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Epic Sciences, MSKCC Research Suggests Utility for CTC Platform in Prostate Cancer MDx


NEW YORK (GenomeWeb) – New research presented last week at the American Society for Clinical Oncology 2016 Genitourinary Cancers Symposium by researchers from Epic Sciences and Memorial Sloan Kettering Cancer Center shows that the phenotypic and genotypic heterogeneity of circulating tumor cells can predict prostate cancer patients' response to hormonal therapies.

The results suggest this type of heterogeneity assessment, enabled by Epic Sciences' CTC isolation platform, could potentially guide the use of androgen receptor inhibitor therapies (enzalutamide or abiraterone) versus taxane chemotherapy.

“Not all men respond equally to either enzalutamide or abiraterone, and some men don’t respond at all," Howard Scher, the study's lead author and chief of the Genitourinary Oncology Service at MSKCC, said in a statement. "If the 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 one that is ineffective."

As the field of liquid biopsy has rapidly become crowded, a variety of tools are now available for isolating CTCs — not to mention other sources of blood-based cancer markers such as cell-free DNA and exosomes — raising the bar for companies to distinguish the unique capabilities of their particular tool or system.

Ryan Dittamore, Epic's vice president of translational research and clinical affairs, told GenomeWeb that the study results presented last week help to highlight the ability of Epic's technology to capture the full range of circulating cancer cell types and sizes, something that is necessary for a comprehensive understanding of the genomic or physical heterogeneity of this population.

Unlike many other methods for isolating CTCs from plasma or serum, Epic's platform, which it calls "no cell left behind," does not rely on antibody-based capture. Instead, it involves lysing red blood cells from a sample and spinning the remaining nucleated cells into a pellet, which is then resuspended and spread out into a monolayer where each cell is fixed in a particular location — a slide representing a snapshot of the complete cellular content of the blood at the time of collection.

Once this slide is created, immunofluorescent staining and imaging then identifies CTCs against the large background of normal cells. Finally, researchers can select individual cells of interest, pick them out of the slide, and perform downstream genomic or other analyses.

In the context of the MSKCC experiments, the ability to capture a wider variety of CTCs allowed the researchers to quantify the heterogeneity of the CTCs in patients' blood samples, both phenotypically — by size, shape and protein markers — and genomically via sequencing-based copy number analysis.

In the study, the group analyzed 221 blood specimens from 179 patients with metastatic prostate cancer about to begin either hormonal therapy or taxane chemotherapy. Using Epic's technology, the researchers were able to isolate almost 10,000 CTCs for phenotypic characterization.

The investigators also sequenced a subset of 741 CTCs from 31 patients to assess copy number variation, including gene amplifications and deletions. The ability to do this type of single-CTC sequencing in parallel with other analyses of CTCs is something Epic has only started to demonstrate recently, with the first data presented at last year's annual meeting of the American Association for Cancer Research.

In the MSKCC study, the results of this paired analysis indicated that patients whose CTC population showed a high degree of heterogeneity — either in their phenotypes or their genetic clonality — did not respond as well to hormone therapy as those with less heterogeneity.

Compared to patients with a low heterogeneity score, patients with a high heterogeneity score experienced shorter median progression-free survival (5 months vs. 17 months) the authors reported.

In contrast, CTC heterogeneity did not appear to affect patients’ response to chemotherapy. This implies that, with appropriate validation, measuring CTC heterogeneity could potentially help guide treatment decisions. Patients with low heterogeneity may be considered better candidates for hormonal therapy, while those with high heterogeneity can be expected to respond to chemotherapy regardless of the diversity of their circulating cancer cells.

Interestingly, the data highlight the fact that a genomic analysis may not actually be necessary for stratifying patients in terms of their CTC diversity. While the genomic heterogeneity and clonality the group saw mirrored the association with therapy response seen based on morphological heterogeneity, it didn't necessarily improve upon that analysis in the team's early data.

However, Dittamore said, genomic analyses were instrumental in the study to confirm and validate the heterogeneity that was seen phenotypically. Having the ability to do both types of analysis on CTCs in parallel, and use them to test and validate each other, is something Epic sees as a unique strength of its platform, he said.

CTC heterogeneity is not the only area in which Epic has been pursuing a toehold for its technology in the personalization of prostate cancer therapy. The MSKCC team's results were from a small preliminary study and would require significant further validation to be clinically impactful.

In more advanced work, Epic is also developing a test to measure AR-V7, a molecular variant of the androgen receptor that has been associated with resistance to anti-androgen drugs. AR-V7 has been named a target for test development by a number of groups.

Epic researchers shared data from another collaboration with MSKCC last year in which they developed a method to measure both AR-V7 protein and AR-V7 mRNA in CTCs from patients with metastatic castration-resistant prostate cancer.

According to Dittamore, AR-V7 is the more clinically ready of Epic's investigations in the prostate cancer space. "From our perspective, ARV7 is a highly specific test that can help inform treatment decisions, and we are pursuing making that commercially available," he said. "However, as good as AR-V7 might be as a biomarker, it may be possible that another approach like looking at CTC heterogeneity could identify additional patients that could be triaged."