• Histologically or cytologically confirmed hormone receptor-positive advanced breast cancer patients

∙ Have recurrent, metastatic, or unresectable disease

‣ Have HER2-low expression status, defined as IHC 2+/ISH- or IHC 1+,with a validated assay by ASCO/CAP guidelines

‣ Have no previous history of HER2-positive breast cancer (IHC 3+ or ISH+) by ASCO/CAP guidelines

‣ The hormone receptor (HR) status is defined by ER/PR IHC nuclear staining, and ER or PgR ≥1% is defined as hormone receptor-positive status

• Patients who progressed on 1st line endocrine + CDK4/6 inhibitor therapy for advanced breast cancer and received no other systemic therapy for advanced breast cancer. The all FDA-approved CDK4/6 inhibitors (palbociclib, ribociclib, and Abemaciclib) are allowed, and combination with aromatase inhibitors or fulvestrant are both allowed.

• Patients who have received chemotherapy or adjuvant endocrine therapy in the neo-adjuvant or adjuvant setting are eligible.

• Female patients with ≥19 years of age

• Radiologic or objective evidence of disease progression on or after the last systemic therapy prior to starting study treatment

• Patients must have at least one measurable lesion by RECIST 1.1 criteria, which was not previously irradiated or showed objective progression after irradiation to that lesion

• Patients must have an adequate tumor tissue sample available for assessment of HER2 by central laboratory and other exploratory biomarker analyses

• Patients with ECOG performance status 0 or 1

• Both pre- and post-menopausal patients are eligible, 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.

⁃ Adequate organ function for treatment Adequate organ and bone marrow function within 14 days before randomization/enrolment as described below:

⁃ a) Haemoglobin: ≥ 9.0 g/dL NOTE: Participants requiring ongoing transfusions or growth factor support to maintain haemoglobin ≥9.0 g/dL are not eligible. (Red blood cell transfusion is not allowed within 1 week prior to C1D1) b) Serum albumin: ≥ 2.5 g/dL c) International normalised ratio or Prothrombin time and either partial thromboplastin or activated partial thromboplastin time: ≤ 1.5 × ULN d) Absolute neutrophil count (ANC) ≥1500 cells/mm3

‣ granulocyte-colony stimulating factor administration is not allowed within 1 week prior to C1D1 ) e) Platelets ≥100,000 cells/mm3

‣ Platelet transfusion is not allowed within 1 week prior to C1D1) f) Estimated creatinine clearance ≥50 mL/min, or serum creatinine \<1.5x institution upper limit of normal (ULN) g) Bilirubin≤1.5 x ULN

‣ if no liver metastases or \< 3×ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline h) AST (SGOT) ≤2.5 x ULN (5.0 x ULN if hepatic metastases) i) ALT (SGPT) ≤2.5 x ULN (5.0 x ULN if hepatic metastases)

⁃ 12-Lead electrocardiogram (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention

⁃ QTc interval ≤470 msec and without history of Torsades de pointes based on average of the screening triplicate 12-lead ECG

⁃ Pointes or other symptomatic QTc abnormality

⁃ LVEF (by MUGA or echocardiogram) of ≥50% within 28 days before randomization/enrollment

⁃ No history of pneumonitis other than radiation pneumonitis

⁃ The patient has provided signed informed consent

⁃ Neither pregnant or breastfeeding female patients

⁃ Fertile women who are not in pregnancy or breastfeeding should use effective contraception for a period from two weeks before the start of research treatment, during treatment and up to seven months after last dose of study treatment

⁃ No other concurrent severe and/or uncontrolled medical disease which could compromise study participation, including any of the following:

⁃ Adequate treatment washout period before enrollment are below -Major surgery ≥ 4 weeks -Radiation Therapy including palliative stereotactic radiation therapy to chest ≥ 4 weeks -Palliative stereotactic radiation therapy to other anatomic areas including whole brain radiation ≥ 2 weeks -Anti-Cancer chemotherapy \[Immunotherapy (non-antibody based therapy)\], retinoid therapy, hormonal therapy ≥ 3 weeks -Antibody based anti-cancer therapy ≥ 4 weeks -Targeted agents and small molecules ≥ 2 weeks or 5 half-lives, whichever is longer -Nitrosoureas or mitomycin C ≥ 6 weeks -Chloroquine/Hydroxychloroquine ≥ 14 days -Cell-free and CART, peritoneal shunt or drainage of pleural effusion, ascites or pericardial effusion ≥ 2 weeks prior to screening assessment