Patients were randomized (1:1) upon completion of definitive surgery, and at least four cycles of chemotherapy to receive no additional treatment (n = 1693) or 1year of Herceptin treatment (n = 1693). Patients undergoing a lumpectomy had also completed standard radiotherapy. Patients with ER+ and/or PgR+ disease received systemic adjuvant hormonal therapy at investigator discretion. Herceptin was administered with an initial dose of 8mg/kg followed by subsequent doses of 6mg/kg once every three weeks for a total of 52weeks. The main outcome measure was disease‑free survival (DFS), defined as in Studies 1 and 2.

Among the 3386patients randomized to the two treatment arms, the median age was 49years (range 21–80), 83%were Caucasian, and 13%were Asian. Disease characteristics: 94%infiltrating ductal carcinoma, 50%ER+ and/or PgR+, 57%node positive, 32%node negative, and in 11% of patients, nodal status was not assessable due to prior neo‑adjuvant chemotherapy. Ninety‑six percent (1055/1098) of patients with node‑negative disease had high risk features: among the 1098 patients with node‑negative disease, 49% (543) were ER− and PgR−, and 47% (512) were ER and/or PgR + and had at least one of the following high risk features: pathological tumor size greater than 2 cm, Grade 2–3, or age < 35 years. Prior to randomization, 94%of patients had received anthracycline‑based chemotherapy regimens.

Study4

In Study4, breast tumor specimens were required to show HER2 gene amplification (FISH+ only) as determined at a central laboratory. Patients were required to have either node-positive disease, or node-negative disease with at least one of the following high-risk features: ER/PR-negative, tumor size > 2cm, age < 35years, or histologic and/or nuclear Grade2 or 3. Patients with a history of CHF, myocardial infarction, Grade3 or 4 cardiac arrhythmia, angina requiring medication, clinically significant valvular heart disease, poorly controlled hypertension (diastolic > 100mmHg), any T4 or N2 or known N3 or M1 breast cancer were not eligible.

Patients were randomized (1:1:1) to receive doxorubicin and cyclophosphamide followed by docetaxel (AC‑T), doxorubicin and cyclophosphamide followed by docetaxel plus Herceptin (AC‑TH), or docetaxel and carboplatin plus Herceptin (TCH). In both the AC‑T and AC‑TH arms, doxorubicin 60mg/m2 and cyclophosphamide 600mg/m2 were administered every 3weeks for four cycles; docetaxel 100mg/m 2 was administered every 3weeks for four cycles. In the TCH arm, docetaxel 75mg/m2 and carboplatin (at a target AUC of 6mg/mL/min as a 30‑ to 60‑minute infusion) were administered every 3weeks for six cycles. Herceptin was administered weekly (initial dose of 4mg/kg followed by weekly dose of 2mg/kg) concurrently with either T or TC, and then every 3 weeks (6mg/kg) as monotherapy for a total of 52weeks. Radiation therapy, if administered, was initiated after completion of chemotherapy. Patients with ER+ and/or PR+ tumors received hormonal therapy. Disease‑free survival (DFS) was the main outcome measure.

Among the 3222patients randomized, the medi