Overview

This is an open-label phase 2 study to evaluate the pCR rate in patients diagnosed with HER2 positive breast cancer treated on an adaptive clinical trial design.

Tumors will undergo testing using a novel molecular phosphoprotein-based biomarker assay, HER2 Activation Response Predictive Signature (HARPS) to identify HARPS-positive breast cancers.

To assess 3-year invasive disease-free survival (iDFS) in patients with HARPS-positive and HARPS-negative HER2-positive breast cancer.

To correlate changes in ctDNA with treatment outcomes in patients with HARPS-positive and HARPS-negative HER2-positive breast cancer.

To understand the changes in quality of life (QOL) measure in patients with HARPS-positive HER2-positive breast cancer treated using an adaptive neoadjuvant trial design.

Eligibility

Inclusion Criteria:

• Inclusion Criteria
  1. Tumor size greater than 2cm or lymph node positive by imaging or clinical exam (cT2-T3 N0-2)
  2. Tumors must be HER2 positive either by IHC (3+) or by IHC 2+ and FISH positive.
  3. Patient must have known estrogen receptor (ER) and progesterone receptor (PR) status locally determined prior to study entry
  4. Patient must have adequate tumor for HARPS testing.
  5. Patients must have ctDNA collection prior to treatment on trial.
  6. Patient must be able to do breast MRI as determined by the study
  7. Baseline LVEF \> 50% (Most recent within the last 5 years)
  8. No prior history of systemic treatment with anthracyclines-based chemotherapy.
  9. Adequate bone marrow function:
     • ANC ≥ 1500/uL
     • platelet count ≥ 100,000/uL
     • hemoglobin ≥ 9.0 g/dL
  10. Adequate hepatic function:
      • Total bilirubin ≤ 1.5 X ULN
      • AST (SGOT) ≤ 5 X ULN
      • ALT (SGPT) ≤ 5 X ULN
  11. Patients with biliary obstruction must have restored biliary flow by placement of an endoscopic common bile duct stent or a percutaneous drainage.
  12. Adequate renal function, Creatinine \< 1.5x institutional ULN or calculated creatinine clearance ≥ 50 mL/min as estimated using the Cockcroft-Gault formula.
  13. Ability to understand the nature of this study protocol and give written informed consent.
  14. Willingness and ability to comply with scheduled visits and treatment plans
  15. Prior cancers allowed if no evidence of disease in last 5 years. Prior history of ipsilateral invasive breast cancers are not allowed.

Exclusion Criteria:

1. Previous treatment with chemotherapy, anti-HER2 therapy, radiation therapy, or endocrine therapy for invasive breast cancer. Exception: patients can start upto 1 cycle of HP prior to starting treatment on study.
2. cT4 and/or cN3 tumors
3. Evidence of metastatic disease by routine clinical assessment
4. Bilateral breast cancer
5. History of other malignancy within the last five years prior to first dose of study drug administration, except for curatively treated basal and squamous cell carcinoma of the skin and/or in situ cervical carcinoma
6. Left ventricular ejection fraction (LVEF) below 50% as determined by multiple-gated acquisition (MUGA) scan or echocardiography (ECHO)
7. No active liver disease.
8. Any condition including the presence of laboratory abnormalities, which, in the opinion of the investigator places the subject at unacceptable risk if he/she were to participate in the study.
9. Pre-existing sensory neuropathy \> grade 1.
10. Clinically significant cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication) or myocardial infarction within the last 6 months.
11. Serious non-healing wound, ulcer, or bone fracture
12. Patient with uncontrolled and/ or active infection with HIV, Hepatitis B or Hepatitis C.
13. Patient who has a history of allergy or hypersensitivity to any of the study drugs.
14. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study