Trial of Neoadjuvant Trastuzumab Emtansine in Patients With HER2-Equivocal Breast Cancer

Inclusion Criteria:

* Female gender;
* Age ≥18 years;
* Eastern Cooperative Oncology Group performance status of 0-1;
* Histologically confirmed invasive breast cancer;
* Primary tumor greater than or equal to 1 cm diameter, as measured by clinical examination and mammography or ultrasound;
* Any N;
* No evidence of metastasis (M0) (isolated supra-clavicular node involvement allowed);
* HER2 low or equivocal status in the invasive component of the primary tumor (confirmed by a central certified laboratory prior to study entry)

  * HER2 low expression: 1+/2+ by immunohistochemistry and/or HER2/CEP17 ratio \<2.0 with HER2 copy number \<6.0 signals/cell
  * HER2 equivocal expression: HER2 copy number ≥4.0 and \<6.0 signals/cell;
* Hematopoietic status:

Absolute neutrophil count ≥ 1.0 x 10\^9/L, Platelet count ≥ 100 x 10\^9/L, Hemoglobin at least 9 g/dL;

• Hepatic status: Serum total bilirubin ≤1 x upper limit of normal (ULN; In the case of known Gilbert's syndrome, a higher serum total bilirubin \[\< 1.5 x ULN\] is allowed), Aspartate aminotransferase and alanine aminotransferase ≤1.5 x ULN, Alkaline phosphatase ≤ 1.5 x ULN;

• Renal status: Creatinine ≤1.5 mg/dL;

* International Normalized Ratio ≤1.5 x ULN;
* Baseline left ventricular ejection fraction ≥50%, as measured by echocardiography or multigated acquisition scan;
* Negative serum or urine β-human chorionic gonadotropin pregnancy test within 7 days prior study entry for patients of childbearing potential. Women of childbearing potential must use effective contraception (barrier method \[condoms, diaphragm\] in conjunction with spermicidal jelly, or total abstinence. Oral, injectable, and implantable hormonal contraceptives are not allowed) for the duration of the study and for at least 7 months after the last dose of study treatment;
* Signed informed consent form (ICF);
* Patient accepts to make available tumor samples for submission to central laboratory to conduct translational studies as part of this protocol.

Exclusion Criteria:

* Previous (less than 5 years) or current history of malignant neoplasms, except for curatively treated basal and squamous cell carcinoma of the skin and carcinoma in situ of the cervix;
* Patients with a prior malignancy diagnosed more than 5 years prior to study entry;
* Preexisting peripheral neuropathy ≥ grade 2;
* Known history of uncontrolled or symptomatic angina, clinically significant arrhythmias, congestive heart failure, transmural myocardial infarction, uncontrolled hypertension (≥180/110), unstable diabetes mellitus, dyspnea at rest, or chronic oxygen therapy;
* Concurrent disease or condition that would make the patient inappropriate for study participation or any serious medical disorder that would interfere with the patient's safety;
* Unresolved or unstable serious adverse events from prior administration of another investigational drug;
* Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of ICF;
* Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy other than the trial therapy);
* Concurrent treatment with an investigational agent or participation in another therapeutic clinical trial;
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trastuzumab emtansine or its components;
* Ejection fraction \<55% or below the lower limit of the institutional normal range;
* Pregnant or lactating women;
* Concomitant use of cytochrome P450 3A4 inhibitors or inducers;
* Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol;
* Active infection requiring intravenous or oral antibiotics;
* Patients unwilling or unable to comply with the protocol.