Longitudinal ctDNA Surveillance in Older Women with ER+ Breast Cancer to Facilitate Surgical De-Escalation: A Prospective, Hybrid-Decentralized Trial with Correlative Studies

For older patients with competing comorbidities, optimizing oncologic therapies is of paramount importance. Circulating tumor DNA (ctDNA) is a validated prognostic factor across solid tumors and may provide a strategy to identify patients for whom safe de-escalation of certain therapies is possible. In this prospective, hybrid-decentralized trial (n = 43 patients; NCT05914792 ) that integrated clinical outcomes, patient- and caregiver-reported outcomes, and correlative tissue analysis, the primary objective was to determine if ctDNA levels were associated with tumor progression in older patients who opted to forgo breast cancer surgery in favor of primary endocrine therapy (pET). ctDNA levels were highly concordant with imaging findings, and a lack of ctDNA clearance at 6 months was associated with tumor progression. In a competing risk regression adjusted for patient age, tumor stage, tumor grade, and tumor Ki-67, pre-treatment ctDNA positivity was associated with a significant risk of tumor progression (HR 30, 95% CI 4.4-209; p = 0.0005). No patients with pre-treatment ctDNA negativity experienced tumor progression. In correlative analyses examining ctDNA-positive tumors progressing on pET, we identified populations of CD11+ T cell-interacting macrophages that upregulate CD109 and CD89 and secrete immunosuppressive chemokines to create a favorable environment for cancer epithelial cell proliferation. These findings suggest that ctDNA may be a surveillance modality for older patients who receive pET, warranting future evaluation in a randomized setting.