Lack of prognostic implications of HER‐2/<i>neu</i> abnormalities in 345 stage I nonsmall cell carcinomas (NSCLC) and 207 stage I–III neuroendocrine tumours (NET) of the lung

Pelosi, Giuseppe; Curto, Barbara Del; Dell’Orto, Patrizia; Pasini, Felice; Veronesi, Giulia; Spaggiari, Lorenzo; Maisonneuve, Patrick; Iannucci, Antonio; Terzi, Alberto; Lonardoni, Alessandro; Viale, Giuseppe

doi:10.1002/ijc.20542

Cited by 31 publications

(38 citation statements)

References 55 publications

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“…The frequency observed in our study is in the range (1-5%) of other studies performing ERBB2 FISH in lung cancer. 11,13,15,16 The predilection of adenocarcinomas for ERBB2 amplification is in line with the results from earlier studies showing a correlation of HER2 expression with this histologic subtype. 11 We did not observe significant associations with tumor stage or presence of metastases but found a significant link between ERBB2 amplification and poor prognosis although in univariate analysis only.…”

Section: Discussionsupporting

confidence: 88%

“…The different analytical methods such as PCR, Southern blot or fluorescence in-situ hybridization (FISH) used and the varying definitions of amplification have resulted in a wide range (1-23%) of cases reported to be amplified. [14][15][16] As the rate of ERBB2 amplified lung cancers is very low in studies using FDAapproved reagents and scoring criteria, it seems possible that treatment of cases with biologically less significant HER2 expression identified by immunohistochemistry, may have contributed to the poor results of HER2 targeted therapy in these tumors. 9,17 Clinical trials evaluating trastuzumab therapy in lung cancer so far have included between 17 and 59% of tested patients based on immunohistochemistry.…”

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confidence: 99%

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Heterogeneity of ERBB2 amplification in adenocarcinoma, squamous cell carcinoma and large cell undifferentiated carcinoma of the lung

et al. 2012

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The HER2 protein, encoded by the ERBB2 gene, is a molecular target for the treatment of breast and gastric cancer by monoclonal antibodies or tyrosine kinase inhibitors. While intratumoral heterogeneity of ERBB2 amplification is rare in breast cancer it is reported to be frequent in bladder and colorectal cancer. To address the potential heterogeneity of the HER2 status in adenocarcinomas, squamous cell carcinomas and large cell undifferentiated carcinomas of the lung, 590 tumors were analyzed for HER2 overexpression and ERBB2 amplification using FDA-approved reagents for immunohistochemistry and fluorescence in-situ hybridization (FISH). Moderate and strong immunostaining (2 þ , 3 þ ) was seen in 10% of the tumors. ERBB2 amplification was found in 17 (3%) lung cancer patients including 10 cases (2%) with high-level amplification forming gene clusters. ERBB2 amplification was significantly related to histologic subtype and tumor grade, resulting in 12% ERBB2 amplified tumors in the subgroup of high-grade adenocarcinomas. Heterogeneity was analyzed in all highly amplified tumors. For this purpose, all available tumor tissue blocks from these patients were evaluated. Heterogeneity of ERBB2 amplification was found in 4 of 10 tumors as assessed by FISH. These included two tumors with a mixture of low-level and high-level amplification and two tumors with non-amplified tumor areas next to regions with high-level ERBB2 amplification. High-level ERBB2 amplification occurs in a small fraction of lung cancers with a strong propensity to high-grade adenocarcinomas. Heterogeneity of amplification may limit the utility of anti-HER2 therapy in some of these tumors. Further attempts to assess the utility of HER2-targeting therapy in homogeneously amplified lung cancers appear to be justified. Keywords: adenocarcinoma of the lung; ERBB2 gene amplification; fluorescence in-situ hybridization; HER2 expression; heterogeneity; large cell undifferentiated carcinoma of the lung; squamous cell carcinoma of the lungThe human epidermal growth factor receptor 2 gene (ERBB2, HER2/neu) is involved in the development of numerous types of human cancers and has been linked to poor prognosis in many of them. 1-3 The ERBB2 gene product HER2 is the target of an antibody-based therapy (trastuzumab), which has been shown to be remarkably effective in both the metastatic and adjuvant setting for HER2-positive breast cancer 4-6 and in advanced HER2-positive gastric cancer. 7 Moreover, with the tyrosine kinase inhibitor lapatinib which targets both EGFR and HER2 an alternative option for HER2-positive breast cancers has been introduced 8 and is under analysis for other tumor types.

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Section: Discussionsupporting

confidence: 88%

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confidence: 99%

Heterogeneity of ERBB2 amplification in adenocarcinoma, squamous cell carcinoma and large cell undifferentiated carcinoma of the lung

et al. 2012

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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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“…This may be because there is a low-level copy-number gain of MET in a much higher percentage of the tumors, but the biologic implications are unclear. In lung cancer, the estimated frequency of mutations is low (1% for SCC (51,52,54) 3q26.3 33% 6% SOX2 amplification (23,24) 3q26.3-q27 23% Very rare FGFR1 amplification (24,25) 8p12 22% 1% PTEN mutation (36,61) 10q23.3 10% 2% MET amplification (34,35) 7q31.1 3%-21% 3%-21% PTEN loss (59,62) 10q23.3 8%-20% 8%-20% KRAS mutation (36) 12p12.1 6% 21% Variant III mutation (36) 7p12 5% Very rare LKB1 mutation (70) 19p13.3 5% 23% DDR2 mutation (30) 1q23.3 4% 1% HER2 overexpression (39)(40)(41)(42) 17q11.2-q12, 17q21 3%-5% 5%-9% PI3KCA mutation (50)(51)(52) 3q26.3 3% 3% BRAF mutation (36,64) 7p34 2% 1%-3% EGFR mutation (36) 7p12 <5% 10%-15% AKT1 mutation (56) 14q32.32 1% Very rare MET mutation (36) 7q31.1 1% 2% HER2 mutation (46,48,49) 17q11.2-q12, 17q21 1% 2% EML4-ALK fusion (66,67) 2p21, 2p23 1% 2%-7% and 2% for adenocarcinoma), and MET-mutated cells reveal enhanced ligand-mediated proliferation and significant in vivo tumor growth (36,37). Human EGF2 (ERBB2/Her2) is a transmembrane tyrosine kinase receptor that has no ligand-binding domain of its own.…”

Section: Translational Relevancementioning

confidence: 99%

“…Studies have shown overexpression in 10% to 35% of NSCLC, and less than that when the cutoff is IHC 3þ (3%-9%). Amplification is higher in adenocarcinoma than in SCC, and it confers sensitivity to gefitinib (38)(39)(40)(41)(42). Mutations in the ERBB2 gene are rare (2% in adenocarcinoma and 1% in SCC) and are associated with resistance to EGFR inhibitors and sensitivity to Her2-targeted therapy (43)(44)(45)(46)(47)(48)(49).…”

Section: Translational Relevancementioning

confidence: 99%

Squamous Cell Carcinoma of the Lung: Molecular Subtypes and Therapeutic Opportunities

Pérez-Moreno

Brambilla

Thomas

et al. 2012

Clinical Cancer Research

287

210

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Lung cancer is the leading cause of cancer-related deaths worldwide. Next to adenocarcinoma, squamous cell carcinoma (SCC) of the lung is the most frequent histologic subtype in non-small cell lung cancer. Encouraging new treatments (i.e., bevacizumab, EGFR tyrosine kinase inhibitors, and ALK inhibitors) have afforded benefits to patients with adenocarcinoma, but unfortunately the same is not true for SCC. However, many genomic abnormalities are present in SCC, and there is growing evidence of their biologic significance. Thus, in the short term, the molecular characterization of patients with SCC in modern profiling platforms will probably be as important as deciphering the molecular genetics of adenocarcinoma. Patients with SCC of the lung harboring specific molecular defects that are actionable (e.g., fibroblast growth factor receptor 1 amplification, discoidin domain receptor 2 mutation, and phosphoinositide 3-kinase amplification) should be enrolled in prospective clinical trials targeting such molecular defects.

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Lack of prognostic implications of HER‐2/neu abnormalities in 345 stage I nonsmall cell carcinomas (NSCLC) and 207 stage I–III neuroendocrine tumours (NET) of the lung

Cited by 31 publications

References 55 publications

Heterogeneity of ERBB2 amplification in adenocarcinoma, squamous cell carcinoma and large cell undifferentiated carcinoma of the lung

Heterogeneity of ERBB2 amplification in adenocarcinoma, squamous cell carcinoma and large cell undifferentiated carcinoma of the lung

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

Squamous Cell Carcinoma of the Lung: Molecular Subtypes and Therapeutic Opportunities

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