Circulating Tumor Cell Number as a Response Measure of Prolonged Survival for Metastatic Castration-Resistant Prostate Cancer: A Comparison With Prostate-Specific Antigen Across Five Randomized Phase III Clinical Trials

Abstract

Measures of response that are clinically meaningful and occur early are an unmet need in metastatic castration-resistant prostate cancer clinical research and practice. We explored, using individual patient data, week 13 circulating tumor cell (CTC) and prostate-specific antigen (PSA) response end points in five prospective randomized phase III trials that enrolled a total of 6,081 patients-COU-AA-301, AFFIRM, ELM-PC-5, ELM-PC-4, and COMET-1-ClinicalTrials.Gov identifiers: NCT00638690, NCT00974311, NCT01193257, NCT01193244, and NCT01605227, respectively. MethodsEight response end points were explored. CTC nonzero at baseline and 0 at 13 weeks (CTC0); CTC conversion ($ 5 CTCs at baseline, # 4 at 13 weeks-the US Food and Drug Administration cleared response measure); a 30%, 50%, and 70% decrease in CTC count; and a 30%, 50%, and 70% decrease in PSA level. Patients missing week-13 values were considered nonresponders. The discriminatory strength of each end point with respect to overall survival in each trial was assessed using the weighted c-index. ResultsOf the eight response end points, CTC0 and CTC conversion had the highest weighted c-indices, with smaller standard deviations. For CTC0, the mean (standard deviation) was 0.81 (0.04); for CTC conversion, 0.79 (0.03); for 30% decrease in CTC count, 0.72 (0.06); for 50% decrease in CTC count, 0.72 (0.06); for 70% decrease in CTC count, 0.73 (0.05); for 30% decrease in PSA level, 0.71 (0.03); for 50% decrease in PSA level, 0.72 (0.06); and for 70% decrease in PSA level, 0.74 (0.05). Seventyfive percent of eligible patients could be evaluated with the CTC0 end point, compared with 51% with the CTC conversion end point. ConclusionThe CTC0 and CTC conversion end points had the highest discriminatory power for overall survival. Both are robust and meaningful response end points for early-phase metastatic castration-resistant prostate cancer clinical trials. CTC0 is applicable to a significantly higher percentage of patients than CTC conversion.

CTC Technologies and Tools

“…The enriched cell suspension was fluorescently labeled with the PE-labeled CAM5.2 antibody recognizing cytokeratins 7 and 8, a PerCP-labeled antibody recognizing CD45 and a nucleic acid dye that could be measured in the FITC channel of a flowcytometer. By now the original results have been confirmed and validated in numerous studies and expanded to different cancers and earlier disease stages (15)(16)(17)(18)(19)(20). These results were sufficiently encouraging to further develop the CTC technology and design and conduct clinical studies to explore the clinical utility of CTC.…”

“…The real excitement arose when the results of the prospective studies became available which showed that CTC were superior to serum tumor markers and/or radiographic imaging in predicting efficacy of ongoing therapy (10)(11)(12)(13)(14). By now the original results have been confirmed and validated in numerous studies and expanded to different cancers and earlier disease stages (15)(16)(17)(18)(19)(20).…”

A pilot study of prostate‐specific membrane antigen (PSMA) dynamics in men undergoing treatment for advanced prostate cancer

“…Most metastatic prostate cancers spread through the blood as circulating tumor cells (CTCs), and enumeration of CTCs correlates with baseline and postbaseline prognosis in the mCRPC population . PSMA expression on circulating tumor cells is emerging as a potential method of measuring treatment response .…”

“…10 Most metastatic prostate cancers spread through the blood as circulating tumor cells (CTCs), and enumeration of CTCs correlates with baseline and postbaseline prognosis in the mCRPC population. 11 PSMA expression on circulating tumor cells is emerging as a potential method of measuring treatment response. 12 PSMA and PSA biomarkers are being used to identify circulating PCa cells in blood, 13,14 and high concordance with results of FDA-cleared CellSearch assays have been demonstrated in studies using realtime quantitative reverse-transcription polymerase chain reaction (RT-PCR) methods for messenger RNA (mRNA) detection and quantification.…”

Associations between the cyclooxygenase‐2 expression in circulating tumor cells and the clinicopathological features of patients with colorectal cancer

“…3 While there is obvious heterogeneity among CTCs, CTCs can be defined as epithelial type (eCTC), mesenchymal type (mCTC), biophenotypic type (bCTC), and CTCs mass (CTM) according to different expression patterns of epithelial and mesenchymal markers of CTCs. [5][6][7] Wu et al 8 reported that changes in gene expression in CTCs can affect the prognosis of CRC, such as the expression of mesenchymal markers. [5][6][7] Wu et al 8 reported that changes in gene expression in CTCs can affect the prognosis of CRC, such as the expression of mesenchymal markers.…”