Trastuzumab in the Treatment of Advanced Non-Small-Cell Lung Cancer: Is There a Role? Focus on Eastern Cooperative Oncology Group Study 2598

Langer, Corey J.; Stephenson, Patricia; Thor, Ann D.; Vangel, Mark; Johnson, David H.

doi:10.1200/jco.2004.04.105

Cited by 200 publications

(110 citation statements)

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“…Two phase II studies did not find any convincing effect of trastuzumab treatment. 18,19 The first study by Gatzemeier et al enrolled 103 patients with HER2-positive lung cancers of different histologic subtypes (non-small cell lung cancer). In all, 17% of 617 screened patients were found to be HER2 positive by immunohistochemistry (2 þ , 3þ ) and were subsequently randomized.…”

Section: Discussionmentioning

confidence: 99%

“…9,17 Clinical trials evaluating trastuzumab therapy in lung cancer so far have included between 17 and 59% of tested patients based on immunohistochemistry. 18,19 Intratumoral heterogeneity of overexpression/ amplification is another potential cause for nonresponding HER2-positive cancers. Heterogeneous ERBB2 amplification is rare in breast 20 but seems to be frequent (450%) in bladder or colorectal cancer.…”

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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: Discussionmentioning

confidence: 99%

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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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“…26 The single erbB2 mutation we have found was the same as the one repeatedly found by Shigematsu et al 26 Because very few NSCLC patients have gene amplification of erbB2, trastuzumab in the treatment of NSCLC might have a limited role. 9 Lung cancers that coexpress both EGFR and erbB2 appear to have more virulent behavior. 27 In addition, EGFR-erbB2 heterodimers are associated with a stronger and more sustained proliferative signal than EGFR homodimers.…”

Section: Discussionmentioning

confidence: 99%

“…Trastuzumab was approved for breast cancer 8 and clinical trials for NSCLC is underway. 9,10 Recently, we have found that novel EGFR mutations' status at ATP binding pockets in Japanese NSCLC patients were correlated with the clinicopathologic features related to good response to gefitinib. 11 These EGFR mutations are predominantly found in Japanese lung cancer patients (about 25%) when compared to USA patients (about 8% [12][13][14] to 10% 15 ).…”

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EGFR and erbB2 mutation status in Japanese lung cancer patients

Sasaki

Shimizu

Endo

et al. 2005

Intl Journal of Cancer

152

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Much evidence has accumulated that the epidermal growth factor receptor (EGFR) and its family members are strongly implicated in the development and progression of lung cancers. Somatic mutations of the EGFR gene were found in about 25-40% of Japanese lung cancer patients. More recently, erbB2 mutations are found in about 4% of European-derived lung cancer patients. We have investigated EGFR and erbB2 mutation status in 95 surgically treated nonsmall cell lung cancer (NSCLC) cases from Nagoya City University Hospital. Seventy-five adenocarcinoma cases were included. The presence or absence of EGFR and ernB2 mutations of kinase domains were analyzed by reverse transcription polymerase chain reaction (RT-PCR) amplifications and direct sequences. We have also investigated erbB2 mutation status in 27 surgically treated NSCLC cases followed by treatment with gefitinib from Kinki-chuo Chest Medical Center. EGFR mutations (CTGfiCGG; L858R) were found from 14 of 95 lung cancer patients. We also detected the deletion 1a-type mutations from 9 patients and deletion 4-type mutations from 6 patients in exon 19. In exon 20, 4 mutations including 2 novel mutations were found. Total EGFR mutations were present in 35 patients (36.8%). These mutation statuses were significantly correlated with gender (women 73.3% vs. men 20%, p < 0.0001), smoking status (never smoker 69.4% vs. smoker 16.9%, p < 0.0001), pathologic subtypes (adenocarcinoma 45.1% vs. nonadenocarcinoma 12.5%, p 5 0.0089) and differentiation status of the lung cancers (well 51% vs. moderately or poorly 18.4%, p 5 0.0021). On the other hand, erbB2 mutation was only found from 1 of 95 patients, at exon 20. This patient was female and a never smoker with adenocarcinoma. This 12 nucleotide insertion mutation (2324-2325 ins ATACGTGATGGC) was located in the exon 20 at kinase domain (775-776 ins YVMA). There was no erbB2 mutation in 27 gefitinib-treated NSCLC patients. In total, we have found only 1 erbB2 mutation from 122 (0.8%) Japanese NSCLC patients. There was a significantly higher erbB2 positive (21/31) ratio in EGFR mutant patients (13/25, 52.0%) compared to EGFR wild-type patients (10/ 62, 16.1%; p 5 0.0247). The NSCLC specimen with erbB2 mutation showed 11 immunoreactivity. The EGFR mutation status might correlate with the clinicopathologic features related to good response to gefitinib, such as gender, smoking history and pathologic subtypes of lung cancers. However, erbB2 mutation is rare from Japanese lung cancer and is of limited value for molecular target therapy. ' 2005 Wiley-Liss, Inc.Key words: EGFR; lung cancer; mutations; erbB2; Japanese Lung cancer is a major cause of death from malignant diseases, due to its high incidence, malignant behavior and lack of major advancements in treatment strategy.1 Lung cancer was the leading indication for respiratory surgery (42.2%) in 1998 in Japan.2 More than 15,000 patients underwent surgical operations at Japanese institutions in 1998. 2 The clinical behavior of the lung cancer is largely associated with its stage. ...

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“…In 2006, response to trastuzumab in a patient with human epidermal growth factor receptor 2-(HER2-) mutated lung cancer was reported [11]. This was exciting because the activity of trastuzmab in previous lung cancer trials had been only modest [12]. In 2013, a European cohort study provided further evidence to support HER2-targeted therapy in patients with HER2-mutated lung cancer [13].…”

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confidence: 83%