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

ABSTRACT: 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.

SUBMITTER: Wang T

PROVIDER: S-EPMC5406600 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Wang Tonghui T Xu Ye Y Sheng Shuyan S Yuan Hua H Ouyang Tao T Li Jinfeng J Wang Tianfeng T Fan Zhaoqing Z Fan Tie T Lin Benyao B Xie Yuntao Y

Cancer science 20170421 4

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 ...[more]

PMID: 28164408

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Project description:Intratumour heterogeneity fuels carcinogenesis and allows circumventing specific targeted therapies. HER2 gene amplification is associated with poor outcome in invasive breast cancer. Heterogeneous HER2 amplification has been described in 5-41% of breast cancers. Here, we investigated the genetic differences between HER2-positive and HER2-negative admixed breast cancer components. We performed an in-depth analysis to explore the potential heterogeneity in the somatic mutational landscape of each individual tumour component. Formalin-fixed, paraffin-embedded breast cancer tissue of ten patients with at least one HER2-negative and at least one HER2-positive component was microdissected. Targeted next-generation sequencing was performed using a customized 53-gene panel. Somatic mutations and copy number variations were analysed. Overall, the tumours showed a heterogeneous distribution of 12 deletions, 9 insertions, 32 missense variants and 7 nonsense variants in 26 different genes, which are (likely) pathogenic. Three splice site alterations were identified. One patient had an EGFR copy number gain restricted to a HER2-negative in situ component, resulting in EGFR protein overexpression. Two patients had FGFR1 copy number gains in at least one tumour component. Two patients had an 8q24 gain in at least one tumour component, resulting in a copy number increase in MYC and PVT1. One patient had a CCND1 copy number gain restricted to a HER2-negative tumour component. No common alternative drivers were identified in the HER2-negative tumour components. This series of 10 breast cancers with heterogeneous HER2 gene amplification illustrates that HER2 positivity is not an unconditional prerequisite for the maintenance of tumour growth. Many other molecular aberrations are likely to act as alternative or collaborative drivers. This study demonstrates that breast carcinogenesis is a dynamically evolving process characterized by a versatile somatic mutational profile, of which some genetic aberrations will be crucial for cancer progression, and others will be mere 'passenger' molecular anomalies.

Project description:In one of every four or five cases of breast cancer, the human epidermal growth factor receptor-2 (HER2) gene is overexpressed. These carcinomas are known as HER2-positive. HER2 overexpression is linked to an aggressive phenotype and a lower rate of disease-free and overall survival. Drugs such as trastuzumab, pertuzumab, lapatinib, neratinib, and the more recent afatinib target the deregulation of HER2 expression. Some authors have attributed somatic mutations in HER2, a role in resistance to anti-HER2 therapy as differential regulation of HER2 has been observed among patients. Recently, studies in metastatic ER?+?tumors suggest that some HER2 mutations emerge as a mechanism of acquired resistance to endocrine therapy. In an effort to identify possible biomarkers of the efficacy of anti-HER2 therapy, we here review the known single-nucleotide polymorphisms (SNPs) of the HER2 gene found in HER2-positive breast cancer patients and their relationship with clinical outcomes. Information was recompiled on 11 somatic HER2 SNPs. Seven polymorphisms are located in the tyrosine kinase domain region of the gene contrasting with the low number of mutations found in extracellular and transmembrane areas. HER2-positive patients carrying S310F, S310Y, R678Q, D769H, or I767M mutations seem good candidates for anti-HER2 therapy as they show favorable outcomes and a good response to current pharmacological treatments. Carrying the L755S or D769Y mutation could also confer benefits when receiving neratinib or afatinib. By contrast, patients with mutations L755S, V842I, K753I, or D769Y do not seem to benefit from trastuzumab. Resistance to lapatinib has been reported in patients with L755S, V842I, and K753I. These data suggest that exploring HER2 SNPs in each patient could help individualize anti-HER2 therapies. Advances in our understanding of the genetics of the HER2 gene and its relations with the efficacy of anti-HER2 treatments are needed to improve the outcomes of patients with this aggressive breast cancer.

Dataset Information

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

Publications

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

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