In this study, the objective was to evaluate whether perioperative anti-HER2 therapy retarded cell proliferation and/or induced apoptosis in HER2-positive breast cancer. Women with HER2-positive invasive breast cancer who were undergoing surgery were enrolled in this randomized phase II, two-part, multicenter study.Patients were assigned to one of three groups in part 1: part 1 (1:2:2), no treatment (control); trastuzumab or lapatinib; part 2 (1:1:2) control, trastuzumab, or lapatinib and trastuzumab combination. About 11 days before the operation, treatment was administered. Primary endpoints were Ki67 and apoptosis changes between baseline and surgery tumor samples (biological response: ≥30% change). Residual cancer burden (RCB) was quantified by pathologic analysis in the study. RFS investigated long-term affects.Between November 2010 and September 2015, 257 patients were randomized (part 1: control 22, trastuzumab 57, lapatinib 51; part 2: control 29, trastuzumab 32, combination 66). Ki67 response was calculative for 223 patients: in part 1 Ki67 outcome occurred in 29/44 (66%) lapatinib versus 18/49 (37%) trastuzumab (P = 0.007) and 1/22 (5%) control (P<0.0001); in part 2 in 36/49 (74%) combination versus 14/31 (45%) trastuzumab (P=0.02) and 2/28 (7%) control (P<0.0001). Apoptosis was not enhanced in the treated groups after 11 days. About 13 patients had a complete pathological response (pCR, RCB0) with the combination therapy, six in the double-combination arm and seven in the triple-combination group. All but two of these were in the combination regimen. After a median of 6 years, 28 (11%) had recurrence and 19 (7%) had died. Patients who achieved a pCR did not have any recurrences or deaths. Ki67% falls ≥50% connected with fewer recurrences (P=0.002). A short duration anti-HER2 dual therapy’s early response predicts HER2-dependent cancers, allowing for risk-adapted individualized treatment de-escalation.