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Abstract
Gastric cancer is the leading cause of cancer-related mortality across the world, with poor prognosis and a median overall survival of ≤12 months for advanced stage gastric cancer. Environmental, genetic and other predisposing factors contribute to the development of gastric cancer and a predominant factor was found to be infection of Helicobacter pylori. Advances in understanding the deranged signalling pathways that are critical for normal cellular homeostasis helped in the development of novel drugs that target specific proteins and pathways to curtail the growth of gastric cancer. Genetic studies revealed several single nucleotide polymorphisms, chromosomal aberrations and epigenetic alterations that likely play a major role in elevating the susceptibility to develop gastric cancer. Methylation pattern of specific genes may likely prove to be a valid biomarker for early detection of gastric cancer, but much progress is needed to establish specific markers. Important developments have been made in targeting human epidermal growth factor receptor-2 and vascular endothelial growth factor receptor 2 for treating advanced gastro-oesophageal junction cancer, using specific monoclonal antibodies. Lack of efficacy with regard to targeting other signalling pathways including mesenchymal-epithelial transition/hepatocyte growth factor and mammalian target of rapamycin is probably due to suboptimal patient selection for these clinical trials, which is probably due to the lack of appropriate biomarkers, to decide on responsive patient population. Besides the development of antagonists for the cell growth-related signalling pathways, advances are also being made to tackle gastric cancer by immunotherapies, targeting immune check-points, which may hold promise for better treatment options in future.
- Cancer: gastric
- Cancer: oesophageal
- Epigenetics
- Genetics
- Stomach and duodenum
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Introduction
Gastric cancer is one of the cancers that is diagnosed only at an advanced stage of the disease with a median survival of the affected patients <1 year1 and this is the fourth most prevalent cancer and second leading cause of cancer-related mortality across the globe.2 ,3 The geographical distribution of gastric cancer is apparently dependent on its anatomical location. Thus, adenocarcinomas of the distal stomach are more prevalent in East Asia, Eastern Europe and parts of South and Central America, whereas cancers of the proximal stomach or the gastro-oesophageal junction are common in Western Europe and North America.4 Epidemiological studies5 revealed that about two-thirds of all gastric cancer cases worldwide occur in low-income and middle-income countries in Eastern Europe, South America and Asia. Approximately, 42.6% of all new cases originate in China and also ∼45% of gastric cancer-related mortality, indicating a rather disproportionately high incidence and death due to gastric cancer in China (GLOBOCAN 2012).6 Incidence in more advanced regions such North Americas, is much lower, by only 2.5% of the total world cases (GLOBOCAN 2012). Environmental, genetic and other predisposing factors contribute to the development of gastric cancer. Among these, dietary factors and Helicobacter pylori infection are the major risk factors for the development of distal tumours, whereas gastro-oesophageal reflux disease and obesity appear to be the risk factors for the proximal gastric tumours.7 According to 2012 statistics, approximately 1 million new cases of gastric cancer are identified each year with more than 700 000 deaths each year.8 Even though there was some decline in the incidence of gastric cancer in Western countries, this rate of decline has decreased, particularly in the USA, which is probably due to long-term infection with H. pylori.9 A steep rise has been reported in the incidence of gastro-oesophageal-junction adenocarcinomas,10 even though there is a decline in non-cardia (ie, all parts of stomach except that joining oesophagus) gastric cancers in adults.11
Gastric cancers are classified either according to the WHO guidelines, which include four histological subtypes, viz., papillary, tubular, mucinous and poorly cohesive tumours or according to the Lauren system that identifies intestinal, diffuse or mixed subtypes.12 However, because of the lack of prognostic and predictive capabilities, neither of these classifications is useful in clinical management of patients with gastric cancer. In about 6%–23% of gastric cancers, human epidermal growth factor receptor-2 (HER2, also known as ERBB2) is found to be elevated and is thought to contribute to the development of tumour. However, the prognostic value of HER2 level in gastric cancer is controversial as HER2 positivity was suggested as an adverse prognostic factor in few studies, whereas others indicated HER2 positivity as better survival. Recently, a combination of HER2 status with Lauren system was described to be a better prognostic factor than either of these approaches alone.13 Because of this current treatment practices do not take into account the histopathological, anatomical and epidemiological distinctions of gastric cancer.14 It is thought that the majority of the gastric cancers are intestinal-type adenocarcinomas, located in the antrum and body region of the stomach. Non-cardia intestinal adenocarcinomas probably develop via a specific pathway that starts with chronic gastritis, which leads to gland loss, development of atrophic gastritis, intestinal metaplasia and dysplasia culminating in gastric adenocarcinoma15 (table 1). Apparently, infection of H. pylori is not the only determinant of gastric cancer incidence and other factors play an important role.16 In the current review, we will discuss the recent advances in our understanding of the molecular events that cause gastric cancer and the new emerging targets for therapeutic intervention.
Molecular characteristics of intestinal and diffuse subtypes of gastric cancers
Environmental factors
H. pylori infection
Gastritis induced by H. pylori infection is considered a primary risk factor for gastric cancer and many eradication programmes across the world to control this infection led to significant reduction in the incidence of gastric cancer.17–19 However, whether eradication of H. pylori infection is critical for the reduction of gastric cancer is questioned in some retrospective multicenter trial studies from Japan, which did not find any significant reduction in metachronous gastric cancer incidence following eradication of infection.20 Later studies reiterated the importance of eradication of H. pylori in controlling metachronous gastric cancer incidence.21 The high costs involved in screening and potential problems due to non-compliance to pharmacological treatments and also microbial resistance necessitate the development of vaccination approaches to control H. pylori infection. However, such measures have been disappointing until now.22 This is because of the failure of oral vaccines consisting of H. pylori proteins with bacterial exotoxin adjuvants or live attenuated bacterial vectors expressing H. pylori proteins to consistently reduce bacterial load even though these could induce adaptive immune mechanisms in clinical trials.22 Dietary salt is known to be an important factor that contributes to gastric cancer development in patients with H. pylori infection, by enhancing H. pylori colonisation as well as enhancing the expression of CagA in H. pylori.23
Occupational risk factors
Besides H. pylori infection, a number of occupational exposures have been reported to increase the risk of gastric cancer including asbestos, ionising radiation, nitrogen oxides and N-nitroso compounds. Asbestos has been known to be a major risk factor for various forms of cancer.24 Dietary nitrates, which are contributed by many vegetables, soil, fertilisers, etc, are converted to carcinogenic N-nitroso compounds by gastric acid and these compounds increase gastric cancer risk.25 A recent meta-analysis of 40 mortality cohort studies indicated association of asbestos with moderate or elevated risk of gastric cancer.26 Dietary salt is also known to lead to hypergastrinemia and endogenous mutations in epithelial cells, promoting their proliferation and eventually gastric cancer progression.27 Cigarette smoking, low intake of vitamins A and C are also environment-related risk factors that contribute to the development of gastric cancer.
Precursor lesions such as chronic atrophic gastritis, intestinal metaplasia, dysplasia and Ménétrier's disease are suggested to be risk factors for gastric cancer.28 However, it is also possible that these lesions may in fact are dependent variables associated with independent variables that do modify the risk for gastric cancer.29
Genetic factors
It is widely accepted that alterations in DNA sequence, either acquired or inherited, can contribute to activation of oncogenic pathways, leading to cancer development and progression. Even though many of these pathways are common to various types of cancers, there is no clear pattern of mutations in gastric tumours.30 Contribution of heredity as the source of mutation was suspected in early onset gastric tumours, but the true hereditary gastric cancers makeup only about 3% of the diffuse gastric tumours while more than 80% of the diffuse gastric tumours are of sporadic type.31 Nearly 40% of the hereditary gastric cancers harbour mutated CDH1 leading to defective or loss of expression of E-cadherin, which in turn results in activation of epidermal growth factor receptor (EGFR).32 Genetic susceptibility to develop gastric cancer may also be conferred by a number of single nucleotide polymorphisms (SNPs), particularly in the genes coding for inflammatory cytokines (interleukin-1, tumour necrosis factor-α, etc) and one carbon metabolism methylenetetrahydrofolate reductase (MTHFR), which plays a critical role in the regulation of DNA methylation and epigenetic modulation.33
Somatic mutations
Acquired mutations can lead to chromosomal and microsatellite instability, epigenetic modifications resulting in altered gene expression and also somatic mutations that all lead to activation of oncogenic processes. Chromosomal instability includes alteration in the number of chromosomes and/or different regions of selected chromosomes, which may result altered gene expression.33 Intestinal gastric cancer, which is strongly associated with H. pylori infection, correlates with a gain of copy number of chromosomal regions 8q, 17q and 20q and this contributes to the elevated expression of epidermal growth factor (EGF) and c-ErbB2.34 On the other hand, diffuse gastric cancers exhibit a gain of copy number at 12q and 13q chromosomal regions with the resultant overexpression of fibroblast growth factor receptor (FGFR), c-myc as well as HER2.34 Thus, patients with gastric cancer with HER2 overexpression could be effectively treated with trastuzumab, a monoclonal antibody directed against HER2 (see below). Small deletions or expansions in the microsatellite regions of the gastric tumour cell DNA that do not occur in normal DNA and are often caused by epigenetic alterations in the mismatch repair genes lead to microsatellite instability.33 This disturbed mismatch repair leads to several mutations in genes controlling cell growth (transforming growth factor (TGF)-β RII, IGFIIR, TCF4, etc), apoptosis (BAX, FAS, APAF1, etc) and DNA repair (hMSH6, hMSH3).31
Epigenetic modifications
Changes in gene expression that are brought about by modifying methylation of DNA bases, acetylation and methylation of histones, miRNAs etc, are considered as epigenetic alterations and while these are important for normal regulation, disturbances in these mechanisms often contribute to tumourigenesis.35 DNA methylation is a major epigenetic modification in which the DNA methyltransferase family enzymes methylate the fifth carbon of the cytosine residue in the context of 5′-CG-3′ (CpG dinucleotide) clustered regions, called as CpG islands (CGIs). The methyl group needed for this is supplied via one-carbon metabolism and methyl-tetrahydrofolate, which is controlled by MTHFR. Aberrant DNA methylation of more than 100 genes, including tumour suppressor genes such as CDH1, RASSF1A, p16, GSTP1, SOCS1, SFRP1 and phosphatidylinositol-3,4,5-phosphate 3-phosphatase (PTEN) have been reported in gastric tumour cell DNA.36 A recent meta-analysis of DNA methylation frequency in patients with gastric cancer demonstrated hypermethylation of at least 70 genes in tumour cells as compared with normal surrounding tissue.37 Most frequently methylated genes are listed in table 2. It is interesting to note that even though CDH1, which codes for E-cadherin is heavily methylated in its promoter region and silenced in gastric tumour cells,38 this modification is also noticed in ageing non-cancerous gastric mucosa,39 suggesting that this mutation may not be a causative factor but may help in the progression or increasing susceptibility to gastric cancer. However, epigenetic silencing of promoter region of RASSF1A is rare and is seen mostly in cancer cells and affects the Ras signalling pathway and cell cycle and apoptosis.40 Studies indicated the potential of following DNA methylation pattern as biomarkers for early stage detection of gastric cancer, which can potentially help increase the survival rate from 20% to 25% to nearly 60%.41 However, much progress is required to precisely identify such markers for gastric cancer.
Genetic factors contributing to gastric cancer
Targeted therapy of gastric cancer
Several signalling pathways are known to be altered during gastric carcinogenesis and the precise cause and effect relationship for these changes is not clear. The altered pathways include: EGFR, c-MET oncogene overexpression, vascular endothelial growth factor receptor (VEGFR), mammalian target of rapamycin (mTOR), FGFR, Hedgehog PATCH1 smoothened pathway and also mitogen-activated protein kinase kinase-extracellular signal-regulated kinase pathway (figure 1). Many of these altered pathways are involved in cell proliferation, angiogenesis, apoptosis and cell cycle and thus disturbances in these cellular events result in cancer and therefore many of the current therapies target the components of these pathways (table 3) such as HER, c-MET, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt)/mTOR, VEGFR and VEGF.28
Summary of targeted therapies for gastric cancer
Targeting signalling pathways as a therapeutic measure for gastric cancer. Various components of signalling pathways that are critical for cell proliferation and growth are altered and activated in tumour cells and thus targeting these components prevents tumour cell proliferation. Some of these pathways and the different antagonists that have been tested in clinical trials for treating gastric cancer have been shown here. HER, human epidermal growth factor receptor; VEGF, vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor-2; HGF, hepatocyte growth factor; Raf, GTPase Raf; Ras, GTPase Ras; MEK, MAP kinase; ERK, extracellular signal-regulated kinase; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin.
Inhibitors of ErbB family
There are four types of EGFR family of receptors (Erb1-4/HER1-4) that are tyrosine kinases, which play an important role in normal cellular functions such as cell growth and proliferation, differentiation and survival under stress conditions through localised paracrine signals.42 These receptors can bind various ligands including TGF-α, EGF, amphiregulin, heparin-binding EGF-like growth factor, betacellulin and epiregulin and upon engagement with ligand, these receptors can either homodimerise or heterodimerise to initiate downstream signalling through the activation of PI3K and RAS in the cell. Monoclonal antibodies, for example, cetuximab and panitumumab that target EGFR prevent the dimerisation of these receptors and their signalling. These monoclonal antibodies have been tested in combination with chemotherapy in clinical trials for their efficacy to improve overall survival of patients with gastric cancer, but the results did not show such improvement and even showed negative results.43 ,44
Patients with gastric cancer show significant HER2 positivity that depends upon the location and histological subtype and ranges from 6% to 34%. The expression is maximal in intestinal type tumours and in cancers located in the gastro-oesophageal junction.45 ,46 Several tyrosine kinase inhibitors and monoclonal antibodies are currently being tested to target HER2. ToGA phase III clinical trial in which trastuzumab (Herceptin) for gastric cancer was tested in combination with chemotherapy, showed significant clinical benefit with enhanced response rate (47% vs 35%) and also improved progression-free survival (PFS) (6.7 vs 5.5 months) as well as improved overall survival (13.8 vs 11.1 months), as compared with the chemotherapy-alone arm.47 A tyrosine kinase inhibitor, lapatinib, yielded mixed results in its efficacy in improving overall survival, when administered in combination with capecitabine and oxaliplatin.48 A conjugate, called trastuzumab emtansine (TDM-1), of trastuzumab and DM1, a potent microtubule inhibitor has been evaluated against taxane-alone-based therapy for advanced gastric cancer in a multicenter phase II/III trial and the results showed no added benefit as compared with taxane-alone therapy.49 In late 2010, the Food and Drug Administration (FDA) granted approval for the use of trastuzumab in combination with cisplatin and fluoropyrimidine for the treatment of patients with gastric cancer and gastro-oesophageal junction cancer with HER2 overexpression.
VEGFR inhibitors and anti-angiogenesis inhibitors
Abnormal angiogenesis is an important feature of the malignant tumours, which is brought about by signalling via VEGFR, after its binding with vascular endothelial growth factor (VEGF) secreted by tumour cells or tumour stromal cells.50 In the case of many cancers, neoangiogenesis is an important factor for tumour metastasis and elevated VEGF expression is associated with tumour aggressiveness and poor prognosis in gastric cancer.28 In Avastin in Gastric Cancer (AVAGAST) study, bevacizumab (Avastin), a monoclonal antibody against VEGF-A, has been tested in combination with first-line chemotherapy capecitabine or cisplatin in patients with gastro-oesophageal junction adenocarcinoma, and it was observed that even though addition of bevacizumab significantly improved PFS and overall response rate, there was no major change in overall survival. It was also observed that there was some variation in disease response in terms of patient's ethnicity, Americans of Latin American origin being more responsive as compared with Asians of predominantly of Japanese and Korean origin.51 Similar results were reported in another study from China.52 It has been indicated that lack of proper biomarkers during screening for patient selection may be a reason for the observed lack of efficacy.53
It has been observed in a limited number of clinical trials that apatinib, a tyrosine kinase inhibitor developed against VEGFR2, demonstrated improved PFS and overall survival in patients with metastatic gastric cancer and pretreated heavily with chemotherapy but with treatment failure.54 ,55 Other tyrosine kinase inhibitors (eg, sunitinib, sorafenib, pazopanib, etc) that target VEGFR and also other receptors were found to have mixed effects in patients with gastric cancer.56–58
Another approach for targeting VEGF pathway and angiogenesis is through VEGFR2, by ramucirumab, a fully humanised monoclonal antibody.59 Two separate phase III trials Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD) and Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW)) demonstrated the efficacy of ramucirumab against gastro-oesophageal junction adenocarcinoma in improving PFS as well as overall survival.60–62 These results prompted the approval of ramucirumab in 2014 by FDA, as a single therapeutic agent for treating patients with advanced gastric or gastro-oesophageal junction cancer after progressing on prior treatments, and also in combination with paclitaxel.
Other approaches that are being developed to block VEGF pathway and angiogenesis in gastric cancers include Endostar, a recombinant human endostatin, which inhibits VEGF-induced KDR/Flk-1 (VEGFR2) tyrosine phosphorylation and suppresses VEGFR2 expression63 and regorafenib, also known as BAY 73-4506, an oral multikinase inhibitor with a broad-spectrum anticancer activity.64 ,65 Thus, overall a significant advance has been made in targeting the VEGF pathway as a therapy for gastric cancers and new therapeutics are in the pipeline of development. However, it is important that proper biomarkers should be identified that need to be employed for the selection of right group of patients to assess the efficacy of these drugs clinically as not all patients with gastric cancer respond in a similar fashion.
Therapies based on PI3K/Akt/mTOR targeting
A frequently activated signalling pathway in gastric cancers that may be amenable for therapeutic targeting is the mTOR pathway.66 As a key upstream activator of PI3K and Akt, the serine/threonine protein kinase mTOR, involved in the regulation of cell growth, apoptosis, motility, metabolism and angiogenesis67 and dysregulation of mTOR pathway contributes to poor survival and resistance to chemotherapy.68 Clinical trials using everolimus, an oral mTOR inhibitor in patients with advanced gastric cancer and in whom previous chemotherapy was not successful, yielded contradictory results. One study69 showed improvement in PFS and overall survival, whereas another study70 did not find any efficacy with everolimus. However, in the later study it was observed that non-Asian patients had a trend for reduced risk of death.70 Everolimus in combination with paclitaxel is currently being evaluated for efficacy in gastric cancers as a second-line treatment in phase III clinical trials (ClinicalTrials.gov identifier: NCT01248403).48 Again, these discrepant results indicate the need for the selection of suitable patient population for these trials using appropriate biomarkers. A recent study analysing transcriptomic data from 1065 patients with gastric cancer concluded that BIRC5, CASP3, CTNNB1, tissue inhibitor of metalloproteinase-1, matrix metalloproteinase (MMP)-2, Silent Mating-type Information Regulation 2 (SIRT) and VEGF are the best performing survival-associated genes in these patients.71 Several of the previously identified biomarkers for diagnosis and prognosis of gastric cancer are non-tumour tissue based, such as carcinoembryonic antigen, carbohydrate antigen (CA) 125, CA 19–9, CA 72–4 and α-fetoprotein, serum pepsinogen I and also proteases including pepsinogen C, plasminogen activator, MMPs.72–74
Akt inhibitors are also being examined for efficacy in clinical trials and ipatasertib or placebo in combination with mFOLFOX (a combination of FOLinic acid, 5-Fluorouracil, OXplatin) is being tested in a recently initiated randomised phase II trial (ClinicalTrials.gov identifier: NCT01896531). In a specifically selected patient population bearing phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA) mutation or amplification, an orally available AKT inhibitor, AZD5363, is currently being examined in combination with paclitaxel in a second-line therapy setting (ClinicalTrials.gov identifier: NCT02451959). MK-2206, another allosteric inhibitor of Akt, has been tested in phase I and phase II clinical trials and it was found that even though this drug was effective in blocking Akt, the study efficacy point of increasing overall survival was not achieved.75 ,76 An important modulator of PI3K/Akt/mTOR pathway is PTEN, which dephosphorylates PI-3,4,5 phosphate and thereby abrogates this signalling pathway.77 It has been shown that methylation of PTEN promoter leads to silencing of this gene and this causes elevated signalling through the PI3K/Akt/mTOR pathway. In Epstein-Barr virus (EBV)-induced gastric cancer, it has been observed that gastric epithelial cell DNA methyltransferase-1 levels increase, which in turn methylates the promoter region of PTEN and reduces its expression.78 Decreased expression of PTEN in breast cancer has been shown to cause resistance to anti-Her2-based therapies.79 ,80 Recent studies showed similar results in patients with gastric cancer and it has been suggested that deficiency of PTEN is a predictive biomarker for targeted therapies against HER2, such as trastuzumab.81 It has been indicated that activation of PI3K/Akt pathway or PTEN inactivation leads to overexpression of HER2, which results in reduced response to anti-HER2-based therapies.82
The Cancer Genome Atlas (TCGA) for gastric cancer indicated that 80% of EBV gastric tumours harbour mutation in PIK3CA, highlighting the rationale for targeting this protein in EBV gastric tumours.83 PIK3CA mutations are known to facilitate tumour invasion and escape from apoptosis.84 Currently, three types of PI3K inhibitors are available for targeting this pathway and these include Pan-class I inhibitors, isoform-specific PI3K inhibitors and dual PI3K/mTOR inhibitors.85 Pan-class inhibitors target all the isoforms of p110 and include Wortmannin, LY294002, PX-866, etc. Wortmannin and LY294002 are toxic or have short half-life and thus are not acceptable as drugs, whereas PX-866 has been found to have better pharmacokinetics and biological activity and tolerable toxicity with prolonged stable disease in clinical trials.86 There are several other pan inhibitors, which are still in development stage. Among the isoform-specific PI3K inhibitors, NVP-BYL719 and INK1117, which are selective for the α-isoform, have been recently been tested in phase I clinical trials and are found to have tolerable side effects and oral availability.87 GSK2636771, which is an β-isoform selective inhibitor is still in development stage. Dual PI3K/mTOR inhibitors are expected to overcome the loss of mTORC1-dependent negative feedback on PI3K signalling and these include NVP-BEZ235, NVP-BGT226 and VS-5884 and are still in development stage.88
Inhibitors of mesenchymal epithelial transition pathway
Hepatocyte growth factor (HGF) activates mesenchymal-epithelial transition (MET) factor receptor and also several signalling pathways that promote gastric cancer cell proliferation, survival and migration and thus this pathway is important in metastasis process.89 Thus, antagonising MET/HGF pathway can have therapeutic implications for gastric cancer. Approaches using anti-HGF monoclonal antibody, rilotumumab, revealed marginally positive results in terms of PFS in a phase II trial,90 whereas in a larger phase III trial, no efficacy was seen in overall survival and in fact the trial was stopped due to increased mortality in patients receiving rilotumumab.91 This discrepancy was attributed to differences in methodology used for assessing MET expression in patient samples. Trials employing anti-MET monoclonal antibody, onartuzumab, therapy in different combinations were not successful and this approach is now abandoned.53 A multikinase inhibitor, foretinib, which can target several pathways including MET, VEGFR2, etc, has been found to be effective in preclinical studies,92 but phase II trials did not show any efficacy in improving overall survival of patients with advanced gastric cancer.93
Other therapies that are currently being evaluated include poly-ADP-ribose polymerase (PARP) inhibitors, which block DNA base excision repair mechanism and thus lead to tumour cell apoptosis.94 A phase II trial using olaparib, a PARP inhibitor, in combination with paclitaxel, as a second line of therapy in patients with metastatic gastric cancer, showed significant improvement in overall survival but without any benefit in PFS.95 More studies are currently being conducted to evaluate the efficacy of olaparib. Besides the antagonists of critical signalling pathways, immunotherapies, in particular targeting the antigens cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death protein 1 expressed on T-cells, are also being developed currently and hold promise for better and specific therapies against gastric cancer.48
Conclusions
The primary treatment approach for advanced gastric cancer has been the standard chemotherapy and the combination of cytotoxic regimens could improve the overall response rates by ≥40%; however, the median survival of the patients is still under 12 months. Recent advances in molecular targeting to improve on this outcome led to the development of trastuzumab as a new standard of care for HER2-positive patients with gastric cancer. But as only about 20% of the patients with gastric cancer are HER2 positive, this therapy addresses their needs effectively but not others. Similarly, ramucirumab is able to control the disease and improve outcomes in patients with VEGFR2-positive gastric tumours. Genetic studies led to the identification of several SNPs and epigenetic alterations that enhance the susceptibility to develop gastric cancer and contribute to its rapid progression. DNA methylation pattern of specific genes may likely prove to be a valid biomarker for early detection of gastric cancer in future. Further work is needed to better define the biomarkers to identify patient population who may be benefited by a particular targeted therapy and also to develop more effective and specific therapies that hopefully have less adverse events compared with the currently available therapeutic regimens.
References
Footnotes
Contributors PZ supervised the writing of this review. XZ and PZ collected the relevant literature and wrote the manuscript.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.