The Impact of HER2 Heterogeneity on the Treatment of Early-stage HER2-positive Breast Cancer: a Phase II Study of T-DM1 in Combination With Pertuzumab in the Preoperative Setting

• Patients must have HER2-positive Stage II or III histologically confirmed invasive carcinoma of the breast. A minimum tumor size of 2 cm determined by physical exam or imaging is required.

• HER-2 positive, confirmed by central testing (Clarient labs): IHC 3+ and/or FISH positive based on one of the three following criteria:

• Single-probe average HER2 copy number≥6.0 signals/cell OR

• Dual-probe HER2/CEP17 \<2.0 with an average HER2 copy number ≥6.0 signals/cell OR

• Dual-probe HER2/CEP17 ratio ≥2.0

• ER/PR determination is required.

• Bilateral breast cancers are allowed if both cancers are HER2-positive.

• Patients with multifocal or multicentric disease are eligible as long as one area meets eligibility criteria.

• Breast imaging should include the ipsilateral axilla. For subjects with a clinically negative axilla, a sentinel lymph node biopsy will be performed either before or after preoperative therapy at the discretion of the subject's physicians. For subjects with a clinically positive axilla, a needle aspiration, core biopsy or SLN procedure will be performed to determine the presence of metastatic disease in the lymph nodes.

• Men and women (with any menopausal status) ≥ 18 years of age

• ECOG performance status 0 or 1

• Required laboratory values:

‣ ANC ≥1500/mm3

⁃ Hemoglobin ≥ 9 g/dl

⁃ Platelets ≥100,000/mm3

⁃ Serum creatinine \< 1.5 X ULN (institutional)

⁃ Total bilirubin ≤ 1.0 X ULN (institutional) For patients with Gilbert syndrome, the direct bilirubin should be within the institutional normal range.

⁃ AST and ALT ≤ 1.5x ULN (institutional)

⁃ Alkaline phosphatase ≤1.5x ULN (institutional)

• Documentation of hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies is required: this includes hepatitis B surface antigen (HBsAg) and/or total hepatitis B core antibody (HBcAb) in addition to HCV antibody testing.

• Only for patients who test positive for hep B/C virus: PTT/INR \< ULN (institutional)

• Left ventricular ejection fraction (LVEF) ≥ 55%

• Premenopausal women must have a negative serum pregnancy test, including women who have had a tubal ligation and for women less than 12 months after the onset of menopause.

• Women of childbearing potential and men with partners of childbearing potential must be willing to use one highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception by the patient and/or partner and continue its use for the duration of the study treatment and for 7 months after the last dose of study treatment.

• Potent CYP3A4 inhibitors, such as ketoconazole and erythromycin, should be avoided during the study treatment period with T-DM1.

• Excessive alcohol intake should be avoided (occasional use is permitted).

• Patients with a history of ipsilateral DCIS are eligible.

• Patients undergoing breast conservation therapy (i.e. lumpectomy) must not have any contraindications to radiation therapy.

• Willing and able to sign informed consent.

• Willing to provide tissue for research purposes.