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Background: Extinction of HER2 signaling in HER2 driven BC may be curative. Alternative activation pathways (HER1, HER3) & mutated downstream signal transducers allow resistance to therapy. Study aim: molecularly characterize HER2 BC before & after 2 wks anti-HER2 therapy (AHT) with T, L, or TL & to correlate these with pCR to continuation of same AHT with neoadjuvant chemo (FEC75 x 4 Q3W–Paclitaxel x 12W). pCR is absence of all invasive cancer in breast & lymph nodes. pCR-Breast used for molecular analysis. Methods: 100 consenting patients (pts) with stage II/III, HER2 BC, normal cardiac function were randomized to T, L or TL. Before & after AHT, all pts had core needle biopsies for tissue microarray, stem cell analysis & reverse phase protein microarrays, measuring 60 different phosphoprotein/ post-translationally modified protein signaling & gene expression analysis endpoints. Results: pCR in the ITT-E (ITT-E: Pts who had surgery, 75% compliant to chemo and took no prohibited meds.) pts: 54%, 45%, 74% for T, L, TL arms. Analysis by response: 1) Responders (R) have altered HER2 downstream interconnections with PI3K (Spearman rho correlation [rho] 0.5, p0.12) vs the non-responders [NR] (rho 0.9, p0.037) & HER3Y1289 correlated (p0.001 for all endpoints) with EGFRy1173, mTOR 2448, & Beta Catenin 33. 2) NR have a) intact signaling with PI3K (rho 0.9, p0.037); b) intact interactions with autophagy (PI3K - LC3B rho 0.83, p0.04); c) intact stem cell – proliferation signaling (Musashi - p70S6 Kinase T389 (p0.007, rho 0.89), CD44 - PTEN S380 (p0.001, rho 0.92) were not significant in R. Analysis by AHT, prior to AHT R vs. NR: 1) TRZ MMP-14, 2) LAP EGFRtyr1068 & Fox01/03T24/32 were statistically different. Conclusions: Our study provides a unique in vivo snapshot of molecular changes in signaling pathways of microdissected tumor cells before & after anti-HER2 therapy. Molecular profiles suggest NR use autophagy & stem cell related pathways to evade therapy, while R have disruption of HER2-HER3 linkages & known downstream regulators of growth & transcription. These results provide insights into novel candidate “drugable” targets.