Cardiomyopathy Clinical Trials

• To be eligible to participate in this study, an individual must meet all of the following criteria:

• Histologically confirmed triple-negative breast cancer (TNBC) or hormone receptor-low invasive breast carcinoma, with clinical anatomic Stage II or Stage IIIA/B disease as defined by the AJCC 8th Edition Breast Cancer Stating System.

• a) The invasive tumor must be hormone receptor-negative or low, defined as estrogen receptor (ER) and/or progesterone receptor (PR) staining present in ≤10% of invasive cancer cells by immunohistochemistry (IHC).

• b) HER2-negative disease, defined in accordance with current ASCO-CAP HER2 guidelines.

• Measurable or evaluable tumor in the breast larger than 1 cm, with or without axillary involvement.

• Patients with multifocal or multicentric disease are eligible, provided the dominant tumor focus is ER and/or PR ≤10% and HER2 negative.

• Female or male, age ≥18 years.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

• Medically fit to undergo curative-intent breast surgery per institutional standard of care.

• No prior chemotherapy, immunotherapy, radiation therapy, or surgery for the current breast cancer (diagnostic core or vacuum-assisted biopsies allowed).

• Ability to be followed by a cardiologist and/or primary care physician for optimization of cardiac comorbidities, as needed.

• Adequate organ function at the time of screening, defined as:

• a) Hematologic

‣ Absolute neutrophil count ≥1,500/µL.

‣ Platelet count ≥100,000/µL.

‣ Leukocytes ≥3,000/µL.

‣ Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L (without erythropoietin dependency and without packed red blood cell transfusion within 14 days prior to testing).

• b) Renal

• a. Serum creatinine ≤1.5 mg/dL or creatinine clearance ≥50 mL/min. Note: Patients with creatinine clearance 30-50 mL/min may be enrolled at the discretion of the Principal Investigator, given that paclitaxel is primarily hepatically metabolized and carboplatin dosing can be adjusted to renal function.

• c) Hepatic

‣ AST (SGOT) and ALT (SGPT) ≤2.5 × ULN.

‣ Serum albumin ≥3.0 g/dL.

‣ Participants without a history of Gilbert's syndrome must meet one of the following:

• i. Total bilirubin ≤1.5 × IULN, or ii. Total bilirubin \>1.5 × IULN with direct bilirubin ≤ULN. d. Participants with a history of Gilbert's syndrome must have total bilirubin ≤5 × ULN.

• d) Coagulation

• a. For patients receiving anticoagulant therapy, PT and/or aPTT within the therapeutic range for the intended use of anticoagulants.

• b. For patients not receiving anticoagulant therapy, INR, PT, and aPTT ≤1.5 × ULN.

⁃ Breast and axillary imaging (including ultrasound and MRI) within 42 days (6 weeks) prior to registration.

⁃ Patients with clinically and/or radiologically abnormal axillary lymph nodes must have pathological confirmation with image-guided core biopsy or fine needle aspiration showing metastatic carcinoma.

⁃ Patients should undergo staging scans to exclude metastatic disease if any of the following apply:

⁃ a) Axillary imaging shows two or more abnormal lymph nodes, or b) There are clinical signs or symptoms concerning for metastatic disease, or c) At the treating physician's discretion.

⁃ Patients with bilateral breast cancer are eligible if both tumors are HER2 negative and all other eligibility criteria are met (eligibility should be determined based on the higher-risk side when applicable).

⁃ Baseline peripheral neuropathy grade ≤2 (per CTCAE).

⁃ An individual of childbearing potential must be willing and able to use highly effective contraception from the time of informed consent, throughout study treatment, and for at least 6 months after the last dose of trial therapy.

⁃ Note: Highly effective contraception is defined as methods with a failure rate \<1% per year when used consistently and correctly, and include: copper intrauterine device (IUD); bilateral tubal ligation/occlusion or other documented surgical sterilization; vasectomized partner with documented azoospermia, provided this is the sole sexual partner; or true sexual abstinence, defined as complete abstinence from heterosexual intercourse, when this is the participant's usual and preferred lifestyle. Use of hormonal contraceptive methods (including combined oral contraceptives, progestin-only pills, injectables, implants, hormonal IUDs, patches, or vaginal rings) is not permitted during the study.

⁃ Ability and willingness to comply with all study procedures, including scheduled visits, treatment plans, laboratory tests, and other study requirements.

⁃ Ability and willingness to sign and date written informed consent prior to initiation of any study-specific procedures.

⁃ Participants with known human immunodeficiency virus (HIV) infection must be on effective anti-retroviral therapy at registration and have undetectable viral load test on the most recent test results obtained within 6 months prior to registration.

⁃ Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV load while on suppressive therapy on the most recent test results obtained within 6 months prior to registration, if indicated. NOTE: No testing for Hepatitis B is required unless mandated by local health authority.

⁃ Participants with a history of hepatitis C virus (HCV) must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 6 months prior to randomization, if indicated. NOTE: No testing for Hepatitis C is required unless mandated by local health authority.

⁃ Patient is ineligible for anthracycline treatment due to at least one of the following of A, B, C, or D:

∙ Individuals identified as being at high risk for cardiotoxicity from anthracycline treatment have one or more of the following characteristics.

• 1\. Preexisting cardiomyopathy with ejection fraction (EF) between 25-49%. 2. Severe valvular disease on echocardiogram. 3. Previous exposure to anthracyclines. 4. Previous exposure to high dose chest wall radiation \>30Gy. 5. Participants who have experienced myocardial infarction, unstable angina pectoris, an arterial thrombotic event, or stroke, within the last 12 months but not less than 3 months ago.

• b) Medium or high risk for Congestive Heart Failure (CHF) at 3 years as defined by the Cardiotoxicity Prediction Tool from Ezaz et al. \[24\]

• c) Patients declining anthracycline therapy after thorough discussion regarding its significant role in treating TNBC.

• d) Patients who are deemed ineligible for anthracycline due to other medical conditions not listed here, as determined by the primary oncologist and confirmed by the study PI.