HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target

Grávalos, Cristina; Jimeno, Antonio

doi:10.1093/annonc/mdn169

Cited by 1,003 publications

(852 citation statements)

References 45 publications

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“…We have found that inhibition of nuclear import using wheat germ agglutinin abrogated the effect of EGFR inhibitors on DNA repair. 3 Therefore, we investigated the effects of blocking HER2 nuclear expression by using a construct lacking the putative NLS. In these experiments, the HER2-expressing cells showed no effect of trastuzumab treatment and indeed were less efficient at repairing ICL than the vectorexpressing controls.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, increased expression of HER2 has also been found in other malignancies including gastric and prostate cancers (3). Activation of HER2, primarily through heterodimerization with other members of the epidermal growth factor receptor (EGFR) family, results in downstream signaling through the Ras and phosphoinositide-3-kinase pathways (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

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Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents

Boone

Bhosle

Tilby

et al. 2009

Molecular Cancer Therapeutics

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HER2 (ErbB2) is overexpressed in up to 30% of human breast cancers. Preclinical and clinical studies suggest synergy between some chemotherapeutic agents and the humanized anti-HER2 antibody trastuzumab (Herceptin). This study investigated the effects of etoposide and cisplatin on the repair of DNA damage in breast cancer cell lines. We examined the potential significance of HER2 nuclear expression in DNA repair. MCF-7, SK-BR-3, and MDA-MB-453 cells were treated with cisplatin and etoposide. Repair of DNA interstrand crosslinks (ICL) and strand breaks, following incubation with cisplatin and etoposide, respectively, were quantitated by the single-cell gel electrophoresis (comet) assay. Intrastrand crosslinks produced by cisplatin were assessed by ELISA. The effects of trastuzumab were measured in combination with these drugs. Similar experiments were done using HER2-negative MDA-MB-468 cells transfected with HER2 and a construct lacking the nuclear localization sequence. Incubation of breast cancer cell lines with trastuzumab delayed the repair of ICL produced by cisplatin. There were no effects on the repair of intrastrand crosslinks produced by cisplatin, or repair of DNA strand breaks following etoposide treatment. Transfection of HER2 into MDA-MB-468 cells inhibited the repair of cisplatin-induced ICL, whereas transfection of a HER2 construct lacking the nuclear localization sequence did not affect DNA repair. These results indicate that HER2 expression modulates the repair of specific DNA lesions produced by chemotherapy. The effect on ICL repair requires nuclear expression of HER2. Understanding the mechanisms of interaction between DNA-interacting agents and HER2 inhibitors will inform the design of clinical trials and optimize the therapeutic effects of these combinations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents

Boone

Bhosle

Tilby

et al. 2009

Molecular Cancer Therapeutics

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“…[1][2][3][4][5] ErbB2 amplification or overexpression also seems to be associated with poorer prognosis, more aggressive disease and shorter survival in gastric cancer. [5][6][7] Preclinical and clinical studies of upper gastrointestinal adenocarcinomas, 2 and in particular, the large ToGA trial, which included adenocarcinomas of the stomach and gastro-oesophageal junction, have demonstrated that trastuzumab exerts antitumour activity on ErbB2-overexpressing tumours. 8 Most recently, this has led to the approval of the addition of trastuzumab to fluoropyrimidine/platinum-based therapies for patients with ErbB2-positive advanced gastric cancer by the European Medicines Agency (EMEA), the FDA and Health Canada.…”

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confidence: 99%

Assessment of ErbB2 (Her2) in oesophageal adenocarcinomas: summary of a revised immunohistochemical evaluation system, bright field double in situ hybridisation and fluorescence in situ hybridisation

et al. 2011

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Amplification and overexpression of ErbB2 (Her2) is a frequent event in oesophageal adenocarcinomas. Assessment of ErbB2 status is crucial for identifying patients who are likely to benefit from treatment with trastuzumab. In this study, we performed a comprehensive analysis of ErbB2 amplification and expression in 142 oesophageal adenocarcinomas by comparing the most commonly used methods for ErbB2 assessment: ErbB2 expression was determined by immunohistochemistry and was scored (0, 1 þ , 2 þ and 3 þ ) according to a recently described modified scoring system for gastric cancer. ErbB2 amplification was evaluated by bright field double in situ hybridisation. The results were compared with pathologic features, patients' survival and previously published data from fluorescence in situ hybridisation analysis. On the basis of immunohistochemistry, which was applicable in 110 cores of the cases, 83 tumours (75%) had a score of 0 or 1 þ (immunohistochemistry negative), 13 tumours (12%) were scored as 2 þ and 14 tumours (13%) were scored as 3 þ . In situ hybridisation data were obtained from 142 cases. There was a highly significant correlation of immunohistochemistry, bright field in situ hybridisation and fluorescent in situ hybridisation (Po0.001 each). In total, 41 tumours (29%) were categorised as ErbB2 positive, which was defined as immunohistochemistry 3 þ and/or an ErbB2/Chr17 quotient of Z2 as assessed by either bright field double in situ hybridisation or fluorescence in situ hybridisation. ErbB2 positivity was observed more frequently in tumours with lower differentiation grades (P ¼ 0.029). Patients with ErbB2-positive tumours had a significantly worse prognosis, both in univariate analysis (P ¼ 0.004) and in multivariate analysis (P ¼ 0.03).In conclusion, we demonstrate that a significant number of oesophageal adenocarcinomas are positive for ErbB2. Assessment of ErbB2 amplification can be equivalently performed by conventional fluorescence in situ hybridisation or other lightmicroscopy-based methods, such as the novel bright field double in situ hybridisation technique. Modern Pathology (2011) 24, 908-916;

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“…One potential therapeutic target is the HER family (19,20). HER2 overexpression or amplification has been reported in 6%-33% of gastric cancer and gastroesophageal junction, a similar rate to that observed in breast cancer (21)(22)(23)(24)(25). The largest analysis to date of the incidence of HER2 amplification in gastric cancer was from the Phase III ToGa trial, which evaluated the combination of trastuzumab with chemotherapy in patients with metastatic gastric cancer.…”

Section: Introductionmentioning

confidence: 98%

A Phase II Biomarker-Embedded Study of Lapatinib plus Capecitabine as First-line Therapy in Patients with Advanced or Metastatic Gastric Cancer

LaBonte

Yang

Zhang

et al. 2016

Molecular Cancer Therapeutics

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An exploratory phase II biomarker-embedded trial (LPT109747; NCT00526669) designed to determine the association of lapatinib-induced fluoropyrimidine gene changes with efficacy of lapatinib plus capecitabine as first-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma independent of tumor HER2 status. Tumor biopsies obtained before and after 7-day lapatinib (1,250 mg) to analyze changes in gene expression, followed by a 14-day course of capecitabine (1,000 mg/m 2 twice daily, 14/21 days) plus lapatinib 1,250 mg daily. Blood samples were acquired for pharmacokinetic analysis. Primary clinical objectives were response rate (RR) and 5-month progression-free survival (PFS). Secondary objectives were overall survival (OS), PFS, time to response, duration of response, toxicity, and identification of associations between lapatinib pharmacokinetics and biomarker endpoints. Primary biomarker objectives were modulation of 5-FU-pathway genes by lapatinib, effects of germline SNPs on treatment outcome, and trough steady-state plasma lapatinib concentrations. Sixty-eight patients were enrolled; (75% gastric cancer, 25% gastroesophageal junction). Twelve patients (17.9%) had confirmed partial response, 31 (46.3%) had stable disease, and 16 (23.9%) had progressive disease. Median PFS and OS were 3.3 and 6.3 months, respectively. Frequent adverse events included diarrhea (45%), decreased appetite (39%), nausea (36%), and fatigue (36%). Lapatinib induced no changes in gene expression from baseline and no significant associations were found for SNPs analyzed. Elevated baseline HER3 mRNA expression was associated with a higher RR (33% vs. 0%; P ¼ 0.008). Lapatinib plus capecitabine was well tolerated, demonstrating modest antitumor activity in patients with advanced gastric cancer. The association of elevated HER3 and RR warrants further investigation as an important player for HER-targeted regimens in combination with capecitabine. Mol Cancer Ther; 15(9); 2251-8. Ó2016 AACR.

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HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target

Cited by 1,003 publications

References 45 publications

Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents

Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents

Assessment of ErbB2 (Her2) in oesophageal adenocarcinomas: summary of a revised immunohistochemical evaluation system, bright field double in situ hybridisation and fluorescence in situ hybridisation

A Phase II Biomarker-Embedded Study of Lapatinib plus Capecitabine as First-line Therapy in Patients with Advanced or Metastatic Gastric Cancer

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