BackgroundHuman epidermal growth factor receptor 2 (HER2) overexpression is an independent prognostic factor of poor prognosis and a predictor of efficacy of anti‐HER2 therapy. A limited number of patients can receive standard second‐line therapy (DS‐8201 or T‐DM1) for metastatic HER2‐positive in some parts of the world, including China, due to many factors, such as cost–benefit ratios.CaseA 51‐year‐old premenopausal woman was diagnosed with HER2‐positive breast cancer. The pathological stage was ypT3N2M0 and stage IIIA. Trastuzumab targeted therapy combined with goserelin depot was started along with letrozole endocrine therapy. After eight courses of treatment, magnetic resonance imaging (MRI) examination revealed new multiple metastases in the liver, and progression disease (PD) was evaluated. Due to abnormal activation of the phosphatidylinositol 3‐kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in the patient, treatment was changed to the mammalian target of rapamycin (mTOR) inhibitor combined with the anti‐HER‐2 agents inetetamab and paclitaxel, while partial response (PR) was evaluated after 6 cycles of treatment. As the patient was hormone receptor (HR) positive, treatment was changed to the inetetamab + rapamycin + exemestane regimen. The lesion continued to shrink and PR was evaluated for 8 cycles. The original regimen was continued, PR was evaluated after 12 courses of treatment. The abdominal MRI performed showed an increase in the volume of intrahepatic multiple metastatic tumor lesion. Efficacy was used to assess for PD and the progression‐free survival (PFS) was 317 days.ConclusionA phosphatidylinositol‐4, 5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA) mutation in trastuzumab‐treated metastatic HER2‐positive breast cancer female had a long PFS by treating with the mammalian target of rapamycin inhibitor in combination with the anti‐HER‐2 agent inetetamab.