Résumé
Background: In 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 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). ctDNA was analyzed by targeted resequencing (custom panel 220kb) SNV (28 genes + 8 promoters and CNA (18 genes).
Results: For ctDNA, out of 196 pts analyzed, 147 had at least one somatic mutation (SNV) detected in plasma (75%). Despite no complete overlap, 24 pts (12%) had no CTC nor ctDNA detected at baseline. Including Copy Number Variation analysis (CNV), the number of patients without detectable ctDNA at baseline could be reduced to 18 (9%). The average number of mutations per pt was 2.4 (range 1 to 9). Median Allelic Frequency (MAF) was 9.1%. Most commonly mutated genes were TP53 and GATA3 with 14% and 7% of all mutations, respectively. TP53 mutations were detected in 31 % of patients and were associated with a shorter progression-free and overall survival. PI3KCA mutations were detected in 23.2% of the pts, were correlated with presence of bone metastasis and had no prognostic value. ESR1 was mutated in 10.6% of the pts, restricted to the ER+ subgroup and had no impact on overall survival. At baseline, CTC and ctDNA levels were correlated (r = 0.40, p < 0.0001). CTC detection was correlated with TP53 mutations detection but not with mutations PI3KCA or ESR1. Only 68 pts (36%) had detectable ctDNA at C2 with a MAF of 2% (0.3%-40%). 52.8% of patients positive for ctDNA at D1C1 became negative at D1C2 and only one negative at baseline became positive at C2.
Correlation rate with CTC was the same after one cycle of chemotherapy (r = 0.40). Median follow-up was 53 months and median OS was 32 months. At multivariate analysis, triple negative status, detectable ctDNA at C2, CTC ≥5 at C2 and grade 3 on primary tumor were independent prognostic for OS.
Conclusion: Early decrease of CTC and/or ctDNA after one cycle of chemotherapy are independent predictive markers of favorable outcome. Compared to CTC, ctDNA allows monitoring of tumor burden during chemotherapy and specific detection of targetable mutations as PI3KCA, HER2 or BRCA.
Citation Format: Jean-Yves Pierga, Amanda Silveira, Elodie Girard, Veronique Lorgis, Marie-Laure Tanguy, Benoit Albaud, Olivier Tredan, Coraline Dubot, Caroline Hego, William Jacot, Anthony Goncalves, Marc Debled, Christelle Levy, Jean-Marc Ferrero, Christelle Jouannaud, Marie-Ange Mouret-Reynier, Florence Dalenc, Sylvain Baulande, Jerome Lemonnier, Frederique Berger, Francois-Clement Bidard, Charlotte Proudhon. Predictive and prognostic value of circulating tumor DNA (ctDNA) compared to circulating tumor cells (CTC) in a prospective cohort of metastatic breast cancer patients: The UCBG COMET trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3390.