Prospective Study to Evaluate the Clinical Utility of ctDNA Tumor Fraction (TF) for Detection of ESR1 Mutations in HR-positive HER2-negative Metastatic Breast Cancer (MBC)

Participants are prospectively assigned to undergo ctDNA testing with FoundationOne® Liquid CDx (F1LCDx) at protocol-defined clinical decision points. Participants with an indeterminate negative F1LCDx result (ctDNA TF <1% and negative for ESR1mut) are assigned to undergo reflex tissue biopsy NGS unless deemed medically unsafe. The protocol does not mandate treatment selection; treating clinicians retain full discretion regarding therapy.All research-related procedures will be performed at the time of standard of care clinical visits. No extra visits outside of routine care are required. For participants with algorithm-detected ESR1 mutations, serial Electronic Medical Record review will be performed for up to 2 years to track subsequent treatment patterns, progression events, and survival status to assess other clinical outcomes associated with subsequent SERD-based regimens compared with historical clinical trial benchmarks.

This study will guide clinical decision-making for acquiring new tissue specimens following an indeterminate negative ESR1mut result from liquid biopsy, which is a critical step to ensure accurate detection of actionable mutations and enable the selection of the most appropriate targeted therapy.

Inclusion Criteria:

• Diagnosis of metastatic breast cancer that is hormone receptor-positive (ER≥10%), HER2 low or negative (defined as HER2 Imunohistochemistry (IHC) 0, 1+ or IHC 2+/In Situ Hybridization (ISH)-).
• Progression of metastatic breast cancer that is hormone receptor-positive (ER≥10%), HER2 low or negative (defined as HER2 IHC 0, 1+ or IHC 2+/ISH-) while on systemic therapy.
• Currently receiving or have previously received aromatase inhibitor therapy.

Exclusion Criteria:

• Patients with locally or regionally recurrent breast cancer without evidence of metastatic disease.
• De novo metastatic breast cancer.
• Presence of symptomatic metastatic visceral crisis.
• Participants with inflammatory breast cancer.
• Intact uterus with a history of endometrial intraepithelial neoplasia (atypical endometrial hyperplasia or higher-grade lesion).
• Diagnosis of any other malignancy within 5 years before enrollment, except for adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or second primary breast cancer.
• Other conditions that, in the opinion of the treating investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results.
• Pregnant and breastfeeding women are excluded from the study