Association of HER‐2 overexpression with prognosis in nonsmall cell lung carcinoma: A metaanalysis

Nakamura, Hiroki; Kawasaki, Norihito; Taguchi, Masahiko; Kabasawa, Kazuyuki

doi:10.1002/cncr.20957

Cited by 81 publications

(51 citation statements)

References 59 publications

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“…S6). This is significantly higher than HER2-positive staining reported for adenocarcinomas, squamous cell carcinomas, or large-cell carcinomas of the lung (Table S3) (18). Although none of the human adenosquamous tumors we analyzed carried a HER2 mutation, membranous HER2 protein localization or HER2 overexpression may activate signaling molecules analogous to mutant HER2 because overexpression of wildtype human HER2 is also transforming in NIH 3T3 cells and mammary epithelial cells (19,20).…”

Section: Discussionmentioning

confidence: 70%

HER2 ^YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy

Perera

Shimamura

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

158

138

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Mutations in the HER2 kinase domain have been identified in human clinical lung cancer specimens. Here we demonstrate that inducible expression of the most common HER2 mutant (HER2 YVMA ) in mouse lung epithelium causes invasive adenosquamous carcinomas restricted to proximal and distal bronchioles. Continuous expression of HER2 YVMA is essential for tumor maintenance, suggesting a key role for HER2 in lung adenosquamous tumorigenesis. Preclinical studies assessing the in vivo effect of erlotinib, trastuzumab, BIBW2992, and/or rapamycin on HER2 YVMA transgenic mice or H1781 xenografts with documented tumor burden revealed that the combination of BIBW2992 and rapamycin is the most effective treatment paradigm causing significant tumor shrinkage. Immunohistochemical analysis of lung tumors treated with BIBW2992 and rapamycin combination revealed decreased phosphorylation levels for proteins in both upstream and downstream arms of MAPK and Akt/mTOR signaling axes, indicating inhibition of these pathways. Based on these findings, clinical testing of the BIBW2992/rapamycin combination in non-small cell lung cancer patients with tumors expressing HER2 mutations is warranted. lung cancer ͉ murine model H ER2 (erbB-2/neu) is a member of the erbB receptor tyrosine kinase family that also includes EGFR (HER1/erbB-1), HER3 (erbB-3), and HER4 (erbB-4). Whereas these family members usually dimerize upon ligand binding, HER2, for which no ligand is reported, exists mainly in its active conformation. HER2 readily heterodimerizes with other erbB family members and is considered to be the preferred dimerization partner for EGFR, HER3, and HER4 (1). In addition to ligand binding, receptor dimerization can be induced by a high concentration of receptors at the plasma membrane or by kinase domain mutations (2, 3), resulting in receptor activation by the transphosphorylation of tyrosine residues in the C terminus of the respective molecules (4). The phosphorylated residues act as docking sites for an array of downstream signaling molecules activating several biochemical pathways such as the MAPK, the PI3K/Akt/mTOR, the phospholipase C, and the Jak/Stat signaling pathways (2, 3, 5). These signal transduction cascades in concert regulate cellular processes such as proliferation, apoptosis, angiogenesis, migration, adhesion, and differentiation.Mutations in the HER2 kinase domain have been reported in lung adenocarcinomas at a relatively low frequency of 2-4% (6, 7). Thus far, majority of the HER2 mutations identified in non-small cell lung cancer (NSCLC) samples are in-frame duplications or insertions in a small 8-codon region (codons 774-781 or 775-782) on exon 20. These mutations are analogous to the duplications/ insertions in the 9-codon region of exon 20 in EGFR, translating to the C terminus of the ␣C helix in the TK (tyrosine kinase) domain. Based on this similarity, it has been postulated (7) that mutations in HER2 cause a shift in the helical axis that narrows the ATP binding cleft, resulting in both increased TK activity and...

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Section: Discussionmentioning

confidence: 70%

HER2 ^YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy

Perera

Shimamura

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

158

138

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“…Although HER-2 gene amplification or 3+ staining by immunohistochemistry is only present in 2% to 5% of patients with NSCLC, HER-2 expression detectable by immunohistochemistry is present in f25% of NSCLCs (29,30). If a new agent has antitumor activity in lung cancer or other types of cancers where the receptor density is less than that needed for trastuzumab antitumor activity, the agent can be used in a larger percentage of lung cancers.…”

Section: Discussionmentioning

confidence: 99%

Rationale for a Phase II Trial of Pertuzumab, a HER-2 Dimerization Inhibitor, in Patients with Non–Small Cell Lung Cancer

Johnson

Jänne

2006

Clinical Cancer Research

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Background and Rationale: In non^small cell lung cancer (NSCLC) HER-2 gene amplification and 3+ staining by immunohistochemistry are present in only 2% to 5% of the tumors. Therefore, relatively few patients with lung cancer are likely to benefit from treatment with trastuzumab, the humanized monoclonal antibody that is effective in the 20% of patients with breast cancer and HER-2 gene amplification and/or 3+ staining by immunohistochemistry. Pertuzumab (rhuMAb 2C4), a humanized HER2 antibody, represents a new class of targeted therapeutics that inhibit dimerization of HER2 with ligand-activated EGFR (HER1), HER3, and HER-4. Pertuzumab can have antitumor activity in patients with HER-2 present on the tumor without gene amplification or 3+ staining by immunohistochemistry. Preclinical xenograft studies have shown efficacy of pertuzumab in treating NSCLC. Therefore, a trial was undertaken for patients with relapsed NSCLC. Materials and Methods: Subjects with advanced or recurrent NSCLC treated previously with chemotherapy were treated with pertuzumab (840 mg i.v. loading dose then 420 mg every 3 weeks). Mandatory fresh tumor biopsies before treatment were obtained for biomarker analysis including HER-2 phosphorylation. Computed tomography scans were obtained every two cycles to assess tumor response. Tumor response (response evaluation criteria in solid tumors criteria) was the primary end point. Results: As reported in a previous abstract, none of the 33 patients with NSCLC and evaluable disease had a response to the treatment. Conclusions: Pertuzumab has an appropriate rationale for therapeutic use in patients with NSCLC. A phase II trial in patients with NSCLC has completed enrollment, and the details of the trial will be presented in a future publication. This article will review the preclinical rationale for undertaking a study of pertuzumab for patients with relapsed NSCLC.

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“…Surprisingly, overexpression is associated with lower stage and grade of tumor [182]. Interestingly, there is an association of HER2/neu overexpression with NSCLC resistance to chemotherapy [183][184][185][186][187][188][189][190][191], which may account for the fact that HER2/neu overexpression is associated with a poor prognosis [35,[160][161][162][163][164][165][166][167][168][169][170][171][172][173] despite the association of HER2/neu overexpression with lower stage and grade. There is evidence for cooperativity and co-expression of HER1/EGFR [192], potentially associated with poorer prognosis [161,169,193], and there is data to support overexpression of HER2/neu as a mechanism for resistance to antibody inhibition of HER1/EGFR [194].…”

Section: Lungmentioning

confidence: 99%

HER2/neu: an increasingly important therapeutic target. Part 2: Distribution of HER2/neu overexpression and gene amplification by organ, tumor site and histology

Nelson¹

2014

Clinical Investigation

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No biological molecule in the field of oncology has been more extensively or more successfully targeted for therapeutic intent than the product of the c-erbB2 gene, HER2/neu. This is the second of a comprehensive three-part review of the foundation for and therapeutic targeting of HER2/neu. The distribution of HER2/neu overexpression and/or gene amplification by individual tumor sites and histologies will be comprehensively surveyed and described. This provides a bridge between the primarily basic science focused Part I, and the survey of clinical applications to follow in Part III. In combination, this comprehensive survey will identify opportunities and promising areas for future evaluation of HER2/neu-targeted therapies, highlighting the importance of HER2/neu as an increasingly important therapeutic target.

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Association of HER‐2 overexpression with prognosis in nonsmall cell lung carcinoma: A metaanalysis

Cited by 81 publications

References 59 publications

HER2 ^YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy

HER2 ^YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy

Rationale for a Phase II Trial of Pertuzumab, a HER-2 Dimerization Inhibitor, in Patients with Non–Small Cell Lung Cancer

HER2/neu: an increasingly important therapeutic target. Part 2: Distribution of HER2/neu overexpression and gene amplification by organ, tumor site and histology

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Association of HER‐2 overexpression with prognosis in nonsmall cell lung carcinoma: A metaanalysis

Cited by 81 publications

References 59 publications

HER2 YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy

HER2 YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy

Rationale for a Phase II Trial of Pertuzumab, a HER-2 Dimerization Inhibitor, in Patients with Non–Small Cell Lung Cancer

HER2/neu: an increasingly important therapeutic target. Part 2: Distribution of HER2/neu overexpression and gene amplification by organ, tumor site and histology

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HER2 ^YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy

HER2 ^YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy