We previously reported a potential predictive value of HSD17B4 hypermethylation for pathological complete response after preoperative trastuzumab plus chemotherapy in HER2-positive breast cancer. We will prospectively evaluate the predictive performance of HSD17B4 hypermethylation in patients with HER2-positive/HR-negative breast cancer treated with sequential chemo-radiotherapy. The primary endpoint is the rate of pathological complete response, defined as the absence of invasive and intraductal tumor cells in the breast at surgery, in breast cancer with HSD17B4 hypermethylation. If the pCR rates are extremely high, the ultimate breast-conserving treatment excluding the need for surgery could be a future treatment option. A total of 200 patients will be enrolled. This trial is registered at the UMIN Clinical Trials Registry as UMIN000028065 and is financially supported by the Japan Agency for Medical Research and Development, AMED.