Genomic and Transcriptomic Predictors of Sequential SG Sensitivity After T-DXd in ER+/HER2-Low Metastatic Breast Cancer

Inclusion Criteria Patients must meet all of the following inclusion criteria to be eligible for participation in this study: 1. Willing and able to provide signed informed consent approved by UBC/BC Cancer REB 2. Female or male patients, regardless of race and ethnic group, who are ≥18 years old at the time of informed consent 3. Patients with locally advanced or metastatic ER+/HER2 low (defined as IHC 1+ or 2+ but FISH or CISH negative by ratio as per ASCO/CAP guidelines) breast cancer. Patients with imaging confirmed inoperable locally advanced breast cancer for which treatment is palliative in intent are also permitted. 4. Prior treatment must have included prior endocrine based treatment in the metastatic setting in conjunction with a CDK4/6 inhibitor. 5. Prior treatment must include at least 1 line of chemotherapy which must include trastuzumab deruxtecan (T-DXd) as the immediate prior line of therapy prior to study enrollment 6. The tumour must be accessible to be able to safely perform image guided biopsies for WGS and WTS. 7. Negative serum pregnancy test at baseline for pre-menopausal patients (within 14 days prior to randomization) and agreement to use medically approved precautions to prevent pregnancy during the study and for 12 weeks following the last dose of SG 8. Patients can have measurable or non measurable (but assessable) disease by CT or MRI as per RECIST Version 1.1 criteria as evaluated locally. Tumor lesions situated in a previously irradiated area are considered measurable if unequivocal progression has been documented in such lesions since radiation. 9. ECOG PS 0-2 10. Life expectancy ≥ 3 months 11. Acceptable bone marrow and organ function defined by the following laboratory values: 1. Absolute neutrophil count ≥1.0 x 109/L 2. Platelets ≥100 x 109/L 3. Hemoglobin ≥9.0 g/dL 4. INR ≤1.5 5. Serum creatinine clearance \>50 mL/min 6. In absence of liver metastases, direct bilirubin ≤1.5 x ULN, ALT and AST should be below ≤2.5 x ULN. If the patient has liver metastases, ALT and AST should be \< 5.0 x ULN. 12. Controlled brain metastasis (as per clinical determination) is allowed in the study at least 4 weeks before treatment. (Controlled brain metastasis is defined as no longer symptomatic from brain metastasis or no longer requiring higher doses of corticosteroids (\> 10 mg Dexamethasone per day) for CNS management. Anticonvulsants and stable corticosteroids dose can be included in the study). Exclusion Criteria Patients who meet any of the following exclusion criteria are not eligible to be enrolled in this study: 1. Patient is currently participating in any other type of medical research judged not to be scientifically or medically compatible with this study. 2. Patient has a known hypersensitivity to SG, irinotecan or its active metabolite SN-38. 3. Patients not available for follow up 4. Patients who are not willing to consider systemic treatment options 5. Tumor not accessible or not safe to perform biopsies 6. Patient has not had resolution of all acute toxic effects of prior anti-cancer therapy to CTCAE v. 5.0 grade ≤1 (except toxicities not considered a safety risk for the patient at investigators discretion: e.g. grade 2 peripheral neuropathy from prior chemotherapy that is stable). 7. Have an active second malignancy. Patients with a history of malignancy that has been completely treated, with no evidence of active cancer for 3 years prior to enrollment, or patients with surgically cured tumors with low risk of recurrence (e.g. non-melanoma skin cancer, histologically confirmed complete excision of carcinoma in situ, or similar) are allowed to enroll. 8. Have known active central nervous system (CNS) metastases. Patients with previously treated brain metastases may participate provided they have stable CNS disease (defined as no longer symptomatic from brain metastasis or no longer requires higher doses of corticosteroids (\> 10 mg Dexamethasone per day) for CNS symptom management. Anticonvulsants and stable corticosteroids dose can be included in the study). Screening for brain metastasis not required for enrollment. 9. Pregnancy and breast feeding 10. Patient without an adequate hematologic, renal and hepatic function as per above inclusion criteria 11. Patient has a pre-existing condition with uncontrolled diarrhea, chronic inflammatory bowel disease or GI perforation within 6 months prior to enrollment. 12. Have active serious infection requiring antibiotics.