Tumor-agnostic ctDNA levels by mFAST-SeqS in first-line HR-positive, HER2 negative metastatic breast cancer patients as a biomarker for survival

Abstract

This prospective cohort study reports aneuploidy score by mFast-SeqS as a strong prognostic marker in MBC patients. mFAST-SeqS is an affordable and easily implementable method for the assessment of total ctDNA levels and, as such, provides an alternative prognostic tool. One mixed cohort (cohort A, n = 45) starting any type of treatment in any line of therapy and one larger cohort (cohort B, n = 129) consisting of patients starting aromatase inhibitors (AI) as first-line therapy were used. mFAST-SeqS was performed using plasma of blood in which CTCs (CellSearch) were enumerated. The resulting aneuploidy score was correlated with categorized CTC count and associated with outcome. The aneuploidy score was significantly correlated with CTC count, but discordance was observed in 31.6% when applying cut-offs of 5. In both cohorts, aneuploidy score was a significant prognostic marker for both PFS and OS. In the Cox regression models, the HR for aneuploidy score for PFS was 2.52 (95% CI: 1.56-4.07), and the HR for OS was 2.37 (95% CI: 1.36-4.14). Results presented here warrant further investigations into the clinical utility of this marker in MBC patients.

Fig. 1. Association between aneuploidy score and CTC count.

Boxplots showing the association between classes of circulating tumor cell counts and median aneuploidy score (Jonckheere–Terpstra test for trend p < 0.001). The boxes indicate the 25th to 75th percentile, the middle line indicates the median, and the whiskers represent minimal and maximal values. The lines above the graph show interclass comparisons by two-sided Mann–Whitney U tests: n.s. = non significant, ** = p < 0.001, *** = p < 0.0001.

Fig. 2. Kaplan–Meier estimates of probabilities of survival.

Progression-free survival (panel a) and overall survival (panel b) in cohort A and of progression-free survival (panel c) and overall survival (panel d) in cohort B. Panel e and f show Kaplan–Meier estimates of probabilities of progression-free survival and overall survival for aneuploidy score combined with CTC count in cohort B, with an associated number at risk tables below. All p-values were derived from two-sided log-rank tests.