Serial monitoring of circulating tumor cells predicts outcome of induction biochemotherapy plus maintenance biotherapy for metastatic melanoma

Abstract

Purpose: Molecular biomarkers in blood are promising for assessment of tumor progression and treatment response. We hypothesized that serial monitoring of circulating tumor cells (CTC) with the use of multimarker quantitative real-time reverse transcriptase-PCR assays could be a surrogate predictor of outcome for melanoma patients enrolled in a multicenter phase II clinical trial of biochemotherapy (BCT) combined with maintenance biotherapy (mBT).

Experimental design: Blood specimens were collected from 87 patients before and during induction BCT and mBT for stage IV melanoma. Expression of five melanoma-associated CTC biomarkers (MART-1, GalNAc-T, PAX-3, MAGE-A3, and Mitf) was assessed by quantitative real-time reverse transcriptase-PCR, and correlated with treatment response and disease outcome.

Results: The number of positive CTC biomarkers decreased overall during induction BCT (P < 0.0001). CTC biomarker detection after two cycles of BCT was correlated with treatment response (P = 0.005) and overall survival (P = 0.001): an increase in the number of CTC biomarkers was associated with poor response (P = 0.006) and overall survival (P < 0.0001). Multivariate analyses with the use of a Cox proportional hazards model identified the change in CTC biomarkers after two cycles of BCT as an independent prognostic factor for disease progression (risk ratio, 12.6; 95% confidence interval, 4.78-33.4; P < 0.0001) and overall survival (risk ratio, 6.11; 95% confidence interval, 2.37-15.7; P = 0.0005).

Conclusion: Serial monitoring of CTC during induction BCT may be useful for predicting therapeutic efficacy and disease outcome in patients receiving BCT and mBT for stage IV melanoma.

Figure 1

(A) Kaplan-Meier curves of PFS based on CTC biomarker detection after two cycles of induction BCT. (B) Kaplan-Meier curves of PFS based on changes in CTC biomarker detection between BCT1 and BCT3. (C) Kaplan-Meier curves of OS based on CTC biomarker detection after two cycles of induction BCT. (D) Kaplan-Meier curves of OS based on changes in CTC biomarker detection between BCT1 and BCT3. In each panel, the solid line corresponds to no CTC biomarkers, the broken line is 1 CTC biomarker, and the dotted line is ≥2 CTC biomarkers.