Decline in Circulating Tumor Cell Count and Treatment Outcome in Advanced Prostate Cancer

Abstract

BackgroundTreatment response biomarkers are urgently needed for castration-resistant prostate cancer (CRPC). Baseline and post-treatment circulating tumor cell (CTC) counts of ≥5 cells/7.5 ml are associated with poor CRPC outcome.ObjectiveTo determine the value of a ≥30% CTC decline as a treatment response indicator.Design, setting, and participantsWe identified patients with a baseline CTC count ≥5 cells/7.5 ml and evaluable post-treatment CTC counts in two prospective trials.InterventionPatients were treated in the COU-AA-301 (abiraterone after chemotherapy) and IMMC-38 (chemotherapy) trials.Outcome measures and statistical analysisThe association between a ≥30% CTC decline after treatment and survival was evaluated using univariable and multivariable Cox regression models at three landmark time points (4, 8, and 12 wk). Model performance was evaluated by calculating the area under the receiver operating characteristic curve (AUC) and c-indices.ResultsOverall 486 patients (122 in IMMC-38 and 364 in COU-AA-301) had a CTC count ≥5 cells/7.5 ml at baseline, with 440, 380, and 351 patients evaluable at 4, 8, and 12 wk, respectively. A 30% CTC decline was associated with increased survival at 4 wk (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.36–0.56; p < 0.001), 8 wk (HR 0.41, 95% CI 0.33–0.53; p < 0.001), and 12 wk (HR 0.39, 95% CI 0.3–0.5; p < 0.001) in univariable and multivariable analyses. Stable CTC count (<30% fall or <30% increase) was not associated with a survival benefit when compared with increased CTC count. The association between a 30% CTC decline after treatment and survival was independent of baseline CTC count. CTC declines significantly improved the AUC at all time-points. Finally, in the COU-AA-301 trial, patients with CTC ≥5 cells/7.5 ml and a 30% CTC decline had similar overall survival in both arms.ConclusionsA 30% CTC decline after treatment from an initial count ≥5 cells/7.5 ml is independently associated with CRPC overall survival following abiraterone and chemotherapy, improving the performance of a multivariable model as early as 4 wk after treatment. This potential surrogate must now be prospectively evaluated.Patient summaryCirculating tumor cells (CTCs) are cancer cells that can be detected in the blood of prostate cancer patients. We analyzed changes in CTCs after treatment with abiraterone and chemotherapy in two large clinical trials, and found that patients who have a decline in CTC count have a better survival outcome.

The Novel Association of Circulating Tumor Cells and Circulating Megakaryocytes with Prostate Cancer Prognosis

“…Association of detection of !5 traditional CellSearch isolated CTCs/7.5 mL with poor prognosis in patients with advanced prostate cancer was initially reported around a decade ago (27)(28)(29) and has been recently further validated in several large-scaled clinical trials (30)(31)(32)(33). In our small patient cohort, we observed the associations of…”

ALDH1A3 correlates with luminal phenotype in prostate cancer

“…16 On our hands, ALDH1A3 has a relationship with progression-free survival after prostatectomy, which has significant clinical implications for patients with primary prostate cancer. The theory that CSCs could be one of the mechanisms of treatment resistance has been widely accepted.…”

Circulating Tumor Cell Count as an Indicator of Treatment Benefit in Advanced Prostate Cancer

“…In other words, does treatment result in abolition or a marked reduction of specific clones of cells rather than a simple reduction of the overall numbers of tumor cells as a response to treatment? These caveats aside, this paper [1] adds value to our understanding that a 30% decline in CTCs as early as 4 wk after treatment initiation discriminates between men who benefit and those who have no survival benefit and require a switch to alternative therapeutic regimens.…”

“…In the current study [1], 486 patients derived from two trials (IMMC-38 and COU-AA-301) had circulating tumor cell (CTC) counts of five or more cells per 7.5 ml at baseline, with 440, 380, and 351 patients evaluable at 4, 8, and 12 wk, respectively. Patients with CTC counts of four or fewer cells per 7.5 ml were excluded but also had better clinical outcomes.…”