<i>HER2</i> somatic mutations are associated with poor survival in HER2‐negative breast cancers

Wang, Tonghui; Xu, Ye; Sheng, Shuyan; Yuan, Hua; Ouyang, Tao; Li, Jinfeng; Wang, Tianfeng; Fan, Zhaoqing; Fan, Tie; Lin, Benyao; Xie, Yuntao

doi:10.1111/cas.13182

Cited by 56 publications

(42 citation statements)

References 30 publications

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“…However, a recent analysis of patients with breast cancer has identified somatic HER2 gene mutations, in the context of HER2 amplification-negative disease, to be associated with a shorter DFS than those without HER2 gene mutations. 21 In NSCLC, HER2 mutations have generally not been associated with differences in prognosis, although in the absence of stratification for HER2 gene copy number. 18 28–30 Analyses of only those patients with advanced stage lung adenocarcinomas have provided mixed results.…”

Section: Her2 Proto-oncogene Activation By Mutation In Human Cancersmentioning

confidence: 99%

Activating HER2 mutations as emerging targets in multiple solid cancers

2017

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The epidermal growth factor receptor (EGFR) family of transmembrane receptor tyrosine kinases activates signalling pathways regulating cellular proliferation and survival. HER2 is a non-ligand-binding member of this family and exerts its activity through heterodimerisation with other EGFR family members. HER2 functional activation promotes oncogenesis, leading to the investigation of HER2-directed agents in cancers with HER2 alterations. This has been best characterised in the context of HER2 gene amplification in breast and gastro-oesophageal cancers, for which HER2-directed drugs form part of standard treatment regimens. More recently, somatic HER2 gene mutations have been detected in a range of human cancer types. Preclinical data suggest that functionally activating HER2 mutations may drive and maintain cancers in a manner analogous to HER2 gene amplification and that HER2 mutations may similarly confer sensitivity to HER2-directed drugs. Here, we critically review the emerging roles for HER2-directed drugs in HER2 mutant cancers. We review data from experimental models, where our knowledge of the underlying biology of HER2 mutational activation remains incomplete. We discuss clinical data from Phase I and II clinical trials which evaluate HER2-directed agents (tyrosine kinase inhibitors and antibody-based drugs) in several cancer types. We highlight the heterogeneity of HER2 mutations in human cancers, differences in the clinical efficacy of HER2-directed drugs between cancer types and possible mechanisms of primary and acquired resistance, in order to guide clinical practice and future drug development.

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Section: Her2 Proto-oncogene Activation By Mutation In Human Cancersmentioning

confidence: 99%

Activating HER2 mutations as emerging targets in multiple solid cancers

2017

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“…More recently, HER2 mutations have been found in a variety of cancer types [ 74 , 75 ] (Figure 3B ), including breast [ 76 – 78 ], colorectal [ 79 ], and bladder cancers [ 80 ]. HER2 somatic mutations correlate with poor survival in HER2-negative (non-amplified) breast cancer [ 81 ]. Nearly 2% of all cancers harbor hotspot or putative activating mutations in ERBB2 (Figure 3B ), suggesting that these cancers may be sensitive to HER2-targeted therapies.…”

Section: Her2 Alterations In Cancermentioning

confidence: 99%

Genomic alterations of ERBB receptors in cancer: clinical implications

2017

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The ERBB family of receptor tyrosine kinases has been implicated in carcinogenesis for over three decades with rigorous attention to EGFR and HER2. ERBB receptors, consisting of EGFR, HER2, HER3, and HER4 are part of a complicated signaling network that activates downstream signaling pathways including PI3K/AKT, Ras/Raf/MAPK, JAK/STAT and PKC. It is well established that EGFR is amplified and/or mutated in gliomas and non-small-cell lung carcinoma while HER2 is amplified and/or over-expressed in breast, gastric, ovarian, non-small cell lung carcinoma, and several other tumor types. With the advent of next generation sequencing and large scale efforts to explore the entire spectrum of genomic alterations involved in human cancer progression, it is now appreciated that somatic ERBB receptor mutations occur at relatively low frequencies across multiple tumor types. Some of these mutations may represent oncogenic driver events; clinical studies are underway to determine whether tumors harboring these alterations respond to small molecule EGFR/HER2 inhibitors. Recent evidence suggests that some somatic ERBB receptor mutations render resistance to FDA-approved EGFR and HER2 inhibitors. In this review, we focus on the landscape of genomic alterations of EGFR, HER2, HER3 and HER4 in cancer and the clinical implications for patients harboring these alterations.

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“…These mutations are further enriched in patients with lobular histology, where the rate may be as high as 10% (5,6). A subset of HER2 mutations are activating and associated with worse prognosis (3,(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Determinants of Response to HER Kinase Inhibition inHER2-Mutant Metastatic Breast Cancer

et al. 2020

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HER2 mutations defi ne a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversi ble pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER + patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2 -activating events , as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefi t from neratinib. Collectively, these data defi ne HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. SIGNIFICANCE: HER2 mutations defi ne a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modifi ed by the presence of concurrent activating genomic events in the pathway. These fi ndings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defi ned subset of breast cancer.

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

Cited by 56 publications

References 30 publications

Activating HER2 mutations as emerging targets in multiple solid cancers

Activating HER2 mutations as emerging targets in multiple solid cancers

Genomic alterations of ERBB receptors in cancer: clinical implications

Efficacy and Determinants of Response to HER Kinase Inhibition inHER2-Mutant Metastatic Breast Cancer

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