Analysis of the phenotypic and genotypic profile of circulating tumor cells (CTCs) – a so-called liquid biopsy – may help guide treatment decisions in men with castration-resistant metastatic prostate cancer, according to a cohort study being reported at the Genitourinary Cancers Symposium.
Investigators analyzed CTCs in 221 blood samples from 179 patients with metastatic prostate cancer about to begin either hormonal therapy (enzalutamide or abiraterone) or chemotherapy based on a taxane (docetaxel or cabazitaxel).
Dr. Howard I. Scher
Among patients given hormonal therapy, those whose CTCs exhibited high versus low scores for phenotypic heterogeneity had poorer radiographic progression-free survival (5 months vs. 17 months) and overall survival (9 months vs. not reached), first author Dr. Howard I. Scher reported in a press briefing held before the 2016 genitourinary cancers symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
In contrast, among those given chemotherapy, heterogeneity score did not affect these outcomes.
In other key findings, the heterogeneity score increased with each additional line of therapy patients received in the metastatic setting.
“We were able to show that single cell morphology, protein, and genomic characterization is feasible and can be used to assess tumor heterogeneity,” commented Dr. Scher of the Genitourinary Oncology Service at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York. “For characterizing disease at the point of decision making, a noninvasive liquid biopsy that enables the characterization of individual cells from a patient with metastatic prostate cancer can be used to guide treatment selection. Clinical trials to validate these findings are currently in development.”
He speculated that CTC heterogeneity was important only for hormonal therapy because it is a targeted therapy; as the disease becomes more diverse, essentially evolving into multiple diseases, this therapy is less likely to be effective. “The mechanism of taxanes is more general and not quite as targeted as these specific agents, which is why we believe they are more effective in a more diverse population,” he explained.
ASCO spokesperson and moderator of the press briefing Dr. Sumanta K. Pal, commented, “This is really fascinating work. We’ve always relied on a patient’s tumor to get genetic information, but that can be incredibly complicated for a number of reasons.” Among them, metastases may be located in hard-to-biopsy locations, and it is not practical to repeatedly perform needle biopsies over time.
The new findings show that “prostate cancer appears to get more complex over time as the disease evolves. The genetic diversity, quote unquote, increases, potentially suggesting that the cancer cell is crafting machinery to resist treatment,” he said.
From the clinical perspective, the ability to link CTC characteristics to response or lack thereof to a given therapy “is of incredible value,” according to Dr. Pal of the City of Hope, Duarte, Calif. “We have a number of new treatments for advanced prostate cancer and right now, we have little means of personalizing them and offering the right treatment to the right patient. With the studies that Dr. Scher has proposed to potentially validate this modality, we would have this personalized selection tool in our hands.”
Giving some background to the research, Dr. Scher noted, “Tissues are composed of a mixture of cells that differ morphologically and biologically. The result is diversity at single sites and multiple sites, broadly termed heterogeneity, so that we are not treating a single disease but a collection of diseases, and that is one reason we have difficulty achieving cures.”
“One could think of the blood as sampling, at least in theory, from all of the metastatic sites that are present. And we think you’ll have a greater chance of getting a more relevant characterization of the disease as a whole, in particular, by looking at the individual cells,” he further noted.
In the study, the investigators collected CTCs from blood samples, deposited them onto slides, stained them with DAPI and for various proteins (cytokeratin, androgen receptor, and CD45), and then scanned them, using a commercial platform (Epic Sciences).
They analyzed morphologic and phenotypic features of 9,225 single CTCs, splitting them into 15 distinct subtypes. They also performed whole-genome sequencing in a subset of 741 CTCs to assess copy number variation, clonality, and gene amplifications and deletions.
“The samples can be run quickly, and you can get results within 48 hours, which is important if you are trying to make a treatment decision,” Dr. Scher noted.
Findings showed that among patients given hormonal therapy, a high versus low CTC heterogeneity score was associated with much greater risks of radiographic progression-free survival events (hazard ratio, 2.2; P = .00182) and death (HR, 5.5; P less than .0001). In contrast, among patients who received taxane-based chemotherapy, CTC heterogeneity did not significantly affect either outcome.