Background: HER2-Enriched (HER2-E) intrinsic subtype within HER2-positive breast cancer is characterized by high expression of ERBB2 and related genes. Here we retrospectively evaluated the value of the HER2-E subtype and ERBB2 mRNA expression alone to predict pathological complete response (pCR) in tumor samples from PAMELA and TBCRC 006/023 trials. Methods: All patients had HER2-positive early breast cancer and were treated with neoadjuvant lapatinib and trastuzumab. Patients with hormone receptor-positive tumors were also treated with letrozole or tamoxifen. In PAMELA (NCT01973660), 151 patients were treated for 18 weeks. TBCRC 006 (NCT00548184) treated 66 patients for 12 weeks and TBCRC 023 (NCT00999804) randomized 97 patients to 12 vs. 24 weeks of treatment. pCR was defined as no residual invasive carcinoma in the breast. Baseline intrinsic subtypes and ERBB2 mRNA expression were determined using the nCounter-based PAM50 predictor. ERBB2 expression was dichotomized as low (lowest 1/3) vs high (highest 1/3) as used in PAMELA. Results: Two-hundred and sixty-five tumors (84.4%) were profiled; 65.7% were classified as HER2-E. pCR was more likely to occur if HER2-E (35.1% vs. 9.9%; odds ratio [OR] = 4.92; 95% CI 2.31-10.50; P < 0.001) or ERBB2-high (36.1% vs. 8.2%; OR = 6.51; 95% CI 2.96-14.31; P < 0.001). HER2-E subtype represented 84.0% and 46.0% of ERBB2-high and ERBB2-low groups, respectively. Rates of pCR in HER2-E/ERBB2-high, nonHER2-E/ERBB2-high, HER2-E/ERBB2-low, and nonHER2-E/ERBB2-low groups were 45.0%, 16.1%, 10.8%, and 6.7%, respectively. Finally, the HER2-E/ERBB2-high group independently predicted pCR (adjusted OR = 6.0; 95% CI [3.1-11.8]; P< 0.001). Conclusions: Combining HER2-E subtype and ERBB2 mRNA levels better identifies anti-HER2 sensitivity than each variable alone in HER2-positive breast cancer. The combined biomarker identified nearly 50% of patients with pCR to an all-biologic regimen, and if validated may provide a means for rational therapeutic de-escalation.