Phase II Study of Ultrasound and ctDNA Guided Neoadjuvant Systemic Therapy for Patients With HER2-positive Early Breast Cancer (UC HER Trial)

Diagnosis: HER2-positive Primary Invasive Breast Cancer

Patients must meet the following criteria for study entry:

1. Histologically confirmed invasive breast carcinoma

2. HER2-positive breast carcinoma

   1. HER2-positive status will be based on pretreatment biopsy material and defined as an immunohistochemistry (IHC) score of 3+ and/or positive by fluorescence in situ hybridization (FISH) prospectively confirmed by a pathology laboratory before study enrollment.
   2. FISH positivity is defined as a ratio of ≥ 2.0 for the number of HER2 gene copies to the number of signals for chromosome 17 copies.

3. Clinical stage at presentation: T1-4, N0-3, M0 (T1N0M0 tumors will not be eligible)

4. Patients must be willing to receive preoperative systemic chemotherapy with taxanes and HER-2-targeting treatment for at least 4 to 6 cycles.

   1. Systemic therapy must consist of at least 4 to 6 cycles of chemotherapy with taxanes plus trastuzumab (TH) or
   2. Systemic therapy must consist of at least 4 to 6 cycles of chemotherapy with taxanes plus trastuzumab and pertuzumab (THP).
   3. After completion of 4 to 6 cycles of TH or THP, if the following clinical features and pathological characteristics are eligible for Lipo-Dox® and cyclophosphamide plus trastuzumab and pertuzumab:

   c.1 Core biopsy showed the residual invasive breast cancer. c.2 Breast echo or other imaging studies disclosed no complete remission. c.3 Complete remission of core biopsy or breast echo or other imaging studies, but positive for ctDNA.

5. Age ≥ 20 years.

6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

7. Adequate organ function during screening, included:

   1. Absolute neutrophil count ≥ 1,200 cells/mm3
   2. Platelet count ≥ 100,000 cells/ mm3
   3. Hemoglobin ≥ 9.0 g/dL;
   4. Serum creatinine < 1.5 × upper limit of normal (ULN)
   5. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 ×ULN
   6. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 ×ULN
   7. Serum total bilirubin (TBILI) ≤ 1.0 ×ULN (within normal limits)
   8. Serum alkaline phosphatase (ALK) ≤ 1.5 ×ULN

8. Screening LVEF ≥ 50% on echocardiogram (ECHO) or multiple-gated acquisition (MUGA) before receiving neoadjuvant chemotherapy with 4 to 6 courses of TH or THP and no decrease in LVEF by more than 10% absolute points from the pre-chemotherapy LVEF after 4 to 6 courses of TH or THP.

9. For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 7 months after the last dose of study drug.

10. Documentation of hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies is required: this includes HB surface antigen (HBsAg) and/or total HB core antibody (anti-HBc) in addition to HCV antibody testing. If positive for HBsAg or positive for Anti-HBc, DNA testing for HBV will be performed. If active HBV infection is ruled out, the patient may be eligible. The most recent serologic testing must have occurred within 3 months prior to initiation of neoadjuvant therapy. If such testing has not been done, it must be performed during screening.

11. They should receive examination of HBV DNA to document no active HBV activation (if HBeAg-positive, or HBeAg-negative but abnormal liver function accompanied by ALT ≥ 2 normal limits during the half a year and HBV DNA > 2000 IU/ml: indication of HBV activation). If test of HBsAg is positive and inactive, and they should receive prophylactic anti-HBV drugs during the enrollment period of this clinical trial.

1. Stage IV (metastatic) breast cancer.

2. History of any prior (ipsilateral- or contralateral) breast cancer except lobular carcinoma in situ.

3. History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ (CIS) of the cervix, non-melanoma skin carcinoma, stage I uterine cancer, or other non-breast malignancies with an outcome similar to those mentioned above.

4. Patients for whom radiotherapy would be recommended for breast cancer treatment, but for whom it is contraindicated because of medical reasons (e.g., connective tissue disorder or prior ipsilateral breast radiation).

5. Current NCI common terminology criteria for adverse events (CTCAE) (Version 4.0): Grade ≥ 2 peripheral neuropathy.

6. Cardiopulmonary dysfunction as defined by any of the following:

   History of NCI CTCAE (Version 4.0): Grade ≥ 3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) criteria Class ≥ II.

7. Prior treatment with anthracycline or Lipo-Dox®

8. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers).

9. For female patients, current pregnancy and/or lactation. 10. Any known active liver disease, for example, due to HBV, HCV, autoimmune hepatic disorders, or sclerosing cholangitis.

   • Patients who have positive HBV or HCV serologies without known active disease must meet the eligibility criteria for liver function on at least two consecutive occasions, separated by at least 1 week, within the 30 days-screening period.