Cited by 151Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchLung Cancer Research Studies

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Prognostic and predictive implications of HER2/ERBB2/neu gene mutations in lung cancers

Tomizawa, Kenji, Suda, Kenichi, Onozato, Ryoichi, Kosaka, Takayuki, Endoh, Hideki, Sekido, Yoshitaka, Shigematsu, Hisayuki, Kuwano, Hiroyuki, Yatabe, Yasushi, Mitsudomi, Tetsuya·2011·Lung Cancer

DOI 10.1016/j.lungcan.2011.01.014

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Abstract

Background Activating mutation in the kinase domain of the human EGF receptor 2 (HER2) gene (also known as ERBB2 or neu) is reported to be present in a small fraction of lung adenocarcinomas. However its prognostic and predictive implications are not yet established.Patients and methods We examined 504 Japanese lung cancer patients who underwent pulmonary resection for HER2 mutations by direct sequencing and evaluated their prognostic and predictive implications. Updated prognostic data of 14 Japanese patients with HER2 mutation from previous two reports were also gathered.Results HER2 mutations were identified in 13 of 504 cases (2.6%). Patients with HER2 mutations were common in female, nonsmokers and adenocarcinomas as those with EGFR mutations. When confined to the subgroup of nonsmokers with adenocarcinoma or adenosquamous cell carcinoma without EGFR mutations, the frequency of HER2 mutations was 14.1% (11/78). There was no difference in the overall survival of patients with HER2 mutations, compared with patients harboring EGFR mutations and patients harboring wild types for both EGFR and HER2. Within the patients with HER2 mutation, two of three with TP53 mutation and one of 13 without TP53 mutation died of the disease, suggesting negative prognostic role of the TP53 mutation. Three patients with HER2 mutations did not respond to platinum-based chemotherapy and EGFR-TKIs. Of note, one patient with the most common HER2 mutations, YVMA776-779ins, responded to trastuzumab plus vinorelbine after failure of multiple round of platinum-based chemotherapy and gefitinib.Conclusion HER2 mutations are present in a subset of patients with lung cancer having distinct clinical features. HER2 mutations were not associated with the prognosis of patients with lung cancers. Patients with HER2 mutations might benefit from anti-HER2 therapy.

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Result
The mutations of the EGFR and K-ras genes in resected stage I lung adenocarcinoma and their clinical significance
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“The frequency of EGFR mutations ranges from 40 to 60 % in Japanese lung adenocarcinomas [8, 23–28].”
Background
Targeting HER2 genomic alterations in non-small cell lung cancer
Zeng, J., Ma, W., Young, R. B., & Li, T. (2021) · Journal of the National Cancer Center · doi:10.1016/j.jncc.2021.04.001 · Cited by 37
HER2 mutations in Chinese patients with non-small cell lung cancer
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“, a tendency of shorter overall survival in HER2 mutations was reported compared with HER2-negative cases [26].”
Result
Clinical Activity of Pan-HER Inhibitors Against HER2-Mutant Lung Adenocarcinoma
Oh, I., Hur, J. Y., Park, C., Kim, Y., Kim, S. J., Lee, M. K., Kim, H. J., Lee, K. Y., Lee, J. C., & Choi, C. (2018) · Clinical Lung Cancer · doi:10.1016/j.cllc.2018.05.018 · Cited by 32
Lung cancer in never-smokers. Does smoking history matter in the era of molecular diagnostics and targeted therapy?
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Risk of Second Primary Malignancy in Breast Cancer Survivors: A Nested Population-Based Case-Control Study
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“Overexpression of HER2 protein has been detected in several other human cancers, including ovarian [24], lung [25], thyroid [25,26], and gastric cancers [27].”
Background
Braf and erbB2 mutations correlate with smoking status in lung cancer patients
Sasaki, H., Shitara, M., Yokota, K., Okuda, K., Hikosaka, Y., Moriyama, S., Yano, M., & Fujii, Y. (2012) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2012.500 · Cited by 28
“Although the erbB2 mutation was also investigated in Japanese NSCLC (13,22), the Braf mutation frequency in Japanese NSCLC is not well known.”
HER2 Mutations in Non–Small-Cell Lung Cancer Can Be Continually Targeted
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Rare Mutations in Non-Small-Cell Lung Cancer
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Epidemiological study of HER-2 mutations among EGFR wild-type lung adenocarcinoma patients in China
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“HER-2 mutations are more common in female nonsmokers with moderately to poorly differentiated adenocarcinoma, small tumor load, and early-stage lung cancer, but are not linked to patient prognosis [10, 11, 17].”
Comprehensive characterization of early-onset lung cancer, in Chinese young adults
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“However, given the low mutation frequency of ERBB2 in overall lung cancer (2 – 3% in NSCLC patients) 22 – 24 , the clinical application of HER2-targeted drugs was rare.”
A review of recent advances in the novel therapeutic targets and immunotherapy for lung cancer
Khadela, A. D., Postwala, H. I., Rana, D. K., Dave, H., Ranch, K. M., & Boddu, S. H. S. (2023) · Medical Oncology · doi:10.1007/s12032-023-02005-w · Cited by 24
Does Immunohistochemistry Represent a Robust Alternative Technique in Determining Drugable Predictive Gene Alterations in Non-Small Cell Lung Cancer?
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Catalog of Lung Cancer Gene Mutations Among Chinese Patients
Xue, X., Asuquo, I. P., Hong, L., Gao, J., Dong, Z., Pang, L., Jiang, T., Meng, M., Fan, J., Wen, J., et al. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01251 · Cited by 25
“Of particular interest is the finding that Asian women with the EGFRmutation developed adenocarcinoma at an earlier age than other lung cancer patients (5, 39).”
Background
Lung cancers unrelated to smoking: characterized by single oncogene addiction?
Suda, K., Tomizawa, K., Yatabe, Y., & Mitsudomi, T. (2011) · International Journal of Clinical Oncology · doi:10.1007/s10147-011-0262-y · Cited by 25
“One adenocarcinoma case with KIF5B-ALK fusion was also reported as TTF-1-positive [43].”
BackgroundInfluential
Emerging Targets in Advanced Non-Small-Cell Lung Cancer
Valentino, F., Borra, G., Allione, P., & Rossi, L. (2018) · Future Oncology · doi:10.2217/fon-2018-0099 · Cited by 23
Prevalence and Clinicopathological Characteristics of HER2 and BRAF Mutation in Chinese Patients with Lung Adenocarcinoma
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“Based on published studies, the presence ofHER2mutations seems associated with female gender and never smokers in lung ADC patients [11,29,30].”
Background
p95HER2 Truncated Form in Resected Non-small Cell Lung Cancer
Cappuzzo, F., Cho, Y. G., Sacconi, A., Alì, G., Siclari, O., Incarbone, M., Destro, A., Terracciano, L., Fontanini, G., Marchetti, A., et al. (2012) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e318249e13f · Cited by 22
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“Our results showed that patients had a worse OS when co-occurring mutation in TP53, which is also validated in a previous study (29).”
Result
Targeting rare and non-canonical driver variants in NSCLC – An uncharted clinical field
Volckmar, A., Christopoulos, P., Kirchner, M., Allgäuer, M., Neumann, O., Budczies, J., Rempel, E., Horak, P., Glade, J., Goldschmid, H., et al. (2021) · Lung Cancer · doi:10.1016/j.lungcan.2021.02.022 · Cited by 18
Somatic mutation analysis of KRAS, BRAF, HER2 and PTEN in EGFR mutation-negative non-small cell lung carcinoma: determination of frequency, distribution pattern and identification of novel deletion in HER2 gene from Indian patients
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“associated with the female gender, Asian ethnicity and nonsmoking status [17], similar to the clinical profile of EGFR-”
A highly specific and sensitive massive parallel sequencer-based test for somatic mutations in non-small cell lung cancer
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Single‐Dose Pharmacokinetics and Tolerability of the Oral Epidermal Growth Factor Receptor Inhibitor Mobocertinib (TAK‐788) in Healthy Volunteers: Low‐Fat Meal Effect and Relative Bioavailability of 2 Capsule Products
Zhang, S., Jin, S., Griffin, C., Feng, Z., Lin, J., Baratta, M., Brake, R. L., Venkatakrishnan, K., & Gupta, N. (2021) · Clinical Pharmacology in Drug Development · doi:10.1002/cpdd.951 · Cited by 18
Driver mutations of young lung adenocarcinoma patients with malignant pleural effusion
Wu, S., Liu, Y., Yu, C., Yang, J. C., & Shih, J. (2018) · Genes Chromosomes and Cancer · doi:10.1002/gcc.22647 · Cited by 18
“Total 142 82 24 7 7 3 19 Age, median, years (range) 44 (28-50) 44 (30-50) 45 (28-50) 44 (32-46) 48 (45-50) 42 (30-43) 42 (29-50) .”
Afatinib as first‐line treatment for advanced lung adenocarcinoma patients harboring HER2 mutation: A case report and review of the literature
Shi, Y., & Wang, M. (2018) · Thoracic Cancer · doi:10.1111/1759-7714.12906 · Cited by 15
Current and future molecular diagnostics in non-small-cell lung cancer
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Targeting Lung Cancer with Precision: The ADC Therapeutic Revolution
Tawfiq, R. K., Correia, G. S. D. C., Li, S., Zhao, Y., Lou, Y., & Manochakian, R. (2025) · Current Oncology Reports · doi:10.1007/s11912-025-01655-5 · Cited by 14
“Among these, exon 20 insertions, particularly the YVMA variant, are the most common HER2 mutations [27].”
In vitro antiproliferative effect of trastuzumab (Herceptin®) combined with cetuximab (Erbitux®) in a model of human non-small cell lung cancer expressing EGFR and HER2
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The role of molecular analyses in the diagnosis and treatment of non-small-cell lung carcinomas
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Genomic landscape and efficacy of HER2-targeted therapy in patients with HER2-mutant non-small cell lung cancer
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BackgroundInfluential
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Authors: Tomizawa, K., Suda, K., Onozato, R., Kosaka, T., Endoh, H., Sekido, Y., Shigematsu, H., Kuwano, H., Yatabe, Y., & Mitsudomi, T.
Affiliations: Gunma University (JP)
Aichi Cancer Center (JP)
Okayama Medical Center (JP)
Corresponding author: Mitsudomi, Tetsuya
ORCID: Tomizawa, Kenji
Suda, Kenichi
Onozato, Ryoichi
Kosaka, Takayuki
Endoh, Hideki
Sekido, Yoshitaka
Kuwano, Hiroyuki
Yatabe, Yasushi
Mitsudomi, Tetsuya
Venue: Lung Cancer
Publisher: Elsevier BV
Published: 2011-10
Volume: 74
Issue: 1
Pages: 139-144
ISSN: 0169-5002 (ISSN-L)
DOI: 10.1016/j.lungcan.2011.01.014
OpenAlex: W2107002118
Cited by: 151
References: 33
Citations by year: 2026: 2 · 2025: 9 · 2024: 8 · 2023: 10 · 2022: 7 · 2021: 8 · 2020: 10 · 2019: 2 · 2018: 11 · 2017: 12 · 2016: 12 · 2015: 16 · 2014: 13 · 2013: 13 · 2012: 13
FWCI: 11.99
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Lung Cancer (publishedVersion)
PubMed (publishedVersion)
Funders: Japan Society for the Promotion of Science (21390110)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Keywords: HER2 mutation, ErbB2/Neu, lung adenocarcinoma, prognostic factors, predictive biomarkers, TP53 mutation, EGFR mutation, adenosquamous carcinoma, non-smokers, platinum resistance, EGFR tyrosine kinase inhibitors, trastuzumab, vinorelbine, gefitinib, HER2-targeted therapy, overall survival
MeSH terms: Trastuzumab, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, DNA Mutational Analysis, Female, Humans, Japan, Lung Neoplasms, Male, Middle Aged, Mutation, Predictive Value of Tests, Prognosis, Sex Factors, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Antibodies, Monoclonal, Humanized

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Prognostic and predictive implications of HER2/ERBB2/neu gene mutations in lung cancers

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