Background: Trastuzumab (T) and Lapatinib (L) containing neoadjuvant chemotherapy (NACT) increases pathological complete response (pCR) (vs. T or nihil) in HER2+ early breast cancer (EBC). Early clinical response markers (e.g. Ki67) in a 3-week biopsy or in residual tumor correlate with therapy efficacy and risk of relapse. This WSG Neo-Predict trial aimed to define early predictive markers for therapy response in a dual blockade (T+L) NACT setting. Methods: Patients with cT1c-cT4c HER2+ EBC were treated by paclitaxel (P) (80 mg/m²weekly) with L (750 mg p.o. daily) + T (2 mg/kg) weekly for 12 weeks. Adjuvant treatment with 4 cycles of Epirubicin/Cyclophosphamide (omission allowed in patients with pCR) and T for an additional 40 weeks was recommended. Primary objectives were pCR (ypT0/is/ypN0) and identification of a dynamic predictive test for pCR using a re-biopsy after three weeks of NACT (early response defined as central Ki67 decrease >30% (vs. baseline) and/or low cellularity (<500 invasive tumor cells)). Results: From 2013-2015, 64 patients (n=80 planned) were recruited. Overall pCR was 41% (41% for HER2+/HR+ (n=34) and 45.5% for HER2+//HR- (n=22)). A 0% pCR in the “non-responder” (n=7) group (vs. 50% in the “responder” (n=34) and 42% in the “missing response” (n=20) groups) is intriguing despite methodological limitations. Missing data for early response assessment in a substantial number of patients and negative DFS data from the ALTTO trial did not justify trial continuation. 27% of patients experienced severe adverse events (AE). 11.5% had > grade 3 AEs (including diarrhea, septic shock, leukopenia, and pneumonia). Conclusions: We observed a clinically meaningful pCR with moderate toxicity with only 12 weeks of paclitaxel weekly with dual HER2 blockade (T+L). Effect of additional chemotherapy in patients with pCR after 12 weeks of monochemotherapy remains questionable due to a strong prognostic effect of pCR in HER2+ EBC. In view of 0% pCR (by hypothesis-generating explorative analysis), a different treatment approach should be investigated in patients without “early response” by further prospective trials. Clinical trial information: 2012-003679-21.