Statement: Female Patients with LVEF > 50%,  who have previously undergone treatment with trastuzumab emtansine or lapatinib are still eligible for the secondary trial but are excluded from the primary trial.
Primary_evidence: Inclusion Criteria:   Prospectively confirmed HER2-positive (i.e., IHC 3+ or IHC 2+ and gene amplified by fluorescence in situ hybridization [FISH] positive) as assessed on primary tumor and/or metastatic site   Documented progression of unresectable, locally advanced, or mBC, determined by the investigator   Left ventricular ejection fraction (LVEF) >/= 50% by echocardiogram (ECHO)   Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1   A negative serum Beta-Human Chorionic Gonadotropin (Beta-HCG) test for women of childbearing potential (premenopausal or not meeting the definition of postmenopausal i.e. >/= 12 months of amenorrhea), and women who have not undergone surgical sterilization (i.e., absence of ovaries and/or uterus)   For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use two adequate non-hormonal methods of contraception, including at least one method with a failure rate of <1% per year, during the treatment period and for at least 7 months after the last dose of study drug   For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm. With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of <1% per year during the treatment period and for at least 7 months plus 90 days (a spermatogenesis cycle) after the last dose of study drug. Men must refrain from donating sperm during this same period. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 7 months after the last dose of study drug. Exclusion Criteria:   Prior treatment with trastuzumab emtansine   Prior treatment with lapatinib or lapatinib with capecitabine or non-comparable biologic or biosimilar of trastuzumab   Peripheral neuropathy of Grade >/= 3 per the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE [version 4.03])   History of other malignancy within the previous 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 1 uterine cancer, synchronous or previously diagnosed HER2-positive breast cancer, or cancers with a similar curative outcome as those mentioned above   History of receiving any anti-cancer drug/biologic or investigational treatment within 21 days prior to enrollment except hormone therapy, which can be given up to 7 days prior to enrollment; recovery of treatment-related toxicity consistent with other eligibility criteria   History of exposure to cumulative doses of anthracyclines, as defined in the protocol   History of radiation therapy within 14 days of enrollment   Brain metastases that are untreated, symptomatic, or require therapy to control symptoms, as well as a history of radiation, surgery, or other therapy, including steroids, to control symptoms from brain metastases within 2 months (60 days) before enrollment   CNS only disease   History of a decrease in LVEF to < 40% or symptomatic congestive heart failure (CHF) with previous trastuzumab treatment   History of symptomatic chronic heart failure (New York Heart Association [NYHA] Classes II-IV) or serious cardiac arrhythmia requiring treatment   History of myocardial infarction or unstable angina within 6 months of enrollment   Current dyspnea at rest due to complications of advanced malignancy or requirement for continuous oxygen therapy   Current severe, uncontrolled systemic disease   Pregnancy or lactation   Concurrent, serious, uncontrolled infections or current known infection with human immunodeficiency virus (HIV) or active hepatitis B and/or hepatitis C. For patients who are known carriers of hepatitis B virus (HBV), active hepatitis B infection must be ruled out, based on negative serologic testing and/or determination of HBV DNA viral load per local guidelines   Presence of conditions that could affect gastrointestinal absorption: malabsorption syndrome, resection of the small bowel or stomach, and ulcerative colitis   History of intolerance (such as Grade 3-4 infusion reaction) or known hypersensitivity to trastuzumab or murine proteins or any component of the product   Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol
Secondary_evidence: Inclusion Criteria:   Female gender;   Age 18 years;   Performance Status- Eastern Cooperative Oncology Group (ECOG) 0-1   Histologically confirmed invasive breast cancer:   Primary tumor greater than 1 cm diameter, measured by clinical examination and mammography or ultrasound.   Any N,   No evidence of metastasis (M0) (isolated supra-clavicular node involvement allowed);   Over expression and/or amplification of HER2 in the invasive component of the primary tumor and confirmed by a certified laboratory prior to randomization.   Known hormone receptor status.   Hematopoietic status:   CBC not less than .75 of institutional lower limit. Absolute neutrophil count  1,5 x 10^9/L, Platelet count  100 x 10^9/L, Hemoglobin at least 9 g/dl,   Hepatic status:   Serum total bilirubin  2 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 (AST) and Alanine Aminotransferase (ALT)  3.5 times ULN, Alkaline phosphatase  2.5 times ULN,  Renal status: Creatinine  1.5mg/dL,  Cardiovascular: Baseline left ventricular ejection fraction (LVEF) ³ 50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan,   Negative serum or urine β-hCG pregnancy test at screening for patients of childbearing potential within 2-weeks (preferably 7 days) prior to randomization.   Fertile patients must use effective contraception (barrier method - condoms, diaphragm - also in conjunction with spermicidal jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not allowed)   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; Carcinoma in situ of the cervix.   Patients with a prior malignancy diagnosed more than 5 years prior to randomization may enter the study.   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 therapy with oxygen;   Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject'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;   Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded;   Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy other than the trial therapies);   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, trastuzumab, lapatinib, paclitaxel, abraxane or their components;   Pregnant or lactating women;   Concomitant use of CYP3A4 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   Patients have an active infection and require IV or oral antibiotics.   Pregnant or breast-feeding women   Patients unwilling or unable to comply with the protocol