Pertuzumab in Combination with Trastuzumab Shows Significantly Enhanced Antitumor Activity in HER2-Positive Human Gastric Cancer Xenograft Models

Yamashita-Kashima, Yoriko; Iijima, Shiro; Yorozu, Keigo; Furugaki, Koh; Kurasawa, Mitsue; Ohta, Masateru; Fujimoto-Ouchi, Kaori

doi:10.1158/1078-0432.ccr-10-2927

Cited by 159 publications

(119 citation statements)

References 39 publications

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“…In a retrospective analysis by Jácome et al of 201 patients with esophageal junction and gastric cancer who underwent primary resection, HER2 and HER3 expression were significantly correlated (33). The findings corroborated by our study may have therapeutic importance in EGA given that the addition of pertuzumab-a drug that inhibits HER2-HER3 heterodimerization-to trastuzumab in the treatment of HER2-positive breast cancer improved outcomes (34,35). This suggests that the concept of inhibiting HER3 dimerization may be a potential therapeutic target in the treatment of HER2 overexpressing EGA.…”

Section: Discussionsupporting

confidence: 82%

EGFR family and cMet expression profiles and prognostic significance in esophagogastric adenocarcinoma

Chan¹,

Alkhasawneh²,

Duckworth³

et al. 2016

J. Gastrointest. Oncol.

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Background: Targeted therapy with anti-human epidermal growth factor receptor-2 (HER2) monoclonal antibody in patients with HER2 overexpressed esophagogastric adenocarcinoma (EGA) improves survival; however, the effect is transient due to the development of resistance. Some studies suggest that cMet overexpression provides cross talk for epidermal growth factor receptor (EGFR) and HER2 inhibition. We sought to characterize the expression profile of the EGFR family and cMet receptors in untreated, resected EGA. and cMet expression scored as low (0, 1+) or high (2+, 3+). Demographic and tumor characteristics were compared using Fisher exact test. Kaplan-Meier curves and univariate analysis compared survival among different receptors. Results: Total 52 patients were included in the study with median age 66 years. High expression of EGFR (73%), HER2 (40%), HER3 (75%), HER4 (35%) and cMet (69%) was detected among the study group. HER3 and HER4 co-expression was found in 18 (35%) cases. Pan expression of all four EGFR family members with cMet was noted in only 17% of cases. On univariate analysis, tumor stage and depth correlated with survival, while cMet + HER3 +/-EGFR receptor co-expression trended towards a worse survival. Conclusions: EGFR family and cMet are frequently co-expressed in treatment naïve resected EGA or GEJ tumors. Although our data do not significantly show receptor status as a prognostic factor, the co-expression profiles support for further investigation to improve targeting of this signal transduction axis.

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Section: Discussionsupporting

confidence: 82%

EGFR family and cMet expression profiles and prognostic significance in esophagogastric adenocarcinoma

Chan¹,

Alkhasawneh²,

Duckworth³

et al. 2016

J. Gastrointest. Oncol.

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“…Based on the current analysis a clear trend towards a potential role for HER2 as a negative prognostics factor in gastric cancer was shown, suggesting that HER2 overexpression and/or amplification is a molecular abnormality that might be linked to the development of gastric cancer Trastuzumab or other HER2 related medication on treatment of HER2 amplification gastric adenocarcinoma: Trastuzumab, a monoclonal antibody that targets HER2, induces antibody-dependent cellular cytotoxicity, inhibits HER2-mediated signaling, and prevents cleavage of the extracellular domain of HER2 [12]. Trastuzumab were found to inhibit tumor growth in gastric carcinoma cell lines, animal model and xenograft models [23,33,57,58]. Fujimoto-Ouchi (2007) used trastuzumab as a single agent inhibited the tumor growth in both of the HER2-overexpressing models but not in the HER2-negative models, GXF97 and MKN-45.…”

Section: Gastricmentioning

confidence: 99%

HER2 Amplification or Overexpression in Upper GI Tract and Breast Cancer with Clinical Diagnosis and Treatment

Zhou¹,

Hick²

2013

Oncogene and Cancer - From Bench to Clinic

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“…These data suggest that assessing both HER2 protein overexpression and gene amplification status may be useful for predicting the efficacy of trastuzumab therapy in gastric cancer. Several new molecularly targeted drugs against HER2 protein are currently being tested in vivo as well as in clinical studies [6][7][8], further highlighting the importance of accurate HER2 status assessment.…”

Section: Introductionmentioning

confidence: 99%

A novel gene–protein assay for evaluating HER2 status in gastric cancer: simultaneous analyses of HER2 protein overexpression and gene amplification reveal intratumoral heterogeneity

et al. 2014

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Background Human epidermal growth factor receptor 2 (HER2) protein overexpression and gene amplification are important biomarkers for trastuzumab treatment in breast and gastric cancer patients. Gastric cancer presents high rates of tumor heterogeneity, which may influence the results of HER2 testing. A novel gene-protein assay (GPA) can allow the simultaneous analysis of HER2 protein and gene status on a single slide.Methods Using the tissue microarray technique, the HER2 status of each of 875 gastric cancer cases was evaluated by immunohistochemistry (IHC), brightfield dual-color in situ hybridization (DISH), and GPA. Intratumoral phenotypic and genotypic heterogeneity were evaluated by comparing the HER2 statuses of two tissue cores from each case. Results There was excellent concordance between GPA and IHC (99.2 %), as well as between GPA and DISH results (99.3 %). HER2 positivity obtained by GPA was almost identical (99.8 %) to the results obtained by IHC and DISH assays. Intratumoral phenotypic heterogeneity was more frequently observed in IHC 2? cases (63.5 %) compared with IHC 3? cases (28.3 %). Phenotypic heterogeneity (48.8 %) was more frequently observed than genotypic heterogeneity (26.8 %). Tumor heterogeneity was consistently observed from early to advanced stages. Conclusions HER2-positive gastric cancers presented different levels of HER2 protein expression and gene amplification statuses within the same lesion in almost half the cases examined. Evaluating both phenotypic and genotypic heterogeneity may contribute to a deeper understanding and improved prediction of clinical outcome in gastric cancer patients treated with trastuzumab. This newly established GPA technology may also be useful for developing biomarkers for other molecularly targeted therapies.

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Pertuzumab in Combination with Trastuzumab Shows Significantly Enhanced Antitumor Activity in HER2-Positive Human Gastric Cancer Xenograft Models

Cited by 159 publications

References 39 publications

EGFR family and cMet expression profiles and prognostic significance in esophagogastric adenocarcinoma

EGFR family and cMet expression profiles and prognostic significance in esophagogastric adenocarcinoma

HER2 Amplification or Overexpression in Upper GI Tract and Breast Cancer with Clinical Diagnosis and Treatment

A novel gene–protein assay for evaluating HER2 status in gastric cancer: simultaneous analyses of HER2 protein overexpression and gene amplification reveal intratumoral heterogeneity

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