Advances in the Management of HER2-positive Advanced Gastric and Gastroesophageal Junction Cancer
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea. Journal of clinical gastroenterology
(Impact Factor: 3.5).
06/2012; 46(8):637-48. DOI: 10.1097/MCG.0b013e3182557307
In the past, patients with advanced or metastatic gastric or gastroesophageal junction cancer have had few treatment options and generally poor survival rates. The human epidermal growth factor receptor 2 (HER2) has been identified as a potential therapeutic target because of its overexpression or gene amplification in 6% to 35% of gastric or gastroesophageal junction cancers, although the methods of assessment and prognostic value of HER2 have been subject to debate. The phase III Trastuzumab for Gastric Cancer (ToGA) trial showed that adding the HER2-targeted humanized monoclonal antibody trastuzumab to chemotherapy significantly improves survival without negatively impacting quality of life in patients with advanced gastric or gastroesophageal junction cancer. As a result, trastuzumab is now the sole HER2-targeted therapy approved in several countries for this indication. The ToGA trial also demonstrated that patients who expressed higher levels of HER2 (determined by immunohistochemical screening) received the greatest benefit from trastuzumab therapy. This finding underlines the importance of accurate HER2 testing. Because of the unique characteristics of gastric cancer, a new gastric cancer-specific scoring system for HER2 expression was proposed during the ToGA trial. The aim of this review is to inform the gastroenterologist of the potential role of HER2-targeted therapy, to discuss the importance of accurate and reliable HER2 testing, and to discuss ongoing studies with HER2-targeted therapies that may have an impact on the future treatment of HER2-positive gastric cancer.
Available from: PubMed Central
- "Gastric cancer is the fourth most common type of cancer causing ~800,000 mortalities worldwide each year (1). In general, gastric cancer has a 5-year survival rate of ~15% and for patients with advanced gastric cancer, the median overall survival is <1 year (2,3). Considering these statistics, increased research into potential preventative methods for gastric cancer is required, as well as improved early detection and more effective treatments. "
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ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of targeted genes in a post-transcriptional manner. Increasing evidence indicates that miRNAs play important roles in cancer pathogenesis, including apoptosis, proliferation and differentiation, as oncogenes or tumor suppressors. Previously, miR-375 was shown to be involved in human gastric cancer, however, the mechanism remains poorly understood. In the present study, miR-375 was shown to be downregulated in gastric cancer tissues, particularly human epidermal growth factor receptor 2 (ERBB2)-positive gastric cancer tissues. Identified by dual luciferase assays and western blot analysis, ERBB2 was demonstrated to be a target gene of miR-375. In addition, miR-375 overexpression suppressed the proliferation of human gastric cancer cells in vitro and the suppression effect was restored by ERBB2 overexpression. Thus, the results of the present study indicate that miR-375 is associated with human gastric carcinogenesis by targeting ERBB2. Therefore, miR-375 may be used as a potential clinical classification marker and therapeutic target for human gastric cancer.
Available from: bmb.oxfordjournals.org
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ABSTRACT: IntroductionMonoclonal antibody (mAb)-based products are highly specific for a particular antigen. This characteristic feature of the molecules makes them an ideal tool for many applications including cancer diagnosis and therapy.Sources of dataWe performed comprehensive searches of PubMed, Medline and the Food and Drug Administration website using keywords such as 'therapeutic antibodies' and 'anti-cancer antibodies'.Areas of agreementTreatment of cancer patients with antibodies when used alone or in combination with chemotherapy and radiotherapy, or conjugated to drugs or radioisotopes, prolongs overall survival in cancer patients. Currently, there are 14 mAb-based drugs that have been approved for the treatment of cancer patients.Areas of controversyThe response of cancer patients to antibody therapy can be of short duration. Therapeutic antibodies are expensive and may have side effects. There are no reliable predictive biomarkers for sensitivity or resistance to certain therapeutic antibodies.Future focusThere should be additional studies to discover novel therapeutic targets, to develop more effective antibody-based drugs with fewer side effects, to identify more reliable predictive biomarker(s) for response to therapy with antibody-based drugs and to develop alternative strategies (e.g. transgenic plants, transgenic farm animals) for production of large quantities and more affordable batches of therapeutic antibodies.Areas timely for developing researchA better understanding of cancer biology, the hallmarks of human cancers and the immune system would lead to identification of additional cell surface biomarkers. These in turn would facilitate the development of novel and biosimilar antibody-based drugs and their routine use as 'magic bullets' for the targeted therapy of human cancers.
Available from: Matilde Saggese
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ABSTRACT: Gastric cancer and cancer of the gastro-oesophageal junction (GOJ) are the 4th most common cancer diagnoses worldwide with regional differences in incidence rates. The treatment of gastric and GOJ cancers is complex and requires multimodality treatment including chemotherapy treatment, surgery, and radiotherapy. During the past decade considerable improvements were achieved by advanced surgical techniques, tailored chemotherapies/radiotherapy and technical innovations in clinical diagnostics. In patients with advanced or metastatic gastric/GOJ cancer systemic chemotherapy with fluoropyrimidine/platinum-based regimens (+/-human epidermal growth factor receptor-2 antibody) is the mainstay of treatment. Despite these improvements, the clinical outcome for patients with advanced or metastatic disease is generally poor with 5-year survival rates ranging between 5%-15%. These poor survival rates may to some extent be related that standard therapies beyond first-line therapies have never been defined. Considering that this patient population is often not fit enough to receive further treatments there is an increasing body of evidence from phase-2 studies that in fact second-line therapies may have a positive impact in terms of overall survival. Moreover two recently published phase-3 studies support the use of second-line chemotherapy. A South Korean study compared either, irinotecan or docetaxel with best supportive care and a German study compared irinotecan with best supportive care-both studies met their primary endpoint overall survival. In this "Field of Vision" article, we review these recently published phase-3 studies and put them into the context of clinical prognostic factors helping to guide treatment decisions in patients who most likely benefit.
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