Phase 2 Study of Standard Chemotherapy With Trastuzumab, Plus or Minus Pertuzumab, for Pre-treated Metastatic Breast Cancer

Inclusion Criteria:

1. Female, Age ≥ 18 years
2. Histologic or cytologic confirmation of human epidermal growth factor receptor 2 (HER2)-positive breast cancer according to most recent biopsy (local testing permitted)
3. Measurable or evaluable metastatic disease by Response Evaluation Criteria in Solid Tumors (RECIST) (v1.1)
4. Previous treatment with ado-trastuzumab emtansine (T-DM1) for metastatic disease

   a. Prior therapy with pertuzumab is allowed but not required
5. At least 1 but no more than 3 prior chemotherapy regimens for metastatic breast cancer (MBC)
6. Life expectancy \> 6 months
7. Eastern Cooperative Group (ECOG) performance status ≤ 2
8. Left Ventricular Ejection Fraction (LVEF) ≥ 50% at baseline as determined by either echocardiogram (ECHO) or Multi Gated Acquisition Scan (MUGA) and within normal limits per institutional guidelines
9. Adequate bone marrow function as indicated by the following:

   1. Absolute Neutrophil Count (ANC) ≥1500/uL (or 1500 per microliter)
   2. Platelets ≥100,000/uL
   3. Hemoglobin \>9 g/dL
10. Adequate renal function, as indicated by creatinine \<1.5 times upper limit of normal (ULN)
11. Adequate liver function, as indicated by bilirubin \<1.5 times ULN
12. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) \<2 x ULN unless liver metastases are present in which case AST and ALT up to 5.x ULN are allowed
13. Negative serum pregnancy test within 72 hours before starting study medications for women of childbearing potential
14. Women of childbearing potential must be willing to use an acceptable form of birth control (ie, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study Note: Women are considered postmenopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms), or if they have undergone surgical sterilization.
15. Signed informed consent obtained prior to any screening procedures.

Exclusion Criteria:

Patients will be excluded from the study based on the following criteria:

1. Prior treatment in the metastatic setting with the agent chosen as physician's choice of chemotherapy
2. Active infection
3. Uncontrolled central nervous system metastases, defined as clinical or radiologic evidence of progression of brain metastases or clinical signs of leptomeningeal disease

   a. Patients with treated brain metastases are eligible provided they do not have clinical or radiologic evidence of disease progression and have been off of dexamethasone for at least 3 weeks
4. Patient is pregnant or lactating
5. Prior chemotherapy within the last 3 weeks (last 6 weeks for nitrosureas/mitomycin)
6. Prior radiation therapy within the last 2 weeks; prior radiation therapy to indicator lesion (unless objective disease recurrence or progression within the radiation portal has been documented since completion of radiation).
7. Requirement for chronic steroid therapy with a requirement for \> 5mg/day of prednisone or the equivalent.

   a. Treatment with physiologic doses of hydrocortisone up to 20 mg daily (QD) is allowed.
8. Requirement for immunosuppressive therapy, such as those used to treat autoimmune disease.
9. Concomitant malignancies or previous malignancies within the last 3 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
10. History of significant cardiac disease, cardiac risk factors or uncontrolled arrhythmias
11. Ejection fraction \<50% or below the lower limit of the institutional normal range, whichever is lower
12. Known hypersensitivity to trastuzumab or pertuzumab
13. Serious medical or psychiatric limitations likely to interfere with participation in this study.
14. Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs, resulting in dyspnea at rest or requiring supplemental oxygen
15. Patient is currently part of or has participated in any clinical trial of an investigational agent within 1 month prior to enrollment in this study.