The End of the Beginning: Circulating Tumor Cells As a Biomarker in Castration-Resistant Prostate Cancer

Abstract

Although circulating tumor cells (CTCs) were first observed from patients with metastatic malignancies more than 100 years ago, only recently has the clinical and research potential of CTCs become widely recognized. Because CTCs are thought to represent cells that are shed by primary or metastatic tumors, significant interest has focused on examining CTCs as prognostic or predictive biomarkers in several malignancies, including breast and prostate cancer. One could hypothesize that the number of CTCs could be prognostically important by potentially estimating the total-body burden of disease and/or a tumor’s invasiveness. Alternatively, changes in CTC counts might indicate sensitivity or resistance to an anticancer therapy. CTCs could also represent research tools to personalize treatment by serving as a so-called liquid biopsy of an individual’s disease. Quantitation and characterization of CTCs may therefore represent a means to directly inform clinical care but also serve as an investigational platform to elucidate basic mechanisms of tumor biology. The most extensively studied clinical role for CTCs is as a prognostic biomarker; that is, counts at a specific time point are associated with a later discrete clinical end point. In this capacity, CTC counts that are enumerated using the CellSearch platform (Veridex, Raritan, NJ) are the most studied. CellSearch enriches for CTCs with antibodies directed against the epithelial cell adhesion molecule (EpCAM), which is expressed on epithelially derived cells. CTCs are then identified and quantitated on the basis of nuclear staining with 4,6diamidino-2-phenylindole (DAPI), and anticytokeratin and antiCD45 antibodies, which distinguishes CD45 epithelial cells from CD45 leukocytes. In clinical trials, CellSearch CTC counts are prognostic for overall survival (OS) in metastatic breast, colon, and prostate cancers. In prostate cancer, specifically, the Circulating Tumor Cells and the Prediction of Overall Survival in Patients With Androgen Independent Prostate Cancer Entering Onto Chemotherapy (IMMC38) study demonstrated the prognostic value of CellSearch CTCs in 238 men with metastatic castration-resistant disease (mCRPC) starting a new first, second, or third line of chemotherapy. In this study, a pretreatment CTC threshold of 5 CTCs/7.5 mL of blood distinguished patients into favorable and unfavorable groups, the latter having shorter median OS (11.5 v 21.7 months; hazard ratio, 3.3; P .001). In their modeling, the best predictor of survival incorporated baseline high-serum lactate dehydrogenase (LDH) levels with baseline CTC counts; the addition of prostate-specific antigen (PSA) did not improve prediction of survival. In patients with unfavorable baseline counts, conversion to a favorable count after the initiation of treatment was also associated with improved survival. Conversely, conversion to unfavorable counts after treatment initiation was associated with worse survival. Perhaps most importantly, CTC counts outperformed PSA in predicting survival at all time points. More recently, the prognostic value of 5 CTCs/7.5 mL of blood (with the CellSearch assay) was confirmed in a randomized phase III study of abiraterone acetate, a novel hormonal therapy, in men with mCRPC who were previously treated with docetaxel. In this study, CTCs were enumerated at baseline and during the first three cycles. CTC conversion from 5 CTCs to 5 CTCs, along with changes in serum LDH, was strongly predictive of OS. Similar results were recently observed in a phase III study of docetaxel with or without lenalidomide. Building on these findings, in the article that accompanies this editorial, Goldkorn et al present an analysis of the impact of baseline and post-treatment CTC counts on OS and disease response in a subset of men with mCRPC who were treated as part of the Southwest Oncology Group (SWOG) trial 0421, a phase III study comparing the effectiveness of docetaxel plus atrasentan, an endothelin receptor antagonist, versus docetaxel alone. The study itself failed to meet its coprimary end points of improved OS and progression-free survival with the addition of atrasentan and was halted early for futility. Nevertheless, as part of the study, CTCs were enumerated at baseline and 21 days after the first dose of the study treatment. In contrast to the IMMC-38 study, this study had a uniform cohort of men with chemotherapy-naive CRPC and a longer duration of median follow-up (24 v 16 months). In their analysis, the authors showed that baseline CTC counts were correlated with recognized prognostic markers, including PSA, alkaline phosphatase, bone pain, liver disease, and hemoglobin, although relationship with LDH, a widely recognized prognostic marker, was not assessed. Baseline CTC count was associated with subsequent PSA declines and with objective responses. Importantly, median survival for patients with 5 CTCs/7.5 mL of blood at baseline was far better than for those with 5 CTCs (26 v 13 months), and after adjustment for known prognostic factors, the baseline CTC JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 11 APRIL 1