Trastuzumab in combination with cisplatin and gemcitabine in patients with Her2-overexpressing, untreated, advanced non-small cell lung cancer: report of a phase II trial and findings regarding optimal identification of patients with Her2-overexpressing disease

Zinner, Ralph; Glisson, Bonnie S.; Fossella, Frank V.; Pisters, Katherine M.W.; Kies, M. S.; Lee, Pamela M.; Massarelli, Erminia; Sabloff, Bradley S.; Fritsche, Herbert A.; Ro, Jae Y.; Ordóñez, Nelson G.; Tran, Hai T.; Yang, Ying; Smith, Terry L.; Mass, R.; Herbst, Roy S.

doi:10.1016/j.lungcan.2003.09.026

Cited by 117 publications

(66 citation statements)

References 33 publications

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“…Two smaller studies with similar inclusion criteria enrolling 21 and 24 patients could not see any relationship between HER2 expression and response. 32,33 The small molecule lapatinib was recently also tested as monotherapy in adenocarcinoma and squamous cell carcinoma of the lung. 34 Although the results did not show any significant number of tumor regressions, one of two patients with a retrospective tested ERBB2 amplification showed partial response to therapy.…”

Section: Discussionmentioning

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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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%

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

et al. 2012

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“…Ongoing combination trials of another EGFR inhibitor, erlotinib with carboplatin and paclitaxel (TRIBUTE) and gemcitibine and cisplatin (TALENT) reported no clinical benefit (39). Furthermore, a recent clinical trial showed no clinical benefit for the administration of Trastuzumab in combination with cisplatin and gemcitabine in NSCLC, although it has been suggested that this was due to the predominately low to intermediate HER expression status of patients accrued (40). The foundations for these clinical trials were based on in vivo xenograft data and there are numerous reasons for the disparity between the two.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of the Therapeutic Efficacy of Taxol by the Mitogen-Activated Protein Kinase Kinase Inhibitor CI-1040 in Nude Mice Bearing Human Heterotransplants

et al. 2005

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Taxol may contribute to intrinsic chemoresistance by activating the mitogen-activated protein kinase kinase (MEK)/ extracellular signal-regulated kinase (ERK) cytoprotective pathway in human cancer cell lines and tumors. We have previously shown additivity between Taxol and the MEK inhibitor, U0126 in human cancer cell lines. Here, the combination of Taxol with an orally bioavailable MEK inhibitor, CI-1040, was evaluated in human lung tumors heterotransplanted into nude mice. Unlike xenograft models that are derived from cells with multiple genetic alterations due to prolonged passage, heterotransplanted tumor models are more clinically relevant. Combined treatment with both drugs resulted in inhibition of tumor growth in all models and tumor regressions in three of four models tested, supporting our previous observation that Taxol's efficacy is potentiated by MEK inhibition. Concurrent administration was superior to intermittent dosing. Pharmacodynamic assessments of tumors indicated that suppression of MEK was associated with induction of S473 phosphorylated Akt and reduced proliferation in the combination groups relative to single agents, in addition to suppression of fibroblast growth factor-mediated angiogenesis and reduced expression of vascular endothelial growth factor. These findings are significant and indicate that this combination may have broad therapeutic applications in a diverse range of lung tumors with different intrinsic chemosensitivities. (Cancer Res 2005; 65(7): 2854-60)

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“…Zinner et al (27) reported that cisplatin 75 mg/m 2 + herceptin 4 mg/ kg every day are well tolerated to NSCLC patients, with an encouraging 1-year survival rate of 62%, indicating a synergic effect of herceptin and cisplatin. In our study, cisplatin at IC 50 down-regulated the protein expressions of mCRPs CD55 and CD59 in A549 cells, so we supposed that cisplatin enhanced the antitumor effect of herceptin by decreasing the expressions of CD55 and CD59, and thus improving the activity of complement cascade.…”

Section: Discussionmentioning

confidence: 99%

Neutralization of complement regulatory proteins CD55 and CD59 augments therapeutic effect of herceptin against lung carcinoma cells

Chen¹

2009

Oncol Rep

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Abstract. Human monoclonal anti-Her2/neu antibody (herceptin, also named trastuzumab) failed in the treatment of lung cancer when in combination with two chemotherapy agents gemcitabine and cisplatin, despite of its clinical benefit in women with Her2 positive breast cancer. The capacity of herceptin to activate human complement and complementdependent cytotoxicity against tumor cells was investigated in a study of tumor immunotherapy. We found that the expression of membrane complement regulatory proteins (mCRPs), CD55 and CD59 on non-small cell lung cancer (NSCLC) cells was closely correlated with histological types, prognosis and preoperational adjutant chemotherapy of the disease. Herceptin-mediated complement cytotoxicity to two human lung carcinoma cell lines exerted stronger killing effect on tumor cells after the neutralization of mCPRs via their antibodies. Furthermore, treatment of herceptin combined with chemo-agents had advantages over chemotherapy alone, while CD55 and CD59 expression levels both declined remarkably in A549 and H157 cell lines after incubation with IC 50 cisplatin for 72 h. Our data indicated that overexpression of mCRPs on tumor cells contributes to herceptin's acquisition of resistance to NSCLC, and its anticancer efficacy was enhanced when mCRPs were neutralized or cisplatin could be used to down-regulate their expression.

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Trastuzumab in combination with cisplatin and gemcitabine in patients with Her2-overexpressing, untreated, advanced non-small cell lung cancer: report of a phase II trial and findings regarding optimal identification of patients with Her2-overexpressing disease

Cited by 117 publications

References 33 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

Enhancement of the Therapeutic Efficacy of Taxol by the Mitogen-Activated Protein Kinase Kinase Inhibitor CI-1040 in Nude Mice Bearing Human Heterotransplants

Neutralization of complement regulatory proteins CD55 and CD59 augments therapeutic effect of herceptin against lung carcinoma cells

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