenotypic heterogeneity may have better outcomes when treated with taxanes rather than AR directed therapies. CTCs that have both high genomic and phenotypic heterogeneity may be resistant to both AR directed therapies and taxanes. Further prospective validation within other populations and at various points in the disease process will be useful in identifying which of these findings may ultimately be incorporated into clinical care.
Presented By:
Dr. Howard I. Scher, MD
Reported By:
Alicia K. Morgans, MD, at the 2016 Genitourinary Cancers Symposium - January 7 - 9, 2016 – San Francisco, CA
Assistant Professor of Medicine Medical Oncologist
Vanderbilt - Ingram Cancer Center