Activating Mutations in <i>HER2</i>: Neu Opportunities and Neu Challenges

Weigelt, Britta; Reis‐Filho, Jorge S.

doi:10.1158/2159-8290.cd-12-0585

Cited by 28 publications

(20 citation statements)

References 10 publications

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“…However, HER‐2 activating mutations, another novel modus to activate HER‐2, have been reported 41, 42. Bose and his colleagues identified 16 HER‐2 somatic mutations though cancer genome sequencing in HER‐2 gene amplification‐negative breast cancer patients.…”

Section: The Her‐2 Mutations and Variantsmentioning

confidence: 99%

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

Sun

Shi

Shen

et al. 2015

J Cellular Molecular Medi

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Studies over the last two decades have identified that amplified human epidermal growth factor receptor (HER‐2; c‐erbB‐2, neu) and its overexpression have been frequently implicated in the carcinogenesis and prognosis in a variety of solid tumours, especially breast cancer. Lots of painstaking efforts were invested on the HER‐2 targeted agents, and significantly improved outcome and prolonged the survival of patients. However, some patients classified as ‘HER‐2‐positive’ would be still resistant to the anti‐HER‐2 therapy. Various mechanisms of drug resistance have been illustrated and the alteration of HER‐2 was considered as a crucial mechanism. However, systematic researches in regard to the HER‐2 mutations and variants are still inadequate. Notably, the alterations of HER‐2 play an important role in drug resistance, but also have a potential association with the cancer risk. In this review, we summarize the possible mutations and focus on HER‐2 variants’ role in breast cancer tumourigenesis. Additionally, the alteration of HER‐2, as a potential mechanism of resistance to trastuzumab, is discussed here. We hope that HER‐2 related activating mutations could potentially offer more therapeutic opportunities to a broader range of patients than previously classified as HER‐2 overexpressed.

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Section: The Her‐2 Mutations and Variantsmentioning

confidence: 99%

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

Sun

Shi

Shen

et al. 2015

J Cellular Molecular Medi

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“…Interestingly, of the 17 mutations described, the only one that was also unequivocally HER2-positive was the D769H mutation. 9,28 This mutation was also reported in one patient with squamous cell lung cancer, although the prevalence of this HER2 mutation in squamous lung cancers is probably extremely rare. 29 …”

Section: Discussionmentioning

confidence: 72%

Cancer Signature Investigation:ERBB2(HER2)-Activating Mutation and Amplification-Positive Breast Carcinoma Mimicking Lung Primary

Shih

Bashir

Gustafson

et al. 2015

J Natl Compr Canc Netw

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Next-generation sequencing of primary and metachronous metastatic cancer lesions may impact patient care. We present a case of relapsed metastatic breast cancer with a dominant pulmonary lesion originally identified as lung adenocarcinoma. A 72-year-old, never-smoker woman with a protracted cough was found to have a large lung mass and regional lymphadenopathy on a chest CT. Lung mass biopsy showed adenocarcinoma with focal TTF-1 (thyroid transcription factor 1) positivity, favoring a lung primary. In addition to stereotactic brain radiation for cerebral metastases, she was started on carboplatin/pemetrexed. As part of the workup, the tumor was analyzed by a 50-gene targeted mutation panel, which detected 3 somatic mutations: ERBB2 (HER2) D769H activating missense mutation, TP53 Y126 inactivating truncating mutation, and SMARCB1 R374Q missense mutation. Of note, the patient had a history of stage IIA triple-negative grade 3 invasive ductal carcinoma of the left breast 1.5 years ago and received neoadjuvant chemotherapy, lumpectomy, and adjuvant radiation. Further analysis of her primary breast tumor showed mutational profile identical to the lung tumor. Fluorescence in situ hybridization revealed HER2 amplification in the lung tumor, with a HER2/CEP17 ratio of 3.9. The patient was diagnosed with recurrent HER2-positive metastatic breast carcinoma with a coexisting ERBB2 (HER2) activating mutation. Chemotherapy was adjusted to include dual HER2-targeted therapy containing trastuzumab and pertuzumab, resulting in an ongoing partial response. This case demonstrates that a unique genetic mutational profile can clarify whether a tumor represents a metastatic lesion or new malignancy when conventional morphological and immunohistochemical methods are indeterminate, and can directly impact treatment decisions.

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“…40 The development of massive parallel sequencing has shed new light on these activating mutations, mostly present in the tyrosine kinase domain (68%, exons [19][20] and the extracellular domain (20%, exon 8). 41 Tumours considered to be HER2-negative based on current guidelines may still be "addicted" to HER2 signalling due to HER2 activating mutations and hence may also benefit from HER2 targeting agents.…”

Section: Her2 Mutationsmentioning

confidence: 99%

Molecular Diagnostics in Breast Cancer Routine Practice

Hoeve¹,

Moelans²,

Schrijver³

et al. 2017

European Oncology &Amp; Haematology

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T he portfolio of adjuvant systemic treatment of breast cancer nowadays contains novel anti-hormonal and chemotherapeutic drugs, immunotherapeutic approaches and small molecules that are only effective in a limited number of patients and are often associated with high costs and significant side effects. Therefore, a personalised approach based on individual tumour biomarkers is required to arrive at the optimal balance between effectiveness on the one hand, and costs and side effects on the other. The aim of this paper is to provide an overview of the molecular biomarkers and associated molecular tests that are currently relevant in pathology of invasive breast cancer. KeywordsBreast cancer, pathology, molecular biomarkers Disclosure: Natalie D ter Hoeve, Cathy B Moelans, Willemijne AME Schrijver, Wendy de Leng and Paul J van Diest have nothing to disclose in relation to this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. No funding was received for the publication of this article.Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Adjuvant systemic treatment of breast cancer is moving away from the limited portfolio of traditional hormonal drugs and chemotherapy, towards a gamma of novel anti-hormonal and chemotherapeutic drugs, immunotherapeutic approaches and small molecules. All these therapeutic approaches are unfortunately effective in a limited number of patients and are often associated with high costs and significant side effects. Therefore, the traditional "one size fits all" approach can no longer be upheld, and a personalised approach based on individual tumour biomarkers is required to arrive at the optimal balance between effectiveness on the one hand and costs and side effects on the other.Over recent years, progress in molecular techniques has made it possible to analyse formalin fixed paraffin embedded (FFPE) tumour material of larger cohorts of patients. This has incentivised many translational studies relating molecular tumour biomarkers to diagnosis, prognosis and/or response to therapy, yielding many relevant molecular biomarkers that have rather quickly made it to clinical pathology practice. The aim of this paper is to provide an overview of the molecular biomarkers and associated molecular tests that are currently relevant in pathology of invasive breast cancer. Diagnostic markers Hereditary breast cancersAbout 5-10% of breast cancer cases are due to a hereditary predisposition.1 In most of these cases, mutations are found in we...

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Activating Mutations in HER2: Neu Opportunities and Neu Challenges

Cited by 28 publications

References 10 publications

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

Cancer Signature Investigation:ERBB2(HER2)-Activating Mutation and Amplification-Positive Breast Carcinoma Mimicking Lung Primary

Molecular Diagnostics in Breast Cancer Routine Practice

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