An early study showed that an experimental blood test (ie, “liquid biopsy”) that characterizes the phenotype and genomic characteristics of circulating tumor cells appears to have utility in personalizing treatment decisions for individual men with advanced prostate cancer.1 The assay—developed and performed at EPIC Sciences—part of an ongoing work in progress—was used at three different decision points in an effort to inform treatment selection.
“Hormonal agents and taxanes prolong the lives of men with castration-resistant prostate cancer. The optimal sequence to administer them to maximize an individual patient’s survival is unknown. It is also not known if a taxane would be most beneficial after an androgen receptor–directed therapy than a second hormone. Needed are predictive biomarkers that can be used to guide the choice of treatment each time a treatment decision is needed,” explained Howard Scher, MD, Chief of the Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, who presented these findings at the 2016 Genitourinary Cancers Symposium.
“If this test is validated, it could be used to help select the treatment to which a patient is more likely to respond, sparing the toxicities that may result from an ineffective treatment,” he added.
Study Details
The liquid biopsy was obtained from phlebotomy samples and characterized the heterogeneity of circulating tumor cells on a cell-by-cell basis at key decision points. A blood specimen was stained with dye to identify circulating tumor cells and distinguish them from normal cells. Then the cells were scanned for morphologic features, “much like facial recognition software used at airports,” Dr. Scher added.
Dr. Scher and his colleagues identified 15 mathematically defined circulating tumor cell phenotypes. The frequency of these phenotypes differed by sample and line of therapy. Heterogeneity was measured by the Shannon Index score (see box below). Higher heterogeneity scores were seen with each additional line of therapy. The cells of interest were then analyzed for genetic abnormalities.
The investigators obtained 221 blood samples from 179 patients with castration-resistant prostate cancer slated for treatment with enzalutamide (Xtandi), abiraterone acetate (Zytiga), or docetaxel. A higher Shannon Index score was associated with a poor response to androgen receptor–directed therapy with enzalutamide or abiraterone acetate.
Median progression-free survival in those treated with an AR-directed therapy, was 5 months for those with a high Shannon Index score vs 17 months for those with a low Shannon Index score. Overall survival was 9 months vs not yet reached, respectively (P < .0001).
Circulating Tumor Cells in Advanced Prostate Cancer
- A liquid biopsy enables characterization of the heterogeneity of circulating tumor cells.
- A heterogeneity score was associated with response to treatment with enzalutamide or abiraterone acetate, both androgen receptor–directed therapies.
- The heterogeneity score was not correlated with response to taxanes.
No association was seen between Shannon Index score and response to taxane therapy. “Taxanes are usually a later line of therapy in patients who have more advanced disease,” Dr. Scher remarked.
Isolated circulating tumor cells (n = 741 cells isolated from 31 patients) were then analyzed for genotypic heterogeneity by gene-amplification studies. A subtype dubbed “Type K” was associated with poor outcomes. This subtype had a large nucleus, high nuclear entropy, and frequent nucleoli, he continued. This is a preliminary observation and will be studied further.
Future study by Dr. Scher and his colleagues will be aimed at locking down biomarkers, then demonstrating their clinical utility. “We plan to explore whether the heterogeneity score adds value to the measurement of AR-V7 [androgen receptor variant-7] and vice-versa,” he added.
What Is the Shannon Index?
The Shannon index is a mathematical measure of species diversity in a community. Researchers commonly use diversity indices such as the Shannon index to characterize information about the rarity and commonness in a community. For instance, in their study on liquid biopsy presented at the 2016 Genitourinary Cancers Symposium, Howard Scher, MD, and colleagues evaluated circulating tumor cells to identify phenotypic and genomic heterogeneity in patients with metastatic castration-resistant prostate cancer. A subset of these circulating tumor cells was analyzed and assessed for clonality, gene amplification, and deletion. These characteristics were combined and assigned a Shannon Index score. Higher heterogeneity scores were seen with each additional line of therapy. ■Additional Comment
“Prostate cancer tumors change and become more complex over time, suggesting that the cancer cell has machinery to evade treatment. A test such as this would be of incredible value [if validated] and allow us to offer the right treatment to the right patient. This is a personalized selection tool,” said Sumanta Pal, MD, ASCO Spokesperson and moderator of a press conference at which this research was featured. Dr. Pal is a medical oncologist at City of Hope in Duarte, California. ■
Disclosure: Dr. Scher has consulted for Astellas Pharma, AstraZeneca, BIND Therapeutics, Blue Earth, Bristol-Myers Squibb, Chugai Pharma, Endocyte, Ferring, Genentech, Janssen, Med IQ, Medivation, OncologySTAT, Palmetto GBA, Pfizer, Sanofi, Takeda, Ventana Medical Systems, WIRB-Copernicus Group; been on the speakers bureau for WebMD; received institutional research funding from BIND Biosciences, Exelixis, Innocrin Pharma, Janssen Diagnostics, Janssen Pharmaceuticals, and Medivation; and received travel expenses from Astellas Pharma, AstraZeneca, BIND Therapeutics, Bristol-Myers Squibb, Celgene, Endocyte, Ferring, Genentech, Janssen Pharmaceuticals, Medivation, Pfizer, Sanofi, Takeda, and WIRB-Copernicus Group. Dr. Pal has received consulting fees from Pfizer, Novartis, Bristol-Myers Squibb, Exelixis, and Genentech.
Reference
1. Scher HI, Graf R, Louw J, et al: Single CTC characterization to identify phenotypic and genomic heterogeneity as a mechanism of resistance to AR signaling directed therapies in mCRPC patients. 2016 Genitourinary Cancers Symposium. Abstract 163. Presented January 7, 2016.
