Background: CT added to H is the treatment of choice in HER2+ early breast cancer (BC) patients (pts). However HER2+ tumors are clinically and biologically heterogeneous and treatment response varies significantly by hormone receptor (HR) status and molecular subtype. Predictive biomarkers are needed in this context. We have previously shown that RBsig expression correlates with pathological complete response (pCR) rate following CT +/− H in ER+/HER2+ BC pts within a metadataset of 10 neoadjuvant clinical trials. The present study assessed whether RBsig is predictive of response to neoadjuvant CT in combination with H, within the NeoALTTO trial. Methods: We collected RNA-sequencing data from pre-treatment biopsies derived from NeoALTTO, a trial randomizing pts with HER2+ early BC to receive lapatinib, trastuzumab or both together with weekly paclitaxel. RBsig expression was computed retrospectively and correlated with pCR using receiving-operating characteristic (ROC) curves.The RBsig was dichotomized as High/Low in correspondence to the 25^th percentile. The distribution of RBsig expression was evaluated within PAM50 molecular subtypes. Reported p-values resulted from Fisher exact test. Results: Of 455 NeoALTTO pts, 245 had available RNA-sequencing data (HR+ n = 129 HR− n = 116). Overall, pCR rate was significantly higher in pts with RBsig High tumors, than those with RBsig Low (36% vs 18% respectively p = 0.01). The area under the ROC curve (AUC) was 0.60 (95% CI 0.52-0.67). A remarkably low pCR rate of 11% was seen in HR+/ RBsig Low pts vs 28% in HR+/RBsig High. HER2-enriched (HER2e) tumors were the predominant molecular subtype in both HR+ (n = 65) and HR− (n = 89) subsets. RBsig could further stratify HER2e tumors, with RBsig High and Low showing a pCR rate of 44% and 21% respectively (p = 0.02).The pCR rate of HR+/ HER2e/ RBsig High pts was 37% vs 7% for HR+/ HER2e/ RBsig Low (p = 0.04). The ROC curve AUC was 0.65 (95% CI 0.50-0.79). Conclusions: RBsig Low expression identifies a subset of HER2+ pts less likely to respond to CT + H. This is particularly notable in HER2e tumors thus indicating RBsig may add significant information to molecular subtypes.