Role of ctDNA in predicting the outcome of patients with hormone receptor–positive, HER2-negative advanced breast cancer treated with first-line ribociclib and letrozole: BioItaLEE trial

Background: This phase 3b study prospectively evaluated the prognostic and predictive value of baseline and dynamic circulating tumor (ctDNA) in postmenopausal patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) treated with first-lineribociclib/letrozole. Methods: A total of 287 patients were enrolled, with ctDNA analyzed at baseline (n=263), day 15 of cycle 1 (C1D15; n=238), C2D1 (n=241), and at first imaging (n=206). The primary objective was to identify ctDNA alterations, characterize their evolution across treatment time points, and assess their association with progression-free survival (PFS). Results: Median PFS was 23.4 months (95% CI: 20.8-non estimable [NE]). At baseline, the most frequently altered genes were PIK3CA (22.1%) and TP53 (15.5%). Alterations in TP53, MYC, and HER- and CDK4/6- pathway genes were linked to early progression. Absence of a detectable mutation at baseline (n=150, 57.0%) was associated with better prognosis (HR=0.41). Among patients with a detectable mutation at baseline (n=104), early clearance (mutation undetectability) was observed in 47.1% at C1D15 and 52.4% at C2D1, and associated with improved PFS (C1D15, HR=0.51; C2D1, HR=0.44). In patients without a detectable mutation at baseline, 22.7% (n=34) developed new mutations at C1D15, C2D1, or first imaging. Patients without new mutations had a lower risk of progression (HR=0.45). Conclusion: Pretreatment and early dynamics of ctDNA represent promising prognostic and predictive biomarkers in patients with HR+/HER2- ABC treated with ribociclib/letrozole. Early ctDNA dynamic appeared a promising surrogate biomarker for treatment. Further studies are warranted to validate their clinical utility.