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It is well documented that human epidermal growth factor receptor 2 ( HER 2) overexpression/amplification is associated with poor survival in breast cancer patients. However, it is largely unknown whether   HER 2  somatic mutations are associated with survival in  HER 2‐negative breast cancer patients. Here, we identified   HER 2  somatic mutations in tumors from 1348 unselected breast cancer patients by sequencing the entire   HER 2  coding region. All of these mutations were tested for in corresponding blood samples to determine whether they were somatic or germline mutations. We further investigated the associations between   HER 2  somatic mutations and recurrence‐free survival and distant recurrence‐free survival in this cohort of patients. We found that 27 of 1348 (2.0%) of these patients carried a   HER 2  somatic mutation.  In vitro  experiments indicated that some of the novel mutations and those with unknown functions increased  HER 2 activity.  HER 2 status was available for 1306 patients, and the   HER 2  somatic mutation rates in  HER 2‐positive ( n  = 353) and  HER 2‐negative breast cancers ( n  = 953) were 1.4% and 2.3%, respectively. Among the  HER 2‐negative patients, those with a   HER 2  somatic mutation had a significantly worse recurrence‐free survival (unadjusted hazard ratio = 2.67; 95% confidence interval, 1.25–5.72,  P =  0.002) and distant recurrence‐free survival (unadjusted hazard ratio = 2.50; 95% confidence interval, 1.10–5.68,  P =  0.004) than those with wild‐type   HER 2 . Taken together, our findings suggested that   HER 2  somatic mutations occur at a higher frequency in  HER 2‐negative breast cancer, and  HER 2‐negative breast cancer patients with these mutations have poor survival. Therefore,  HER 2‐negative patients with a   HER 2  somatic mutation are potentially good candidates for  HER 2‐targeted therapy.

HER2 somatic mutations are associated with poor survival in HER2‐negative breast cancers