The overlap of biomarkers unfavorable to pCR, such as positive hormone receptor status, PIK3CA mutation, low HER2 levels, and non HER2-E subtypes, reaffirms the complex molecular diversity of HER2-positive breast tumors and should be considered when designing clinical trials of HER2-targeted treatments for early-stage HER2-positive breast cancer. The gene discussed is PIK3CA; the disease is breast neoplasm.