Abstract PS2-09-14: When interception needs a second chance: ctDNA dynamics in ER+/HER2- advanced breast cancer treated with 1st line CDK4/6 inhibitors - Insights from the CICLADES study

Abstract Background: Circulating tumor DNA (ctDNA) is a valuable biomarker to monitor therapeutic resistance and disease progression in advanced breast cancer (ABC). In ER+/HER2- ABC, mutations in ESR1, PIK3CA, and TP53 are frequent and may impact response to endocrine therapy (ET) combined with CDK4/6 inhibitors. The CICLADES study aimed to evaluate the prognostic and temporal dynamics of these mutations and ctDNA-based progression signals. Methods: A prospective cohort of 117 patients with ER+/HER2- ABC treated with first line ET and CDK4/6 inhibitors was analyzed. Plasma ctDNA was profiled using a 35-gene NGS panel at baseline, at follow-up visits, and at radiologic progression. Associations between mutation status and progression-free survival (PFS) were examined for ESR1, PIK3CA, and TP53. Additional analyses explored mutation emergence, polyclonality, and molecular progression, defined as a ≥50% increase in variant allele frequency (VAF). Transient variants not detected at baseline or progression were evaluated as potential markers of subclonal dynamics. Results: Main results are presented in Table1. Baseline ESR1 mutations (n=6) and those acquired during follow-up (n=26) were associated with significantly shorter PFS. Most ESR1 mutations at progression were newly acquired, particularly in ligand-binding domains. PIK3CA and TP53 mutations also predicted shorter PFS at baseline, but not significantly during follow-up. While PIK3CA and TP53 mutations were largely present from baseline, most ESR1 mutations emerged under treatment. Molecular progression, defined by ≥50% increase in VAF, was detected in 16 patients and preceded radiologic progression in 11, with a median lead time of 2.7 months. Polyclonality was not associated with prognosis. Fourteen patients exhibited transient low-VAF variants during follow-up, suggestive of subclonal shedding rather than resistance; these did not correlate with clinical progression. Conclusion: In ER+/HER2- ABC, pre-existing ESR1, PIK3CA and TP53 mutations, and acquired ESR1 mutations, are significantly associated with shorter PFS under CDK4/6i-based therapy.Molecular progression detected via ctDNA may precede radiologic progression by several months, supporting the extension of the concept of molecular progression beyond ESR1 mutations and into real-world settings, and highlighting a window of opportunity for earlier therapeutic intervention. However, episodes of subclonal shedding, reflected by transient low-VAF variants, underscore the importance of confirmatory sampling before clinical decision-making. These results support longitudinal ctDNA monitoring as a refined tool for real-time disease interception. Citation Format: V. Massard, M. Betz, A. Diallo, J. Salleron, A. M. Savoye, D. Spaeth, F. Clatot, P. Barthelemy, R. Longo, Y. Tazi, M. Gardner, A. Witz, J. Dardare, D. Bechet, J. L. Merlin, A. Harlé. When interception needs a second chance: ctDNA dynamics in ER+/HER2- advanced breast cancer treated with 1st line CDK4/6 inhibitors - Insights from the CICLADES study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-09-14.