Esophageal cancer and gastric cancer are aggressive diseases for which treatment approaches are facing a new era. Some molecular pathways, such as VEGF, EGFR, fibroblast growth factor receptor, PIK3CA, and PARP-1, have been studied, and novel targeted drugs are presumed to be developed in the near future. From The Cancer Genome Atlas report, 80% of Epstein-Barr virus tumors and 42% of tumors with microsatellite instability have PIK3CA mutations, suggesting that this pathway could be reevaluated as a possible target for new systemic treatment of gastric cancer. Notably, higher PARP-1 expression can be found in gastric cancer, which might be related to more advanced disease and worse prognosis. In addition, PD-L1 expression, high microsatellite instability, and mismatch repair deficiency can be found in gastric cancer, thus suggesting that immunotherapy may also play a role in those patients. We discuss trends related to the potential of novel therapies for patients with esophageal and gastric cancers in the near future.


  • The Cancer Genome Atlas project proposes the division of gastric cancer into four molecular subtypes: tumors positive for EBV (with recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, PD-L1, and PD-L2), microsatellite-instable tumors, genomically stable tumors, and tumors with chromosomal instability.

  • MSI-H and high PD-L1 and PD-L2 expression raise the potential of immune therapy for patients with EBV-positive gastric cancer.

  • HER2 overexpression in gastric cancer ranges from 9% to 23% and is more frequent in the intestinal subtype. Its prognostic value remains unclear, but HER2 should be tested in all patients with metastatic gastric cancer using an IHC-modified scoring system.

  • Trastuzumab deruxtecan has shown important tumor activity in tumors harboring HER2 overexpression.

  • Currently, there is a marginal benefit of apatinib (1.8 months) and ramucirumab (1.4–2.2 months) for advanced gastric cancer. Further research on biomarkers, drug combinations, sequencing, and maintenance therapies might produce more significant results on targeting VEGF.

The relative prevalence of gastric cancer has decreased over the past few decades, from the leading cause of cancer in 1975 to the fifth most common cancer; it is also the third leading cause of cancer-related death in both sexes worldwide.1,2 Gastric cancer is also the leading cancer associated with infection,3 due to Helicobacter pylori and Epstein-Barr virus (EBV). Gastric cancer has a twofold greater incidence in men than women and heterogeneous distribution across the world, with higher incidence and mortality rates in Asian countries, such as Korea, Japan, and China, and the lowest incidence in the Western world, such as in North America, where it is one of the least common cancers.4,5 Southern Europe, where this disease is the sixth most common malignancy, is also considered a high-risk area.6 Some risk factors that are associated with the development of gastric cancer include high intake of processed red meat or smoked preserved foods, smoking, high alcohol intake, and Helicobacter pylori infection, which is the main cause of noncardia gastric cancer; however, few studies have been conducted in low-income countries with high gastric cancer incidence.7 Histologically, gastric adenocarcinomas are classified as intestinal (85%–90%) or diffuse (10%–15%). The majority of gastric adenocarcinoma cases are sporadic (90%–95%), and only 5% to 10% have familial predisposition. Anatomically, proximal tumors are more common in Western countries, and nonproximal tumors are more frequent in Asian countries.6 By the American Joint Committee on Cancer staging system, proximal stomach tumors crossing the esophagogastric junction are classified and treated as esophageal carcinomas.8

Traditionally gastric cancers are classified into intestinal and diffuse histologic subtypes, the so-called Lauren classification, although mixed subtypes are reported as well.9 Comprehensive analysis of driver mutations in gastric cancer has revealed that a multitude of genes are causally involved in cancer development and progression, including TP53, ARID1A, PIK3CA, and RHOA.10-12 Some of these mutations associate with a specific type of gastric cancer; for example, RHOA mutations are largely confined to diffuse-type gastric cancer. Additional genetic aberrations involve amplifications of genes including ERBB2, FGFR2, MET, and KRAS, resulting in activation of pathways downstream the receptor tyrosine kinases and RAS signaling, providing leads for targeted therapy (see below). However, as in other cancer types, responses to single targeted agents are often disappointing, suggesting additional complexity and the need for additional biomarkers.

In a key publication, The Cancer Genome Atlas (TCGA) project proposes the division of gastric cancer into four genetically defined molecular subtypes: tumors positive for EBV (with recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, PD-L1, and PD-L2), tumors with microsatellite instability (MSI), genomically stable tumors, and tumors with chromosomal instability (i.e., with marked aneuploidy and focal amplification of receptor tyrosine kinases).13 To integrate not only genomic aberrations but also epigenetic modifications and microenvironmental heterogeneity, including properties of the immune infiltrate and activation state of the stroma, comprehensive gene expression–based classifications have been developed. The initial studies focused on gene expression profiles associating with intestinal and diffuse gastric cancer.14 Tan et al15 used representative cell lines to construct profiles that could discriminate the two gastric cancer types on the basis of gene expression data. This distinction also had predictive relevance, as cell lines representing the intestinal type were mostly oxaliplatin responsive, whereas diffuse gastric cancer lines were more responsive to cisplatin. Later this work was expanded to the detection of three subtypes: a proliferative type, a metabolic type, and a mesenchymal type.16 Also here distinct subtypes responded differently to therapeutic interventions: gastric cancers of the mesenchymal subtype were sensitive to PIK3CA, AKT, and mTOR inhibitors, and metabolic gastric cancers showed specific sensitivity to fluorouracil. More recently, the Asian Cancer Research Group (ACRG) proposed another classifications on the basis of gene expression comprising four subtypes: a microsatellite-instable type, a mesenchymal-like type, and p53-active and p53-inactive types.17 The clinical relevance of these classifications is best studied for the TCGA and ACRG taxonomies.

Regarding the TCGA classification, the EBV subtype was associated with the best prognosis, followed by microsatellite-instable and chromosomal-instability subtypes; the genomically stable subtype was associated with the worst prognosis.18 The ACRG classification scheme was also shown to be prognostic in several cohorts, as the microsatellite-instable subtype was associated with good prognosis and the mesenchymal-like type with poor disease outcome. Indeed, the identification of these subtypes (on the basis of TCGA or ACRG classification) might be useful for clinical decisions, prognostics, and research of new target therapies. Chromosomally unstable tumors represent 50% of all gastric cancers.18 Analysis of these tumors can reveal some recurring gene amplifications, such as HER2, EGFR, MET, CCNE1, CCND1, CDK6, VEGFA, and FGFR2, which are potentially targetable. The high-MSI subgroup corresponds to 22% of gastric cancers and is characterized by elevated mutation and hypermethylation rates, a median age of 72, and a higher proportion of females (56%). Higher mutation rates increase the likelihood of neoantigens, and therefore, high-MSI gastric cancer is a possible target for immune oncology.18,19 Genomically stable tumors represent 20% of gastric cancers, and some genetic changes can be found, such as RHOA signaling mutations, CLDN18-ARHGAP26 fusion, and fibroblast growth factor receptor (FGFR) 2 and VEGFA amplification.5 The EBV subtype is more common in fundus or body cancers and in men (81%), and it represents 9% of all gastric cancers and is characterized by high levels of DNA promoter hypermethylation, elevated expression of PD-L1 and PD-L2, JAK2 amplification, and PIK3CA mutation. Thus, the high expression of PD-L1 and PD-L2 raises the potential for immune therapy in this subgroup, as well as in the high-MSI subgroup. JAK-2 amplification and PIK3CA mutations are also possible targets for these patients (Fig. 1).

In 2017, gastric cancer represented 1.7% of all cancer cases in the United States (with 28,000 new cases each year), with 5-year relative survival rates of 67.2% for localized disease, 30.7% for regional disease, and 5.2% for distant disease. Approximately 50% of patients with gastric cancer will be diagnosed with advanced-stage disease, but in some countries, such as Japan and South Korea, where screening is routinely performed, early detection is more frequent.2 The 5-year overall survival (OS) duration of metastatic gastric cancer might range from 3 months with only supportive care treatment to 16 months in fit patients in clinical trials; thus, gastric cancer is still an unmet need in oncology.20 In many Western countries, there is considerable overlap between gastric cancer and distal esophageal cancers in their treatment and clinical trial inclusion. In the United States, esophageal cancer is the fifth most common gastrointestinal cancer, with an estimated 16,940 new cases per year, and it is the sixth most common cancer worldwide.21 Approximately half of patients diagnosed with esophageal cancer present with unresectable or metastatic disease. Treatment of these patients aims to control dysphagia and other cancer-related symptoms, improve quality of life, and prolong survival. In the past 2 decades, modestly improved outcomes have been achieved in the treatment of patients with inoperable nonmetastatic cancer who are medically not fit for surgery or have unresectable, locally advanced disease. In distant metastatic esophageal cancer, several double-agent or triple-agent chemotherapy regimens have been established as first-line treatment options. Furthermore, long-term results of multiple large randomized phase III trials using additional targeted therapies have been published in the past few years, affecting contemporary clinical practice and future research directions.21 Here, we discuss the potential of further therapeutic directions and biomarkers for esophageal cancer and gastric cancer (EGC) in the advanced stage.

How Do We Treat Advanced EGC Today?

Today, treating advanced EGC is a difficult challenge for oncologists worldwide. Chemotherapy regimens, including different combinations of platinum, fluoropyrimidine, taxanes, and anthracyclines, were accepted as the backbone of first-line treatment of advanced disease.22,23 However, some other targeted therapies have been incorporated in this framework in recent years. For patients with advanced HER2-positive gastric cancer, researchers have found a great benefit in adding trastuzumab to platinum-fluoropyrimidine chemotherapy regimens.24 In addition, ramucirumab, in monotherapy or in combination with paclitaxel, an antiangiogenic monoclonal antibody, was approved for metastatic gastric cancer second-line treatment on the basis of results from the RAINBOW and REGARD phase III clinical trials.25,26 The tyrosine kinase inhibitor (TKI) apatinib, a drug against VEGFR-2, has demonstrated some benefit in patients with chemotherapy-refractory advanced or metastatic gastric cancer, becoming a possible third- or further-line treatment.26 Despite the aforementioned issues, the role of targeting therapies in gastric cancer is still limited. However, further research in this field could contribute to more clinical utility for the types of treatment of patients with gastric cancer.

Emerging Targets and Treatments

HER2 overexpression in gastric cancer ranges from 9% to 23% and is more frequent in the intestinal subtype; its prognostic value remains unclear, but HER2 should be tested in all patients with metastatic gastric cancer, using an immunohistochemistry-modified scoring system.27 After outstanding results in breast cancer, different clinical trials have targeted this receptor in gastric cancer.

In the ToGA trial, the median OS duration was 13.8 months in those assigned to trastuzumab plus chemotherapy and 11.1 months in the chemotherapy-alone group, which led to U.S. Food and Drug Administration (FDA) approval of trastuzumab in combination with chemotherapy as a new standard option for patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) cancer in 2010.24 Furthermore, there are different trials targeting HER2, with different combinations of monoclonal antibodies, such as trastuzumab, pertuzumab, TDM-1, or the TKI lapatinib combined with chemotherapy or radiotherapy (RT). Thus, there are still many potential clinical benefits of different targeting combinations for HER2-positive disease. Currently, there are more than 118 trials on HER2-positive gastric cancer registered at See Table 1 for some relevant trials considered by our group. In 2017, Doi et al28 published an interesting phase I study addressing the safety and tumor activity of trastuzumab deruxtecan, an HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastroesophageal tumors. Doi et al assessed 23 patients, of whom 10 (43%) had an objective response rate and 21 (91%) achieved disease control. The most common grade 3 and grade 4 toxicities were decreased lymphocyte count, decreased neutrophil count, and anemia. Trastuzumab deruxtecan therefore shows important tumor activity in those tumors harboring HER2 overexpression. Further phase II and III trials are warranted to investigate the role of this drug in patients with EGC.28


TABLE 1. Phase III Clinical Trials in Gastric Cancer With Published Results

Unlike breast cancers, however, the results of targeting HER2 in EGC have not been consistently positive. Recently, the JACOB trial (NCT01774786) treated 780 patients with HER2-positive metastatic or locally advanced unresectable GEJ cancer or gastric cancer with first-line trastuzumab and chemotherapy with or without pertuzumab. Unfortunately, this trial did not show any benefit in OS for patients treated with the combination of pertuzumab, trastuzumab, and chemotherapy compared with trastuzumab, chemotherapy, and placebo, with OS duration of 17.5 months compared with 14.2 months, respectively (HR 0.84; 95% CI, 0.71–1.00; p = .0565).40 Additionally, the TRIO-013/LOGIC and TyTan trials involved 545 patients. The median OS in the lapatinib and placebo arms was 12.2 months (95% CI, 10.6–14.2 months) and 10.5 months (95% CI, 9.0–11.3 months), respectively, which was not significantly different (HR 0.91; 95% CI, 0.73–1.12). Although there were negative results from the TRIO-013/LOGIC and TyTan trials,35,38 there are other trials of lapatinib therapy for HER2-positive gastric cancer that could be promising, such as MAGIC-B, which tested the addition of lapatinib or bevacizumab to perioperative chemotherapy with epirubicin, cisplatin, and capecitabine. The estimated completion date of this trial was December 2017, and the results are still forthcoming.

Finally, a phase II clinical trial (NCT02015169) was designed to investigate the efficacy and safety of XELOX (capecitabine and oxaliplatin) plus lapatinib treatment in patients with HER2-positive gastric cancer with liver metastasis. The primary outcome was complete resection rate (R0 resection rate). The estimated completion date was May 2017. Despite a small estimated number of participants (32 patients), this trial may determine important issues for other anti-HER2 therapies apart from trastuzumab.

EGFR inhibition.

The EGFR transmembrane glycoprotein activates a cascade of tyrosine kinases in Ras/Raf or Akt/mTOR pathways. This receptor was successfully targeted in wild-type KRAS colorectal metastatic cancer with the monoclonal antibodies panitumumab and cetuximab and in squamous cell head and neck cancers with cetuximab. There are also TKIs targeting EGFR, such as erlotinib, which has been approved for lung cancer treatment.

EGFR could be considered an independent prognostic factor of worse outcomes in patients with gastric cancer41; it is overexpressed by 30% to 50% in gastroesophageal tumors and is a potential target in such cases.23

Cetuximab (the EXPAND trial) and panitumumab (the REAL3 trial) failed to demonstrate benefit in advanced gastroesophageal tumors. It is possible that EGFR overexpression is not the leading oncogenic pathway in advanced gastric cancer, but those trials did not select patients by EGFR expression; that approach might be explored in further trials or subgroup analysis.42

More recently, nimotuzumab, another monoclonal anti-EGFR antibody, did not increase OS or progression-free survival in the overall population in a phase II clinical trial for advanced gastric cancer, but those with EGFR overexpression had a substantial benefit, which increased interest in selecting patients by EGFR status for EGFR-targeting therapies.43 Intriguing retrospective biomarker analyses of the COG trial44 suggest that a subpopulation of tumors with EGFR copy number gain may benefit from anti-EGFR therapy, implying that refining the EGFR biomarker may yet yield positive results.

Immune checkpoint inhibitors.

Upper gastrointestinal (GI) cancers, namely, esophageal cancer, GEJ cancer, and stomach cancer, have high rates of somatic mutations, trailing only melanoma, lung, and bladder cancers with respect to tumoral mutational frequency.45 Given the known success of immunotherapy in these highly mutated cancers, basic science and clinical research have been set forth in upper GI cancers, for which the success rate of cytotoxic chemotherapy remains poor.

The purpose of immunotherapy is to shift the balance between proinflammatory immune effector cells and anti-inflammatory suppressive cells. Immune checkpoints refer to many immune system inhibitory pathways that are important for self-tolerance by moderating the duration and amplitude of the physiologic immune response. Tumors use these pathways as mechanisms of tumor resistance through ligand-receptor interactions. Checkpoint inhibitors have the potential to enhance antitumor immunity by altering the ligand receptor relationship between tumor and T cells.46

Currently two classes of immunotherapy are FDA approved, inhibitors of either the PD-1 and its ligand (PD-L1) or CTLA-4.47 PD-L1 is expressed in 35% to 45% of esophageal cancers,48,49 providing a rationale for the use of immunotherapy drugs in these cancers. Recent and ongoing clinical trials have studied the use of PD-1/PD-L1 or CTLA-4 inhibitors as monotherapy or in combination in upper GI cancers.

PD-L1 expression, high MSI, and mismatch repair deficiency can be found in gastric cancer, which may provide a role for immunotherapeutics in treating patients with these diseases. Pembrolizumab, a humanized monoclonal antibody against PD-1, was initially studied in a phase IB trial in advanced pretreated esophageal and GEJ cancers with PD-L1 expression greater than 1%.28 Overall response rate was 30.4% (95% CI, 13.2%–52.9%). A subset analysis of response rate revealed a response rate of 40.0% for adenocarcinoma and 29.4% for squamous cell carcinoma. Later, a phase II trial showed an overall response rate of 13.3% (95% CI, 8.2%–20%) in advanced gastric and GEJ adenocarcinoma, including a complete response rate of 1.4%50 and a partial response rate of 11.9%.51 Patients were required to have PD-L1 expression of at least 1% tumor or stromal cells using immunohistochemistry. This led to FDA accelerated approval for patients with recurrent, locally advanced, or metastatic gastric or GEJ adenocarcinoma. A larger phase III trial that investigated pembrolizumab as second-line treatment for patients with advanced gastric or GEJ adenocarcinoma did not meet its primary endpoint of OS (HR 0.82; 95% CI, 0.66–1.03; p = .042) in patients whose tumors expressed PD-L1 greater than 1%.52 It is possible that PD-L1 is not a good biomarker in gastric cancer or that limiting its expression to 1% was too optimistic. It is possible that selecting patients with higher PD-L1 expression would provide superior outcomes.

Nivolumab is a human monoclonal IgG4 antibody that inhibits PD-1 expressed on activated T cells. A phase II trial included patients with advanced pretreated esophageal cancer, not preselected by PD-L1 status, and demonstrated a 17% objective response rate (95% CI, 10%–28%).50,53 A similar response rate of 11% was reported in a phase III trial that included advanced gastric or GEJ tumors intolerant to at least two previous lines of chemotherapy. There was also an improvement in 12-month OS rate with nivolumab of 26.2% (95% CI, 20.7%–32.0%) compared with 10.9% (95% CI, 6.2%–17.0%) with placebo.54 A head-to-head phase III trial comparing nivolumab with chemotherapy including docetaxel or paclitaxel in a similar cohort of chemorefractory patients is ongoing.55

Tremelimumab inhibits CTLA-4, a protein receptor member of the immunoglobulin superfamily that functions as an immune checkpoint, that when expressed on the surface of T helper cells, transmits an inhibitory signal to T cells when bound to CD80 or CD86 on the surface of antigen-presenting cells.56 A phase II trial for patients with pretreated metastatic gastric and esophageal adenocarcinomas showed no objective response rates when treated with tremelimumab. Despite this, duration of response in a small select group of patient was encouraging.57

There are limited data to show that combination immunotherapy is more effective than monotherapy. A phase I/II study combining ipilimumab and nivolumab led to durable responses and long-term OS in heavily pretreated patients with advanced gastric, esophageal, and GEJ cancer.58 There are ongoing studies of combination therapy with mogamulizumab, a humanized monoclonal antibody–targeting chemokine receptor, and nivolumab in advanced upper GI cancers.59,60 Additional ongoing studies in patients with metastatic upper GI cancers include the combination of LAG525, which targets LAG-3, and spartalizumab, an anti–PD-1 combination.61 Furthermore, tremelimumab and durvalumab, a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of PD-L1 with PD-1 and CD-80, are also being studied.62

Historically, chemotherapy and radiation therapy have been used in different stages of upper GI cancers. In metastatic upper GI cancers, chemotherapy provides response rates of 35% to 40%, with median survival benefit of 9 to 11 months. Radiation therapy has been used in locally advanced disease as well as palliatively in patients with metastatic disease. With modest benefit seen in the treatment of metastatic disease with chemotherapy, the most logical step was to study immunotherapeutics. Despite some preclinical promise, the clinical benefit of in upper GI cancers has been modest and has not been proved to be superior to chemotherapy. Knowing that chemotherapy has proven benefit, trials have now begun to look at combining chemotherapy with immunotherapy and/or radiation therapy.

The scientific rationale for the use of chemotherapy combined with immunotherapy is based on preclinical data suggesting that cytotoxic agents may act as immunomodulatory agents through tumor antigen presentation. This leads to an upregulation of the expression of tumor antigens and major histocompatibility complex class I molecules, to which the antigens bind. Through an alternative pathway, chemotherapy may also upregulate costimulatory molecules such as B7-1 or downregulate coinhibitory molecules such as PD-L1/B7-1H or B7-H4 expressed on the tumor cell surface. In doing so, this enhances the strength of effector T-cell activity, preferential depletes regulatory T cells, and liberates homeostatic or inflammatory cytokines.63-66 Chemotherapy may also render tumor cells more sensitive to T cell–mediated lysis through fas-, perforin-, and granzyme B–dependent mechanisms.67,68

Using this understanding, clinical trials have begun studying the use of combination chemotherapy with immunotherapy in upper GI cancers. A phase III clinical trial is currently evaluating the use of nivolumab and ipilimumab, nivolumab combined with fluorouracil and cisplatin, or fluorouracil and cisplatin alone.69,70 Primary endpoints of this study include progression-free survival and OS in previously untreated patients with advanced unresectable, recurrent, or metastatic esophageal squamous cell carcinoma. There are ongoing trials of pembrolizumab alone or in combination with chemotherapy versus chemotherapy alone in first-line gastric or GEJ adenocarcinoma70 as well as in the neoadjuvant and adjuvant setting.71 Another phase I/II study will evaluate the safety of durvalumab in combination with oxaliplatin/capecitabine in the metastatic setting.

RT is a key modality in treating many esophageal cancers. Like chemotherapy, radiation has been found in preclinical models to have immunomodulatory effects through different mechanisms, including the creation of neoantigens, increased expression of proinflammatory cytokines capable of activating leukocytes, as well as upregulation and recruitment of immune cells into the tumor microenvironment.72,73 PD-L1 has been reported to be upregulated in the tumor microenvironment after ionizing radiation in mice.74 This increased PD-L1 expression suppresses the antitumor properties of effector T cells, providing a rational combination of immunotherapy and RT.

Using preclinical models,63,75,76 combination RT and immunotherapy has received limited study. Previous small retrospective series have shown acceptable tolerability and some enhanced response rates with combined immunotherapy and RT in different disease subtypes.77,78 On the basis of these data, clinical trials are ongoing in upper GI cancers. Pembrolizumab combined with RT is being studied in metastatic esophageal79 as well as in advanced cancers of the stomach and GEJ.80 In the neoadjuvant setting, pembrolizumab, durvalumab, nivolumab, and ipilimumab are being studied in addition to chemoradiation.81-83

Finally, the discovery of tumor-associated antigens provide specific targets for new immunotherapies, including using these tumor-associated antigens in cell-based therapies by developing autologous T cells that specifically target these antigens in patients whose tumors express them. Two common tumor-associated antigens that are known to be expressed in esophageal cancers are melanoma-associated antigen 3 and NY-ESO-1. In 2017, Lu et al84 addressed 17 patients with metastatic cancer who were treated with a major histocompatibility complex class II–restricted T-cell receptor targeting the cancer germline antigen melanoma-associated antigen 3. Patients received a schedule based on a lymphodepleting preparative regimen, followed by adoptive transfer of purified CD4+ T cells retrovirally transduced with melanoma-associated antigen 3 TCR plus a systemic high dose of interleukin-2. Among nine patients who were treated at the highest dose level, objective partial responses were observed in a patient with esophageal cancer (duration 4 months).84 Ongoing trials will hopefully shed light on the best combinations using immunotherapy, chemotherapy, and/or radiation and the optimal doses and schedules.


The complex PI3K/Akt/mTOR pathway has an important role in different cellular mechanisms, such as cell growth, cell proliferation, protein translation, and metabolism. Dysregulation of this pathway, which involves many different tyrosine kinases, is frequently observed in many tumors and has led to the development of many targeted therapies in this pathway that have been tested in different solid tumors, including gastric cancer.85 In a TCGA report, 80% of EBV tumors and 42% of MSI tumors have PIK3CA mutations, suggesting that this pathway is a possible target for new treatments in gastric cancer.

The GRANITE phase III clinical trial, testing everolimus for previously treated advanced gastric cancer, failed to improve survival; however, PIK3CA mutations were not tested, and thus, patients were not selected or assessed for PIK3CA.34 Targeting the PIK3CA pathway in only mutated patients might be a promising biomarker for future assessment in patients with gastric cancer. Some AKT inhibitors, such as afuresertib and AZD5363, are also being tested in gastric cancer, and the results are forthcoming.5


The high relevance of new blood vessels for cancer growth and survival is well known.86 VEGF, a protein with different isoforms, is a stimulator of endothelial cell growth that is highly expressed in different solid tumors, particularly in necrotic or hypoxic areas. Overexpression of angiogenic markers is associated with more aggressive disease; thus, these markers are potential targets in gastric cancer therapy.

Bevacizumab is an anti-VEGF antibody widely used in different solid tumors, such as colorectal, ovarian, breast, and lung cancer,85,87 but it still did not demonstrate a clinical benefit in gastric cancer. The AVATAR and AVAGAST phase III clinical trials failed to demonstrate the clinical benefit of bevacizumab in advanced gastric or GEJ cancer.29,30 However, ramucirumab, a fully human monoclonal antibody potent against VEGFR-2, demonstrated benefit in the second-line treatment of advanced gastric cancer following the REGARD26 and RAINBOW25 phase III clinical trials. In the REGARD trial, ramucirumab monotherapy versus best supportive care significantly increased OS in second-line treatment of advanced gastric or GEJ adenocarcinomas. The median OS was 5.2 months (interquartile range, 2.3–9.9 months) in patients in the ramucirumab and 3.8 months (interquartile range, 1.7–7.1 months) in those in the placebo group (HR 0.776; 95% CI, 0.603–0.998).26 In the RAINBOW trial, ramucirumab with paclitaxel increased progression-free survival and OS compared with placebo plus paclitaxel. OS was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median, 9.6 months [95% CI, 8.5–10.8 months] vs. 7.4 months [95% CI, 6.3–8.4 months]; HR 0.807; 95% CI, 0.678–0.962).25

The TKI apatinib inhibits VEGFR-2 and demonstrated efficacy and safety in phase II and III clinical trials in patients with chemotherapy-refractory advanced or metastatic gastric cancer, becoming a possible treatment in third- or further-line therapies.88 Despite previous positive results in trials, there are some concerns regarding the clinical benefit of ramucirumab and apatinib in gastric cancer. There is a marginal benefit of afatinib (1.8 months) and ramucirumab (1.4–2.2 months), but hopefully, further research on biomarkers, combination therapies, sequencing, or maintenance therapies might bring more substantial results for targeting VEGF in gastric cancer.89,90


PARPs are a group of enzymes that catalyze the transfer of ADP-ribose to different intracellular proteins.91 PARPs are relevant in many cellular processes, such as transcription, replication, recombination, and DNA repair.92 Their role in DNA repair is particularly relevant because certain tumors defective in homologous recombination mechanisms may rely on PARP-mediated DNA repair for survival and are sensitive to its inhibition.93 PARP inhibition already has an important role in BRCA-associated breast and ovarian cancers and might have additional importance in other cancers, such as gastric adenocarcinoma.94 Higher PARP-1 expression can be found in gastric cancer, and that might be related to more advanced disease and worse prognosis.

After some promising results in a phase II clinical trial, in the GOLD phase III clinical trial, the PARP inhibitor olaparib did not significantly increase OS in patients with advanced gastric cancer, including an ataxia telangiectasia–mutated protein–negative population.33 In some trials, statistical methods (such as a statistically significant p value < .025) and the lack of BRCA biomarker stratification could be some of the reasons for unmet outcomes. Other trials to address PARP inhibitors in gastric cancer are still ongoing. A phase I clinical trial (NCT01123876) is testing velaparib, a PARP inhibitor, with FOLFIRI in gastric cancer. A phase I/II trial (NCT03008278) is still recruiting subjects to test the effectiveness of olaparib and ramucirumab (an anti-VEGFR-2 antibody) in treating patients with metastatic or locally recurrent gastric cancer or GEJ cancer that cannot be removed by surgery. Novel combinations and possible biomarker tailoring are challenging issues that might result in changes in clinical practices in the near future.


Fibroblast growth factors are a family of proteins that interact with four tyrosine kinase transmembrane receptors (FGFRs).95 FGFRs are downstream of different intracellular signaling pathways, including RAS-MAPK, PI3K-AKT, and STAT, and thus regulate different cellular processes, such as proliferation, survival, migration, differentiation, and metabolism.36,95 Interference in this pathway, such as gene amplification, chromosomal translocation, or mutations, is associated with tumor initiation, survival, proliferation, and invasion, particularly in diffuse-type cancers such as gastric cancer.96

To date, there are 11 trials registered at targeting FGFR in gastric cancer. In the phase II SHINE trial, AZD4547, an FGFR2 TKI, compared with paclitaxel in patients with gastric cancer with FGFR2 amplification/polysomy failed to improve the main outcome of progression-free survival.97

Some drugs, such as dovitinib, foretinib, and pazopanib are multi-TKIs, in which inhibition includes FGFR.95 A phase II trial (NCT01719549) is testing the multi-TKI dovitinib in gastric cancer with FGFR2 amplification. Another phase II trial (NCT01921673) is evaluating the role of dovitinib plus docetaxel as second-line chemotherapy in patients with metastatic or unresectable gastric cancer. Both trials are completed, but the results have not yet been published. It is not yet known if targeting only one FGFR will have positive results in gastric cancer, but there might be a place for multi-TKIs that inhibit FGFR along with other kinase pathways.

Currently, the treatment of advanced EGC is still a challenge for oncologists and patients worldwide. EGC is different from other types of tumors, such as lung, prostate, and melanoma, because it lacks extensive, innovative, and effective options based on driver mutations and immunotherapy. Only HER2 expression is validated as a predictive biomarker, which could help tailor patient treatment. To date, only trastuzumab and ramucirumab are well established for the treatment of advanced EGC. More recently, nivolumab showed a modest benefit in later lines of advanced EGC in the ATTRACTION-2 study.54 Novel molecular classifications such as proposed by TCGA and the ACRG will benefit the identification of potential biomarkers that might help the development of new target therapies, the design of new clinical trials, and retrospective subanalysis of completed trials. In HER2 amplification tumors, VEGF, PARP, EGFR, PIK3CA, and FGFR are promising pathways that could be sources of novel target drugs in the near future. However, more extensive translational and clinical studies are warranted to optimize these approaches.

All authors contributed equally to this manuscript.

© 2018 American Society of Clinical Oncology

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to

Ramon Andrade De Mello

Honoraria: AstraZeneca, Novartis

Consulting or Advisory Role: Pfizer, Zodiac

Speakers' Bureau: AstraZeneca

Travel, Accommodations, Expenses: Amgen, AstraZeneca, Merck, Pierre Fabre, Roche

Luis Castelo-Branco

No relationship to disclose

Pedro Castelo-Branco

No relationship to disclose

Louis Vermeulen

No relationship to disclose

Matthew Salzberg

No relationship to disclose

Sofia Palacio

No relationship to disclose

A. Craig Lockhart

No relationship to disclose

Daniel Humberto Pozza

No relationship to disclose

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DOI: 10.1200/EDBK_198805 American Society of Clinical Oncology Educational Book 38 (May 23, 2018) 249-261.

PMID: 30231398


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