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10P Survival according to early ctDNA dynamics in advanced breast cancer (ABC) treated with endocrine therapy (ET) and a CDK4/6 inhibitor (CDK4/6i)

2022; Elsevier BV; Volume: 33; Linguagem: Inglês

10.1016/j.annonc.2022.03.025

1569-8041

Olga Martínez‐Sáez, E. Felip Falgas, MR Cappelletti, Pablo Tolosa, Fara Brasó‐Maristany, E. Sanfeliu Torres, Tomás Pascual, Núria Chic, M. Vidal, Bárbara Adamo, Montserrat Muñoz, I. Faull, Justin I. Odegaard, Gargi Patel, Robert McEwen, Debra Carroll, Eva Ciruelos, Daniele Generali, Mireia Margelí Vila, Aleix Prat,

Advanced Breast Cancer Therapies

A possible association between changes in tumor variant allele fraction (VAF) from baseline to cycle 2/ day 1 (C2D1) using the 74-gene Guardant360 assay and progression free survival (PFS) was observed in 45 patients (pts) with ABC treated with a CDK4/6i + ET. Here, we tested the same methodology in an independent dataset and explored the association between overall survival (OS), intrinsic subtype (IS) and ctDNA dynamics. Baseline and C2D1 plasma samples were obtained from 113 pts with HR+/HER2-negative ABC treated with CDK4/6i + ET in an international, multicentric observational study. The first 45 pts were used to derive the mean VAF ratio (mVAFR: mean of the log VAFR for all mutations) methodology associated with PFS (NPJ Breast Cancer 2021). mVAFR was calculated for each alteration with a VAF ≥0.4% at any time point. Pts with VAFs <0.4% at all timepoints were considered to have ctDNA-low disease. Molecular response was defined by the mVAFR. The main objective was to assess the association of mVAFR with PFS in the 68-pt independent validation cohort. We also explored the association of mVAFR with OS (n=113) and with IS (n=54). PFS and OS uni- and multivariable cox models were performed adjusting for clinical variables. With a median follow up (mFUP) of 16.6 months (m), pts with medium or high mVAFR had shorter median PFS than pts with low mVAFR and ctDNA-low disease (11.2 vs 25.0m; adjusted hazard ratio [aHR]=2.85, 95% confidence interval [CI] 1.2-6.7, p=0.017). mVAFR as a continuous variable was also found associated with PFS (HR=2.0, 95% CI 1.0–4.1, p=0.047). In the 113-pt combined cohort, with a mFUP of 19.4m, pts with medium or high mVAFR had shorter OS than pts with either low mVAFR or ctDNA-low disease (31.3m vs not reached; aHR=10.9, 95% CI 3.7-31.6, p<0.001). mVAFR as a continuous variable was also found associated with OS (aHR=4.1, 95% CI 1.7-9.5, p<0.001). Finally, mVAFR was associated with IS (p=0.022). Early ctDNA dynamics after CDK4/6i + ET can identify different pt populations. The absence of molecular response identifies pts with poor outcome, and future studies should focus on improving treatment options for this population.