HER2 somatic mutations are associated with poor survival in HER2-negative breast cancers.
It is well documented that human epidermal growth factor receptor 2 (HER2) overexpression/amplification is associated with poor survival in breast cancer patients. However, it is largely unknown whether HER2 somatic mutations are associated with survival in HER2-negative breast cancer patients. Here, we identified HER2 somatic mutations in tumors from 1348 unselected breast cancer patients by sequencing the entire HER2 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 HER2 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 HER2 somatic mutation. In vitro experiments indicated that some of the novel mutations and those with unknown functions increased HER2 activity. HER2 status was available for 1306 patients, and the HER2 somatic mutation rates in HER2-positive (n = 353) and HER2-negative breast cancers (n = 953) were 1.4% and 2.3%, respectively. Among the HER2-negative patients, those with a HER2 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 HER2. Taken together, our findings suggested that HER2 somatic mutations occur at a higher frequency in HER2-negative breast cancer, and HER2-negative breast cancer patients with these mutations have poor survival. Therefore, HER2-negative patients with a HER2 somatic mutation are potentially good candidates for HER2-targeted therapy.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Center, Peking University Cancer Hospital and Institute, Beijing, China.
Tonghui
T
Wang
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Center, Peking University Cancer Hospital and Institute, Beijing, China.
Ye
http://orcid.org/0000-0002-5520-3839
Y
Xu
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Center, Peking University Cancer Hospital and Institute, Beijing, China.
Shuyan
S
Sheng
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Center, Peking University Cancer Hospital and Institute, Beijing, China.
Hua
H
Yuan
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Center, Peking University Cancer Hospital and Institute, Beijing, China.
Tao
T
Ouyang
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Center, Peking University Cancer Hospital and Institute, Beijing, China.
Jinfeng
J
Li
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Center, Peking University Cancer Hospital and Institute, Beijing, China.
Tianfeng
T
Wang
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Center, Peking University Cancer Hospital and Institute, Beijing, China.
Zhaoqing
Z
Fan
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Center, Peking University Cancer Hospital and Institute, Beijing, China.
Tie
T
Fan
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Center, Peking University Cancer Hospital and Institute, Beijing, China.
Benyao
B
Lin
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Center, Peking University Cancer Hospital and Institute, Beijing, China.
Yuntao
Y
Xie
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D008875:Middle Aged; D009154:Mutation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome
D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human

HER2
; Breast cancer; somatic mutations; survival; targeted therapy