THE IMPACT OF CIRCULATING TUMOR CELLS IN DISTANT BRAIN FAILURE FOLLOWING STEREOTACTIC FOCAL RADIOTHERAPY FOR BREAST CANCER BRAIN METASTASES

Purpose: Predicting the risk of early distant brain failure (DBF) is a useful and demanding resource for management decisions in patients who are candidates to local treatment of brain metastases. This study aims to analyze the correlation between circulating tumor cells (CTC) and brain disease control after stereotactic radiotherapy/radiosurgery (SRT) for breast cancer brain metastases (BCBM). Experimental Design: Prospective assessment of CTC before (CTC1) and 4 5 weeks after (CTC2) SRT for BCBM and its relations with the number of new lesions suggestive of BCBM (NL). CTC were isolated and quantified by the ISET method (Rarecells, France) and analyzed by immunocytochemistry to evaluate the expression of the proteins COX2, EGFR, ST6GALNAC5, NOTCH1 and HER2. Distant brain failure-free survival (DBFFS), the primary endpoint, diffuse distant brain failure-free survival (D-DBFFS), defined as progression with more than 4 new BCBM or meningeal carcinomatosis, and overall survival (OS) were estimated by Kaplan-Meier estimator. Log-rank tests were applied to compare the survival curves. For multivariate analysis of prognostic factors that affected DBFFS and OS, the Cox proportional model was adjusted. Competing risk analysis for DBF in the presence of death was performed. Results: CTC were detected in all 39 patients before and 34 of 35 patients after SRT. After median follow-up of 16.6 months, median DBFFS, D-DBFFS and OS were 15.3, 14.1 and 19.5 months, respectively. DBF at 6 months was 40% with CTC1 < 0.5 and 8.82% with CTC1 > 0.5 CTC/mL (P = .007) and of D-DBF at 6 months was 40% with CTC1 < 0.5 and 0 with CTC1 > 0.5 CTC/mL (P = .005) and 25% with NL/CTC1 > 6.8 and 2.65% with NL/CTC1 ≤ 6.8 (P = .063). On multivariate analysis, DBFFS was inferior with CTC1 ≤ 0.5 (HR 8.27, 95% CI, 2.12 32.3; P = .002) and D-DBFFS was inferior with CTC1 ≤ 0.5 (HR 10.22, 95% CI, 1.99 52.41; P = .005). There was no association between protein expression in CTC and DBF and OS. Conclusions: CTC were detectable in almost all patients with BCBM. CTC1 was an independent prognostic factor of DBFFS and D-DBFFS and NL/CTC1 was an independent prognostic factor of OS and a potential prognostic factor of D-DBF at 6 months. These data suggest that CTC1 and NL/CTC1 may have a role as a biomarker of early D-DBF, helping define the timing and type of salvage radiotherapy aiming to optimize the control of BCBM (NCT02941536).