The predictive value of CTCs characterization for time to castration resistance of high-volume metastatic castration sensitive prostate cancer

Abstract

Objective To explore the predictive value of circulating tumor cells (CTCs) characterization for time to castration resistance of newly diagnosed high volume metastatic castration sensitive prostate cancer (mCSPC) patients. Methods Newly diagnosed high volume mCSPC patients were prospectively enrolled in this study from September 2015 to February 2017. The inclusion criteria include that the patients' age should be between 18 to 85 years old. The Prostate cancer should be diagnosed by biopsy or cytopathology. No endocrinological therapy, radiative therapy or chemotherapy was used before the study. High-volume metastatic lesion was confirmed by imaging. Those patients who accepted previous endocrinological therapy, radiative therapy or chemotherapy were excluded in this study. Those patients combined with concomitant tumor were also excluded. The health males were enrolled in the control group. All patients received androgen deprivation therapy (ADT) with goserelin plus bicalutamide (goserelin 3.6 mg subcutaneous injection, once a month plus bicalutamide 50mg orally, once a day). CanPatrol system was used to count CTCs in peripheral blood of patients and characterize CTCs based on expressions of epithelial markers(EpCAM and CK8/18/19) and mesenchymal markers(vimentin and twist). Primary endpoint was time to castration resistance. Survival analysis was conducted using Kaplan-Meier method and log-rank test was used to assess the difference of survival between groups, and univariate and multivariate analyses of prognostic factors were conducted using the Cox proportional hazards model. Results A total of 108 newly diagnosed high volume mCSPC patients were enrolled in this study. The median age of enrolled patients was 68 years old (ranging 51-85 years old), and median PSA was 196.2 ng/ml(ranging 5.8-5 011.9 ng/ml). The median level of hemoglobin was 32 g/L(ranging 9-172 g/L). The median level of LDH was 179 U/L(ranging 49-630 U/L). The ECOG scores was 0-1 score in 94 cases(87.0%), 2 scores in 14 cases (13.0%). The Gleason scores was 6-7 in 20 cases (18.5%) and more than 8 in 88 cases (81.5%). All patients had bone metastatic lesions, among which 41 (38.0%) patients had more than 10 metastatic lesions and 6 (5.6%) patients with visceral metastasis, 30(27.8%) patients with limb bone metastasis. The median CTCs count was four, and ranging 0-35. Mesenchymal CTCs positive and negative (negative included CTCs negative, epithelial CTCs positive and biophenotypic CTCs positive) patients were 58(53.7%) and 50, respectively. There was no correlation between CTCs characterization with age, baseline PSA, Gleason score, ALP and other clinical parameters (P>0.05). In control group, the mean age was 26 years old (ranging 20-31 years old). No CTCs were detected among those people. After a median follow-up of 24 months (ranging 18-32 months), 90 patients (83.3%) progressed to castration resistant prostate cancer (CRPC). The median time to CRPC for patients of mesenchymal CTCs positive and negative was (10.5±1.4) and (14.0±3.4) months, respectively(P<0.001). Univariate analysis revealed CTCs characterization(HR=1.647, P=0.003), the number of metastatic lesions (HR=1.624, P=0.025)and limb bone metastasis(HR=1.706, P=0.019) were prognostic factors of time to CRPC; further multivariate analysis showed that only baseline mesenchymal CTCs positive (HR=1.562, P=0.008) was independent prognostic factors of unfavorable time to CRPC. Conclusions CTCs characterization can predict time to CRPC of newly diagnosed high volume mCSPC patients receiving ADT, and patients of baseline mesenchymal CTCs positive are more likely to progress to CRPC. Key words: Prostatic neoplasms; Castration sensitive prostate cancer; Androgen deprivation therapy; Circulating tumor cells; Epithelial mesenchymal transition; Castration resistant prostate cancer