Abstract PS2-10-01: Mutational profiles from liquid biopsies in early versus late progressors treated with CDK inhibitors in 1st line metastatic breast cancer

Abstract Background: Approximately 10% of patients (pts) with hormone receptor-positive, HER-2 negative (HR+/HER2-) metastatic breast cancer (MBC) experience disease progression within 12 months (m) of initiating first-line treatment with CDK4/6 inhibitors (CDK4/6i). Early progressors (EP) have a particularly poor prognosis, underscoring a need for personalized strategies guided by integrated clinical and molecular profiling. Our objective is to compare clinical and molecular features between EP and late progressors (LP) to uncover mechanisms driving early progression. Methods: We conducted a retrospective analysis of clinical and plasma-derived circulating tumor DNA (ctDNA) genomic data from HR+/HER2- MBC pts treated with CDK4/6i enrolled in the STING molecular screening program (NCT04932525). Eligible pts were identified through the Molecular Tumor Board database at Gustave Roussy. Genomic profiling was carried out by FoundationOne Liquid CDx assay, which analyzes 324 cancer-related genes on ctDNA in peripheral blood. Pts were classified as EP or LP, with EP defined as progression occurring within 12m after initiation of first-line CDK4/6i. Liquid biopsy was performed at disease progression to CDK4/6i. Clinicopathological and molecular characteristics were compared between EP and LP, using a Wilcoxon rank-sum for continuous variables and Chi-squared or Fisher exact tests for categorical variables. Results: From Feb 2021 to Aug 2022, 116 pts were identified. 58% (n = 67) were classified as EP and 42% (n = 49) as LP. This higher proportion of EP aligns with the fact that these pts may have undergone more liquid biopsies. With a follow-up of 48m, the median real-world progression-free survival on CDK4/6i (PFS) in the overall population was 11m (9-13m); 6m (4-9m) for EP, and 21m (16-28m) for LP. Overall, 23 pts (20%) had de novo MBC, of which 10 pts were EP and 13 pts were LP. No significant differences were found for age, menopausal status, hormone sensitivity (defined as the absence of progressive disease on or within the first year of completion of adjuvant hormone therapy), visceral metastases or tumor histology (ductal, lobular or mucinous). A total of 77% of pts (n = 90) had a liquid biopsy just after disease progression on first-line CDK4/6i, including 58 EP and 32 LP. Notably, EP exhibited a statistically significantly higher frequency of TP53 (EP 52% vs LP 16%; p < 0.001) and a non-significant higher proportion of PIK3CA mutations (EP 41% vs LP 22%; p = 0.079). ERBB2 mutations were identified exclusively in EP (n = 4, 3.4%), with a median real-world PFS of 7.6m. ESR1 mutations were numerically more frequent in LP (EP 21% vs LP 27%, p = 0.18). Median tumor mutational burden (TMB) was significantly higher in EP (EP 2.53 vs LP 1.26 mutations/Mb p = 0.026); circulating tumor fraction was higher in EP (mean EP 11.8 vs mean LP 5.21, p = 0.047). No significant differences were found in copy number alterations or gene rearrangements. Conclusion: Early progression to first-line CDK4/6i in HR+/HER2- MBC is associated with distinct genomic features, including a significantly increased frequency of TP53 mutations, increased TMB and increased circulating tumor fraction. These characteristics may be reflective of more aggressive disease biology and a non-luminal phenotype. TP53 is emerging as a known resistance mechanism to CDK4/6i and preclinical data suggest this could be overcome by CDK2 inhibition, indicating that ctDNA-based genomic profiling could be used as a tool to identify high-risk patients and support the development of precision treatment approaches for early progressors. Citation Format: M. Brichard, C. Roussel-Simonin, M. Ibanez Alda, J. Araujo, J. Doxon-Douglas, C. Bousrih, C. Poisson, A. Sabau, T. Grinda, A. Viansone, L. Antoun, S. AKLA, E. Rassy, J. Zeghondy, F. Giugliano, B. Verret, C. Nicotra, M. NgoCamus, A. Bayle, B. Pistilli, A. Italiano, J. M. Ribeiro, A. Fernandez-Martinez. Mutational profiles from liquid biopsies in early versus late progressors treated with CDK inhibitors in 1st line metastatic breast cancer [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 PS2-10-01.