Abstract PS2-06-13: Implementation of Liquid Biopsy in a Real-World Clinical Setting: Guiding Treatment Decisions in Metastatic Breast Cancer through Genomic Profiling

Abstract Introduction: Metastatic breast cancer (mBC) exhibits tumor evolution and genomic heterogeneity with somatic alterations linked to progression and therapeutic resistance. We conducted a prospective Real-World Data study to evaluate ctDNA-detected mutations (MUT) via LB and their association with clinical outcomes. Methods: Prospective, single-center study of 98 mBC pts undergoing pre-treatment ctDNA analysis (mainly 1st/2nd line). Plasma was collected in Streck® tubes and analyzed with the Plasma-SeqSensei™ BC panel (Sysmex®), targeting PIK3CA, ESR1, ERBB2, AKT1, and TP53. Progression free survival to 1st-line metastatic therapy (PFS1) was estimated by Kaplan-Meier and log-rank test according to prevalent mutations; prognostic impact assessed by multivariate (MVA) Cox models (p≤0.05). Results: Of 98 mBC pts, 85 were evaluable and included in the final analysis. Baseline characteristics are summarized in Table 1. ctDNA identified ≥1 mutation in 52 pts (61%) of whom 81% had actionable mutations: PIK3CA (30%), ESR1 (18%), ERBB2 (7%), AKT1 (2%). Most frequent PIK3CA variants were E545K (28%), H1047R (21%), and E726K (15%); ESR1 variants included D538G (38%) and Y537S (15%). TP53 was enriched in grade III tumors (30% vs. 10%; p=0.04), ERBB2 in lobular histology (75% vs. 25%; p=0.01), ESR1 in pretreated pts (21% vs. 12%, p=0.39), and PIK3CA in younger pts (65y: 80% vs. 56%; p=0.03). In the overall cohort, TP53 MUT were associated with shorter PFS1 vs wild-type (WT) (17.7 vs. 23.9 months (mo); p=0.02); PIK3CA and ESR1 MUT showed no significant impact. In CDK4/6 inhibitors-naïve pts (23%), TP53, PIK3CA, and ESR1 MUT were significantly associated with shorter PFS1 (10 vs. 64; 19 vs. 56.6; 17 vs. 41.5 mo; respectively p=0.001/0.01/0.05); no such associations were observed in pretreated patients. MUT-negative patients had significantly longer PFS1 than those harboring ≥1 mutation (66.5 vs. 28.4 mo; p=0.003). In pts with de novo stage IV, relapse during or after adjuvant endocrine therapy (ET), or first-line hormonal treatment, PIK3CA-MUT tumors showed shorter PFS1 compared to WT on both fulvestrant + CDK4/6i (3 vs. 17 mo; p=0.03) and aromatase inhibitor (AI) monotherapy (52 vs. 128 mo; p=0.046). ESR1-MUT conferred worse PFS1 vs. WT on AI - alone (21 vs. 113 mo; p=0.025) and AI+ CDK4/6i (27.5 vs. 59.5 mo; p=0.038) - but not with fulvestrant + CDK4/6i (15 vs. 8 mo; p=0.8). MVA identified TP53 MUT (HR 2.1; p=0.03) and prior ET (HR 3.6; p=0.016) as independent prognostic factors. Conclusion: ctDNA analysis in mBC identifies mutations with prognostic and treatment-specific relevance. These findings support the clinical utility of LB to refine risk stratification and optimize endocrine-based therapy. Citation Format: A. Garcia-Bauto, D. Azuara Garcia, M. Gil-Gil, J. Cruz Velez, A. Vethencourt Casado, B. Fullana Griimalt, A. Fernández Ortega, P. Sabat Viltro, S. Vázquez Fernández, C. Ejarque Martínez, S. Recalde Penabad, A. Stradella, V. Obadia Gil, R. Villanueva Vázquez, S. Pernas Simón, C. Lázaro, C. Falo. Implementation of Liquid Biopsy in a Real-World Clinical Setting: Guiding Treatment Decisions in Metastatic Breast Cancer through Genomic Profiling 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 PS2-06-13.