A critical review of HER2-positive gastric cancer evaluation and treatment: From trastuzumab, and beyond

Gómez‐Martín, Carlos; López‐Ríos, Fernando; Aparicio, Jorge; Barriuso, Jorge; García‐Carbonero, Rocío; Pazo, Roberto; Rivera, Fernando; Salgado, Mercedes; Salud, Antonieta; Vázquez-Sequeiros, Enrique; Lordick, Florian

doi:10.1016/j.canlet.2014.05.019

Cited by 58 publications

(49 citation statements)

References 106 publications

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“…Accumulating evidence demonstrated that ErbB-2 participates in gastric cancer growth, in which targeting MErbB-2 is an effective therapy. 72 As far as we know, among all these different cancer types, ErbB-2 nuclear presence has been reported in small bowel, esophagus and kidney tumor samples, as well as in ovarian cancer cells and in colorectal cancer cell lines upon stimulation with HRG. 17,73 Although Stat3 is expressed in several of these cancer types, its nuclear co-expression with ErbB-2 has only been described in BC.…”

Section: Discussionmentioning

confidence: 98%

Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis

et al. 2015

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Membrane overexpression of the receptor tyrosine kinase ErbB-2 (MErbB-2) accounts for a clinically aggressive breast cancer (BC) subtype (ErbB-2-positive) with increased incidence of metastases. We and others demonstrated that nuclear ErbB-2 (NErbB-2) also plays a key role in BC and is a poor prognostic factor in ErbB-2-positive tumors. The signal transducer and activator of transcription 3 (Stat3), another player in BC, has been recognized as a downstream mediator of MErbB-2 action in BC metastasis. Here, we revealed an unanticipated novel direction of the ErbB-2 and Stat3 interaction underlying BC metastasis. We found that Stat3 binds to its response elements (GAS) at the ErbB-2 promoter to upregulate ErbB-2 transcription in metastatic, ErbB-2-positive BC. We validated these results in several BC subtypes displaying metastatic and non-metastatic ability, highlighting Stat3 general role as upstream regulator of ErbB-2 expression in BC. Moreover, we showed that Stat3 co-opts NErbB-2 function by recruiting ErbB-2 as its coactivator at the GAS sites in the promoter of microRNA-21 (miR-21), a metastasis-promoting microRNA (miRNA). Using an ErbB-2 nuclear localization domain mutant and a constitutively activated ErbB-2 variant, we found that NErbB-2 role as a Stat3 coactivator and also its direct role as transcription factor upregulate miR-21 in BC. This reveals a novel function of NErbB-2 as a regulator of miRNAs expression. Increased levels of miR-21, in turn, downregulate the expression of the metastasis-suppressor protein programmed cell death 4 (PDCD4), a validated miR-21 target. Using an in vivo model of metastatic ErbB-2-postive BC, in which we silenced Stat3 and reconstituted ErbB-2 or miR-21 expression, we showed that both are downstream mediators of Stat3-driven metastasis. Supporting the clinical relevance of our results, we found an inverse correlation between ErbB-2/Stat3 nuclear co-expression and PDCD4 expression in ErbB-2-positive primary invasive BCs. Our findings identify Stat3 and NErbB-2 as novel therapeutic targets to inhibit ErbB-2-positive BC metastasis.

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Section: Discussionmentioning

confidence: 98%

Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis

et al. 2015

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“…The median overall survival time for patients treated with trastuzumab was significantly longer compared with patients in the chemotherapy alone group (22.9 vs. 11.6 months). High efficacy of trastuzumab has been confirmed prior to and following chemotherapy in patients with HER2-positive breast cancer, and expanded indications in gastric cancer are anticipated (14,15). Previous studies that have assessed chemotherapy plus trastuzumab treatment regimens for patients with HER2-positive gastric cancer have revealed good tolerance and high efficacy with cytotoxic chemotherapy including S-1 plus cisplatin, capecitabine plus oxaliplatin (or docetaxel), and cisplatin plus S-1, however, not capecitabine plus cisplatin (16)(17)(18)(19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of a trastuzumab-containing treatment regimen for patients with unresectable advanced or recurrent gastric cancer

Namikawa

Munekage

et al. 2016

Molecular and Clinical Oncology

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Abstract. The present study aimed to evaluate the efficacy and safety of trastuzumab plus chemotherapy for patients with unresectable advanced or recurrent gastric cancer. A retrospective analysis of 213 patients with unresectable advanced or recurrent gastric cancer who received systemic chemotherapy, including 15 patients who were also administered trastuzumab, at Kochi Medical School between 2007 and 2013 was performed. The overall survival was compared between patients who received trastuzumab plus chemotherapy and patients who received chemotherapy alone, and the safety and efficacy of the trastuzumab-containing regimen was evaluated. Human epidermal growth factor receptor (HER)2 status was examined in 86 patients, of whom 15 (17.4%) exhibited strong positive HER2 expression. The rate of strong positive HER2 expression was significantly higher for intestinal type tumors compared with diffuse type tumors [23.6 (13/55) vs. 6.5% (2/31); P=0.044]. The median overall survival of the patients treated with trastuzumab was significantly longer compared with that for patients who were not treated with trastuzumab (22.9 vs. 11.6 months; P= 0.014). The objective response rate and disease control rate for trastuzumab plus chemotherapy were 46.7 and 86.7%, respectively. Frequently encountered grade 3-4 toxicities included neutropenia (26.7%; 4/15), anemia (13.3%; 2/15) and fatigue (13.3%; 2/15). Trastuzumab plus chemotherapy is effective for patients with HER2-positive advanced or recurrent gastric cancer, and the frequencies of hematological and non-hematological toxicities experienced by patients in the present study indicated that it can be safely administered clinically. IntroductionGastric cancer is the third most commonly diagnosed cancer type worldwide and one of the leading causes of cancer-associated mortality (1). In patients with recurrent, metastatic, or advanced gastric cancer, chemotherapy can prolong survival and improve quality of life compared with the best supportive care.Human epidermal growth factor receptor (HER)2 is a member of a family of receptors that is associated with tumor cell proliferation, apoptosis, adhesion, migration and differentiation. It is overexpressed in 15-20% of patients with primary gastric and gastroesophageal junction cancers (2,3). Trastuzumab, a monoclonal antibody that targets HER2, induces antibody-dependent cellular cytotoxicity and inhibits HER2-mediated signaling by binding to the extracellular domain of HER2 (4). The trastuzumab for gastric cancer (ToGA) trial recently validated the additive effects of trastuzumab for HER2-positive, unresectable advanced or recurrent gastric cancer. This trial revealed a significant increase in the overall survival and progression-free survival when trastuzumab was used in combination with chemotherapy, thus supporting the use of trastuzumab in individualized, biomarker-based treatment (5). Additionally, it has been shown that second-line and later lines of chemotherapy can significantly improve patient outcomes, and that the additive...

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“…However, current chemotherapeutic regimens for GC have a limited impact on overall survival [3,4]. Trastuzumab, a monoclonal antibody against human epidermal growth of receptor 2 (HER2, p185) protein, combined with first-line chemotherapy was shown to have survival benefits for GC patients; thus, targeted therapy with trastuzumab is now being considered for metastatic GC patients with HER2 overexpression [5][6][7]. Unfortunately, unlike breast cancer, HER2 is not frequently Yan Cui and Shao-Bo Li have contributed equally to this work.…”

Section: Introductionmentioning

confidence: 99%

Trastuzumab Inhibits Growth of HER2-Negative Gastric Cancer Cells Through Gastrin-Initialized CCKBR Signaling

Cui

Peng

et al. 2015

Dig Dis Sci

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A critical review of HER2-positive gastric cancer evaluation and treatment: From trastuzumab, and beyond

Cited by 58 publications

References 106 publications

Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis

Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis

Evaluation of a trastuzumab-containing treatment regimen for patients with unresectable advanced or recurrent gastric cancer

Trastuzumab Inhibits Growth of HER2-Negative Gastric Cancer Cells Through Gastrin-Initialized CCKBR Signaling

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