To identify trastuzumab-resistant genes predicting drug response and poor prognosis in human epidermal growth factor receptor 2 positive (HER2+) breast cancer….Further survival analysis of hub genes showed that DLD overexpression was significantly associated with an unfavorable prognosis in HER2+ breast cancer patients.... Ten novel trastuzumab resistance-related genes were discovered, of which DLD could be used for trastuzumab response prediction and prognostic prediction in HER2+ breast cancer.