Inclusion Criteria:

• Histologically or cytologically documented breast cancer
• Locally advanced or metastatic breast cancer
• HER2-positive breast cancer documented as FISH-positive, IHC 3 + or CISH-positive by local laboratory assessment
• Prior treatment with an anthracycline and a taxane given in the neoadjuvant, adjuvant, or metastatic setting, or as treatment for unresectable locally advanced disease
• Prior treatment with capecitabine or infusional 5-fluorouracil and at least two HER2-targeted agents, including trastuzumab and lapatinib, in the metastatic and/or unresectable locally advanced setting
• Patients must have had disease progression during their most recent treatment regimen
• Adequate hematologic and end organ function
• Agreement to use an effective form of birth control throughout the study
• Life expectancy ≥ 90 days as assessed by the investigator

Exclusion Criteria:

• Less than 14 days from the first study treatment since the last anti-cancer therapy, including chemotherapy, biologic, experimental, immune, hormonal or endocrine therapy
• Prior T-DM1 therapy
• History of exposure to cumulative doses of select anthracyclines
• History of intolerance or hypersensitivity to trastuzumab, murine proteins, or any of the excipients, that resulted in trastuzumab being permanently discontinued
• Brain metastases that are untreated or progressive or currently require any type of therapy, including radiation, surgery, and/or steroids to control symptoms from brain metastases within 30 days before the first study treatment
• Peripheral neuropathy of Grade ≥ 3 per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0, at the time of the first study treatment
• History of clinically significant cardiac dysfunction
• Current known active infection with HIV, hepatitis B virus, or hepatitis C virus
• Current severe, uncontrolled systemic disease
• Major surgical procedure or significant traumatic injury within 28 days prior to first study treatment
• Pregnancy or lactation

NOTE: The site selection process has been completed. Patients can enroll at participating sites.