Patterns of Progression After First-Line Systemic Therapy in Metastatic Breast Cancer and the Potential of ctDNA to Guide Metastasis-Directed Therapy: Implications for Breast Oligometastases Management.

Abstract

To analyze patterns of progression after first-line systemic therapy in metastatic breast cancer (MBC) patients who did not undergo metastasis-directed therapy (MDT), and to explore whether baseline circulating tumor DNA (ctDNA) copy number aberration burden is associated with progression to widespread metastases. We reanalyzed a prospective cohort of 207 patients with de novo or recurrent MBC enrolled between 2017 and 2021. Serial imaging studies were retrospectively reviewed to enumerate metastatic lesions and classify progression as involving preexisting lesions (L), new lesions (D), or both (L + D). Lesion-burden was categorized as 1-5, 6-10, or >10 lesions. Baseline plasma samples were analyzed using low-pass whole-genome sequencing to quantify genome-wide copy number aberration burden, expressed as the I-score. Among 207 patients, baseline lesion counts were 1-5 in 29.5%, 6-10 in 17.9%, and >10 in 52.7%. With a median follow-up of 47.4 months, 5-year overall survival was 75.4% for 1-5 lesions, 65.9% for 6-10 lesions, and 44.9% for >10 lesions, demonstrating a stepwise gradient by baseline lesion count. Patterns-of-failure were L in 39.3%, D in 27.1%, and L + D in 33.6%, indicating that new lesions accounted for 60.7% of first progression events. Across subsequent therapy lines, progression increasingly manifested as >5 lesions and D-only events. Higher baseline I-score correlated with lesion-burden (ρ = 0.35, P < .001) and independently predicted widespread progression (>10 lesions; hazard ratio, 3.21; 95% CI, 2.01-5.13), along with younger age, triple-negative breast cancer, and higher baseline lesion count. MBC frequently evolves toward widespread dissemination, with new-lesion failures predominating. These patterns provide context for prior MDT trial results and highlight the limitations of lesion count alone. Elevated ctDNA copy number burden independently predicted widespread progression, supporting further study of ctDNA profiling to identify patients at high risk of rapid dissemination, in whom MDT is unlikely to provide benefit.