Abstract Background: Despite therapeutic advances, hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC) remains largely incurable. Genomic characterization of MBC has historically relied on samples collected early in the disease course; however, a lethal phenotype—characterized by accelerated disease progression and profound therapeutic resistance—is clinically well-recognized. The biological mechanisms driving this terminal transition remain largely unknown. By performing a longitudinal ctDNA analysis at the start and end of this disease continuum, we aimed to characterize genomic alterations driving lethal HR+/HER2- MBC. Methods: Serial plasma samples, linked to detailed clinical annotation, were collected from patients with MBC enrolled in the EMBRACE cohort study. We included patients with HR+/HER2- subtype who had paired plasma collection within 180 days of MBC diagnosis (early MBC) and within 180 days of death (lethal MBC). Plasma-derived ctDNA was analyzed using a 700-gene liquid biopsy assay (Guardant360) that assesses single nucleotide variants (SNVs), indels, fusions, copy number alterations (CNAs), and a methylation-derived tumor fraction (TF) score. To limit variation due to tumor shed, comparisons of somatic alterations were restricted to patients with TF 1% at both time points. Significance of enrichment was determined using Fisher’s exact tests with FDR corrections. Results: 56 patients with paired specimens from early and lethal MBC timepoints were included with a median interval of 819 days (range 98-2464) between samplings. Median TF was 0.7% (range 0% to 76%) in early MBC and 29.7% (range 0% to 90%) in lethal MBC draws. In 25 patients with sufficient TF at both collections, lethal MBC exhibited a substantial enrichment of alterations in genes mediating therapy resistance. Patients received a median of 6 lines of therapy (range 3-16), including chemotherapy (100%), CDK4/6i (92%), and antibody-drug conjugates (16%) prior to lethal MBC sampling. Alterations in cell cycle genes were strikingly enriched with a greater than three-fold increase in RB1 alterations (from 12% to 46%), doubling of PTEN alterations (12% to 27%) and significant gains in CDKN2A (4% to 31%), CCND2 (12% to 35%), and CCNE2 (15% to 35%) alterations. Additionally, we found a marked increase in mutations mediating endocrine resistance and growth factor bypass mechanisms, with the prevalence of ESR1 alterations rising from 27% to 65%, ERBB2 from 15% to 42%, NF1 from 12% to 50%, and KRAS from 15% to 35%. Enrichments for ESR1, ERBB2, NF1, RB1, and CDKN2A alterations were statistically significant (FDR q 0.25). Critically, CNAs seemed to be a dominant driver of this evolution, accounting for 64.5% of acquired alterations. Specifically, amplifications drove the rise in CCND2, and CCNE2 alterations, while deletions were the primary mechanism for the increased frequency of NF1, RB1, CDKN2A, and PTEN alterations. Conclusions: We identify dramatic shifts in the prevalence of resistance-driving alterations from early to lethal HR+/HER2- MBC. The striking enrichment of RB1, CDKN2A, PTEN, and cyclin alterations underscore a near-universal development of resistance to CDK4/6 inhibitors in the terminal phase of disease. Furthermore, the prevalence of structural variation as the primary driver suggests a significant degree of genomic instability that precedes death. Collectively, these findings suggest that: (1) routine ctDNA re-evaluation in advancing disease is critical to identify actionable resistance mechanisms, particularly those not present at metastatic diagnosis; and (2) despite inter-patient heterogeneity, lethal HR+/HER2- MBC exhibits convergent evolution towards common resistance pathways, presenting a formidable clinical challenge that demands more innovative therapeutic strategies. Citation Format: N. Priedigkeit, M. E. Hughes, C. Weipert, A. Lebrón-Torres, K. Santos, S. Morganti, K. Smith, C. E. Stever, G. L. Suggs, A. Patel, G. Kirkner, M. E. Skeffington, H. A. Parsons, D. L. Abravanel, C. Snow, E. P. Winer, S. L. Sammons, S. M. Tolaney, R. M. Jeselsohn, N. U. Lin. Convergent genomic evolution from early to lethal 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 PD2-09.
Priedigkeit et al. (Tue,) studied this question.