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CTC Panel Shows Promise as Survival Surrogate in CRPC

Laura Panjwani
Published: Tuesday, Apr 07, 2015

Dr. Howard I. Scher

Howard I. Scher, MD

A biomarker panel containing circulating tumor cell (CTC) number and LDH level was shown to be a surrogate for overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC), according to a recent article published in the Journal of Clinical Oncology.

Demonstrating improved OS with investigational treatments in CRPC has become increasingly difficult with the availability of several new drugs shown to prolong life, the authors wrote. “Future trials designed with a primary endpoint of survival will have to be larger, longer running, and more costly, with a higher risk of failure.”

They added that clinical endpoints, such as CTRCs, that are surrogates for survival, are needed “to guide patient management and facilitate regulatory approval. Such surrogates would make new drugs available to patients more rapidly and significantly reduce drug development timelines and costs.”

In an effort to identify a surrogate for OS in CRPC, Howard I. Scher, MD, Memorial Sloan Kettering Cancer Center (MSKCC), and his colleagues from MSKCC and other institutes examined biomarker data from the phase III COU-AA-301 trial.

Biomarker evaluation as a surrogate for OS was a secondary objective in the multinational, randomized, double-blind COU-AA-301 study, which examined abiraterone acetate (Zytiga) plus prednisone versus prednisone alone in patients with mCRPC who were previously treated with docetaxel. Surrogate biomarker data were available for 711 patients.

Two-year survival of patients with low-risk levels of CTCs (<5 cells/7.5 mL of blood and any LDH) at 12 weeks was 46% versus 2% for patients with high-risk levels of CTCs ≥5/7.5 mL of blood and LDH >250 U/L. One-year survival was 82% and 25% for the low-risk patient group and high-risk patient group, respectively.

The abiraterone acetate plus prednisone and prednisone-alone groups demonstrated a significant survival difference (P = .034); surrogate distribution at 12 weeks differed by treatment (P <.001). Adding the surrogate to the model eliminated the treatment effect on survival. The trial was conducted at 147 sites in 13 countries in North America,Europe, and Australia. The biomarkers were measured at baseline and 4, 8, and 12 weeks, with 12 weeks being the primary measure of interest. Factors measured were CTC, PSA, LDH, hemoglobin, albumin, and alkaline phosphatase levels. Each biomarker panel tested included CTCs analyzed at a fixed time point, the difference from baseline, or the relative difference from baseline.

The biomarker panel used in the study satisfied the Prentice criteria for individual-patient surrogacy. According to the study, this represents the first time that a biomarker panel containing CTC numbers and LDH levels satisfied Prentice criteria for individual-patient surrogacy within a randomized clinical trial where abiraterone acetate plus prednisone improved survival compared to prednisone alone.

To meet Prentice criteria, treatment must have a significant effect on the clinical endpoint and a proposed biomarker; a biomarker must have a significant impact on the clinical endpoint; and a full effect of treatment on the clinical endpoint must be captured by a biomarker. Prentice defines a surrogate as a posttreatment measure that is both prognostic for a clinical endpoint, and captures the effect of the treatment on that endpoint.

Scher et al reported that additional studies are ongoing to confirm their findings.

Using CTCs as a biomarker for prostate cancer has historically been a challenge. Their rarity, typically 1 to 10 CTCs per 10 mL of blood, can make them difficult to identify and isolate.

However, recent advances in analytical technologies have made identifying CTCs easier. According to Daniel F. Hayes, MD, University of Michigan Comprehensive Cancer Center, who has been involved in CTC work for 15 years, at last count there were more than 40 CTC platforms at various stages of development. Three or four platforms have shown analytical validity, according to Hayes.

In order to isolate and enrich CTCs, the majority of analytical technologies use positive selection, which exploits biological or physical properties specific to CTCs and absent in normal blood cells.

The CellSearch system, which was used in Scher et al’s study, takes advantage of the fact that CTCs typically express the epithelial cell–specific antigen—the epithelial cell adhesion molecule (EpCAM). It uses magnetic particles coated with antibodies that bind to EpCAM-expressing cells. The cells are then stained with cytokeratin and CD45 antibodies—markers of epithelial and white blood cells, respectively—and a DNA dye. These stained cells are visualized in a chamber, and a computer imaging algorithm is used to identify cells that are intact, have a nucleus, and express cytokeratins, but do not express CD45. These cells are classed as CTCs.




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