Predicting Endocrine Resistance Using Molecular Imaging and Liquid Biopsy in Metastatic Breast Cancer

Endocrine therapy combined with CDK4/6 inhibitors is a standard first-line treatment for patients with ER-positive, HER2-negative metastatic breast cancer. However, treatment response varies among patients, and both de novo and acquired endocrine resistance remain major causes of disease progression. Changes in ER expression and molecular alterations such as ESR1 mutations and alterations in the PI3K-AKT pathway have been implicated in the development of endocrine resistance. \[18F\]FES PET/CT enables noninvasive whole-body assessment of ER expression in lesions, and may provide information on spatial heterogeneity of ER expression across metastatic lesions. In combination with \[18F\]FDG PET/CT, which reflects tumor glucose metabolism, molecular imaging may provide complementary information regarding tumor biology and treatment resistance. Imaging biomarkers reflecting inter-lesional heterogeneity in FES uptake and quantitative FDG metabolic activity may therefore be useful for predicting outcomes during endocrine therapy. Circulating tumor DNA (ctDNA) provides a minimally invasive method for detecting tumor-derived genomic alterations, including mutations associated with endocrine resistance. Integrating ctDNA and tumor tissue genomic findings with molecular imaging may provide a more comprehensive assessment of the molecular and spatial heterogeneity of metastatic breast cancer. This single-center, prospective observational cohort study will enroll patients with ER-positive, HER2-negative metastatic breast cancer who are scheduled to receive first-line endocrine therapy with an aromatase inhibitor combined with a CDK4/6 inhibitor. Baseline molecular imaging biomarkers will be derived from \[18F\]FES and \[18F\]FDG PET/CT. The primary objective is to evaluate the prognostic value of these imaging biomarkers for progression-free survival during first-line endocrine therapy combined with a CDK4/6 inhibitor. In a subset of participants with adequate tumor tissue available, paired ctDNA analysis and tumor tissue next-generation sequencing will also be performed to investigate their associations with progression-free survival and molecular imaging biomarkers. Changes in \[18F\]FDG PET/CT findings during treatment and molecular and imaging characteristics associated with disease progression will also be explored.