Abstract PS2-07-04: Time-to-progression patterns during first and second-line endocrine therapy across clinical features and liquid biopsy-defined mutational profiles in HR+/HER2- metastatic breast cancer

Abstract Background: Monitoring strategies for HR+/HER2- metastatic breast cancer (MBC) remain largely based on fixed, trial-derived, schedules. Emerging evidence from the SERENA-6 and INAVO120 studies underscore the limitations of this approach and the need for a risk-adjusted, biomarker-guided strategy incorporating adaptive treatment escalation to optimize treatment sequencing. This study investigated the impact of clinical and liquid biopsy-based features on time-to-progression during first and second-line endocrine therapy (ET) in HR+/HER2- MBC. Methods: We retrospectively analyzed a cohort of 909 patients with HR+/HER2- MBC who underwent circulating tumor DNA (ctDNA) profiling through the Guardant360 next-generation sequencing (NGS) panel within the multi-institutional “Precision Medicine Action for Cancer” (PMAC) academic consortium. Single nucleotide (SNVs) and copy number variations (CNVs), as well as clinical variables were evaluated. Oncogenic pathways were defined according to Sanchez-Vega et al. (Cell, 2018). Prognostic impact on progression-free survival (PFS), measured from the time of ctDNA collection, was investigated through log-rank test. Associations were evaluated using chi-square with false discovery rate correction (q value). Temporal patterns of disease progression were modeled through smoothed hazard function estimated up to 30 months. Results: A subset of 264 patients treated with 1st or 2nd-line ET was selected from the overall PMAC cohort of 909 HR+/HER2- MBC cases. The majority of patients were treated in 1st line (n=157, 59.5%), while 107 (40.5%) were treated in 2nd line. De novo MBC was present in 54 patients (20.5%). The majority received ET combined with CDK4/6 inhibitors (n=187, 70.8%), with visceral involvement in 115 cases (43.7%) and bone metastases in 208 (79.1%). Time-dependent hazard estimates revealed distinct temporal patterns of progression across baseline genomic alterations. SNVs in ESR1, PIK3CA, and TP53 were associated with early hazard peaks. ESR1 mutations displayed the steepest initial peak of PFS events at 3.6 months, followed by a plateau and a second peak at 15.3 months. PIK3CA had an early peak at 2.1 months and remained stable until 16 months. TP53 peaked at 4.8 months and steadily declined thereafter. Delayed hazard peaks were observed for SNVs in GATA3 (8.4 months), ARID1A (8.4 months), and RB1 (11.4 months), as well as for CNVs in FGFR1 (16.8 months) and PIK3CA (8.1 months), suggesting a delayed risk of progression. A significantly higher frequency of cell cycle pathway SNVs was observed in patients within the early ESR1 hazard peak (16% vs. 2.1%; p=0.003, q=0.013). RTK pathway CNVs were also significantly enriched in this subgroup (32% vs. 15%; p=0.013, q=0.044). No significant differences were found for the PI3K, TP53, RAS, or MYC pathways. PFS was significantly worse in patients with ESR1 and PIK3CA co-mutations, while double wild-type cases having the best outcomes (p 0.0001). ESR1 SNVs were associated with early progression, irrespective of PIK3CA status. Conclusions: The temporal analysis of progression for patients with HR+/HER2- MBC revealed distinct patterns associated with specific genomic alterations. Early peaks in PIK3CA and TP53 mutations suggest intrinsic resistance, while delayed peaks in RB1, ARID1A, and FGFR1 indicate acquired mechanisms to ET +/- CDK4/6i therapy. The bimodal pattern observed in ESR1-mutant tumors, along with the enrichment of cell cycle and RTK pathway alterations in patients with early progression, further supports their role in endocrine resistance. If validated, these data may have important implications for both disease monitoring using ctDNA and rationale clinical trial design to overcome intrinsic and acquired resistance. Citation Format: L. Gerratana, A. A. Davis, C. Reduzzi, A. J. Medford, L. Foffano, E. Podany, M. Velimirovic, K. Clifton, B. Pastò, L. Pontolillo, R. Occhiogrosso Abelman, C. Gianni, S. Tapiavala, E. Molteni, M. Lipsyc-Sharf, E. Nicolò, E. Andreopoulou, W. J. Gradishar, F. Puglisi, C. X. Ma, A. Bardia, M. Cristofanilli. Time-to-progression patterns during first and second-line endocrine therapy across clinical features and liquid biopsy-defined mutational profiles in HR+/HER2- 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 PS2-07-04.