Multimodality liquid biopsy for early monitoring and outcome prediction in first-line metastatic HER2-negative breast cancer: Final results of the prospective cohort from the French Breast Cancer InterGroup Unicancer (UCBG)— COMET study.

Abstract

3019 Background: Circulating Tumor Cells (CTC) are independent markers of progression-free survival (PFS) and overall survival (OS) in patients (pts) with metastatic breast cancer (MBC). Monitoring circulating tumor DNA (ctDNA) can detect mutation associated with resistance to treatment and its variations reflect changes in tumor burden. We prospectively monitored CTC, Circulating Endothelial Cells (CEC), serum markers and ctDNA during first line chemotherapy for MBC. Methods: The French cohort COMET is a prospective study including first line HER2 negative pts receiving weekly paclitaxel and bevacizumab . Blood samples were obtained at baseline (BL) and before the second cycle of chemotherapy (C2).We present here the final planned analysis. Results: From 09/2012 to 11/2014, 286 patients were included: 198 for ctDNA, 251 for CEC and 283 for CTC. Median age was 56 years and 23% of pts had triple negative BC. At baseline, 71% of pts had ≥1 detectable CTC per 7.5 ml of blood (median 4 CTC, range 1- 30,000). With a threshold of ≥5 CTC, 49% of pts were positive at baseline and 22% at C2. For ctDNA, out of the first 196 pts analyzed, 147 had at least one somatic mutation (SNV) detected in plasma (75%). The average number of mutations per pt was 2.4 (range 1 to 9). Most commonly mutated genes were TP53 and GATA3. ESR1 was mutated in 10.6% of the pts and restricted to the ER+ subgroup. PIK3CA was mutated in 23.2% of the pts. Median Allelic Frequency was 9.1% . Only 68 pts (36%) had detectable ctDNA at C2. At baseline, CTC and ctDNA levels were correlated (r = 0.40, p < 0.0001). Despite no complete overlap, 24 pts (12%) had no CTC nor ctDNA detected at baseline. Median follow-up was 53 months and median OS was 32 months. Detectable CTC and ctDNA at baseline and at C2 were significantly associated with decreased PFS and OS. CEC and serum markers level had no prognostic value. At multivariate analysis, triple negative status, detectable ctDNA at C2, CTC ≥5 at C2 and grade 3 on primary tumor were independent prognostic factors. Conclusions: This is the largest prospective cohort assessing the respective prognostic values of early CTC and ctDNA changes in homogenously treated first line MBC pts. Early decrease of CTC and ctDNA after one cycle of chemotherapy are independent predictive markers of favorable outcome, with a stronger value for ctDNA compared to CTC. Clinical utility of early ctDNA variations monitoring and changes in mutation profile remain to be demonstrated. Clinical trial information: NCT01745757.