Trastuzumab Deruxtecan vs Endocrine Therapy in Low-HER2 HR+ Advanced Breast Cancer

Study Design: Randomized phase II, two-arm, randomized, open label study \- The Hormone receptor (HR)-positive HER2-low advanced breast cancer patients (HER2 IHC 1+ or 2+ \& ISH negative, n=141) who progressed on first-line endocrine + CDK4/6 inhibitor therapy for advanced disease will be enrolled in this study. Patients will be 2:1 randomized to experimental and control treatment arms by stratification factors below Stratification factor 1. Visceral metastasis (with visceral metastasis versus without visceral metastasis) 2. Progression-free survival on prior CDK4/6 inhibitor therapy (\< 6 months versus ≥ 6 months) * In the experimental treatment arm (n=94), patients receive trastuzumab deruxtecan (T-Ddx) 5.4mg/kg intravenous infusion every 3 weeks. In the control treatment arm (n=47), patients receive endocrine therapy of physicians' choice (TPC: fulvestrant, fulvestrant + alpelisib, exemestane, exemestane + everolimus, or tamoxifen; fulvestrant + alpelisib can be selected in PIK3CA activating mutation positive patients). The study treatment will continue until disease progression by RECIST 1.1, unacceptable toxicity, end of study, or death. * This study both enrolls pre- and post-menopausal patients, and pre-menopausal patients should receive ovarian function suppression treatment (GnRH agonist injection or surgical bilateral oophorectomy) while receiving fulvestrant or aromatase inhibitor treatment in the control arm. * The endocrine TPC is pre-selected by investigator in screening period before randomization. The regimens that the patient received for advanced disease before cannot be selected. The regimen that the patients received for (neo)adjuvant therapy for breast cancer before cannot be selected unless the recurrence of disease was diagnosed \> 1 year after the completion of the (neo)adjuvant therapy. * The evaluation of tumor response by computed tomography or magnetic resonance imaging of the chest, abdomen, and pelvis will be performed every 9 weeks from the date of randomization for 54 weeks and performed every 12 weeks after then until objective (RECIST 1.1 defined) disease progression. * Mandatory baseline tissue and ctDNA collection followed by three on-treatment ctDNA samples (Day 1 of Cycle 2, Cycle 3, and Cycle 6) will be collected. The post-treatment ctDNA (mandatory) and tumor tissues (optional) will be also collected * The patient samples will be evaluated to identify predictive biomarkers including copy number aberration (CNA), mutations, molecular subtype, or HRD status on LP-WGS ctDNA analysis.