Key points

Introduction

As this issue of Hematology/Oncology Clinics of North America has outlined, there have been many advances in understanding the molecular underpinnings of gastric and esophageal cancer and how these cancers are now managed. However, despite the many advances in the management of gastric and esophageal cancers discussed herein, the reality remains that most patients diagnosed with gastric or esophageal cancer will ultimately die of their disease, most living for less than 1 year once their disease has metastasized. In countries apart from Japan and Korea, for example, those without an active gastric cancer screening program, most patients with gastric and esophageal cancer will be diagnosed with locally advanced or metastatic disease. Patients with locally advanced disease are more likely to have micrometastatic disease that results in higher rates of recurrence, usually within 2 years, following resection of the primary disease. These sobering data likely explain some of the differences in the epidemiology and natural course between cancers identified on screening and sporadic gastric cancers. Indeed, in the United States, the fatality/case ratio for gastroesophageal cancers is 0.66, suggesting that approximately two-thirds of newly diagnosed patients will have metastatic disease at some point during the course of their illness and will require systemic therapy.

Many drugs are considered active in the treatment of gastric and esophageal cancer, including platinum (cisplatin and oxaliplatin), fluoropyrimidines, irinotecan, taxanes, and targeted therapies (ie, trastuzumab and ramucirumab). It is compelling that we have approval of 2 new targeted antibody approaches to the disease in the past several years. However, despite the many treatment options available, median survival for advanced gastric cancer remains 8 to 10 months for most patients. There are several areas where the author thinks that advances can possibly alter these harsh realities.

Introduction

As this issue of Hematology/Oncology Clinics of North America has outlined, there have been many advances in understanding the molecular underpinnings of gastric and esophageal cancer and how these cancers are now managed. However, despite the many advances in the management of gastric and esophageal cancers discussed herein, the reality remains that most patients diagnosed with gastric or esophageal cancer will ultimately die of their disease, most living for less than 1 year once their disease has metastasized. In countries apart from Japan and Korea, for example, those without an active gastric cancer screening program, most patients with gastric and esophageal cancer will be diagnosed with locally advanced or metastatic disease. Patients with locally advanced disease are more likely to have micrometastatic disease that results in higher rates of recurrence, usually within 2 years, following resection of the primary disease. These sobering data likely explain some of the differences in the epidemiology and natural course between cancers identified on screening and sporadic gastric cancers. Indeed, in the United States, the fatality/case ratio for gastroesophageal cancers is 0.66, suggesting that approximately two-thirds of newly diagnosed patients will have metastatic disease at some point during the course of their illness and will require systemic therapy.

Many drugs are considered active in the treatment of gastric and esophageal cancer, including platinum (cisplatin and oxaliplatin), fluoropyrimidines, irinotecan, taxanes, and targeted therapies (ie, trastuzumab and ramucirumab). It is compelling that we have approval of 2 new targeted antibody approaches to the disease in the past several years. However, despite the many treatment options available, median survival for advanced gastric cancer remains 8 to 10 months for most patients. There are several areas where the author thinks that advances can possibly alter these harsh realities.

Disease prevention

Gastric cancer is responsible for approximately 952,000 new diagnoses (6.8% of new cancer cases worldwide) and 723,000 deaths annually (8.8% of total). In the United States in 2009, an estimated 21,130 new cases (14th most common) of gastric cancer were diagnosed with 10,620 deaths (13th most common). In Europe, gastric cancer ranks fifth with an estimated 159,900 new cases per year in 2006 and 118,200 deaths (fourth most common cause of cancer-related death). Nearly two-thirds of all cases globally occur in developing countries in Eastern Europe, South America, and Asia, with 42% of all new cases developed in China alone.

Gastric cancer is a heterogeneous disease with several established risk factors (summarized by Shah ). Gastric cancer subtypes (proximal nondiffuse, diffuse, and distal nondiffuse) defined by these risk factors have been molecularly classified as unique entities. The most relevant hereditable causes of gastric cancer include constitutional mutations in CDH1 (causing hereditary diffuse gastric cancer ) and DNA repair enzyme deficiency in Lynch syndrome. Individuals carrying a CDH1 mutation have an 80% lifetime risk of developing gastric cancer and are, therefore, recommended to undergo a risk-reducing prophylactic gastrectomy. However, environmental or modifiable factors are also major contributors to the development of this disease. For example, in a study of cancer risk in monozygotic and dizygotic twins, the estimated proportion of nonshared environmental factors contributing to gastric cancer risk is 62%, whereas the contribution from heritable risk is estimated at only 28%.

The most significant environmental risk factor is infection with Helicobacter pylori , a gram-negative bacillus identified in 1983 as the pathogen responsible for gastric ulcers and peptic ulcer disease. H pylori is the most common chronic bacterial pathogen in humans, with a high prevalence in both developing and industrialized countries. In 1994, the World Health Organization and the International Agency for Research on Cancer consensus group classified H pylori as a class I carcinogen. Notably, however, less than 1% of infected patients develop gastric cancer during their lifetime. The bacterium is present in the stomachs of at least half of the world’s population and is usually acquired in childhood. When left untreated, the pathogen generally persists for the individuals’ lifetime. Therefore, exposure to H pylori is chronic and long-standing. This long latency period between infection and the development of malignancy may provide an opportunity to impact on the development of the disease by possibly providing opportunity to intervene to prevent progressive accumulation of cell damage. Understanding the mucosal microenvironmental changes that lead to carcinogenesis will be a key factor in identifying who may benefit from screening programs. In this regard, the microbiome of the stomach and its impact on mucosal immunity are areas that will come to the forefront as we think about improving are strategies for disease prevention.

Molecular classification of disease

Understanding disease subtypes to improve enrichment strategies for targeted therapy will be another transformative area in managing gastric and esophageal cancers. The Cancer Genome Atlas analysis has defined 4 major subtypes of gastric cancer. Chromosomal instability and mismatch repair subtypes are two major classes of gastric cancer that may be related to H pylori infection. The other important subtypes of gastric cancer include genomically stable and Epstein-Barr virus (EBV) subtypes of gastric cancer. Each subtype is molecularly unique, with implications for drug development.

Gastric cancers with chromosomal instability are associated with TP53 mutation with receptor tyrosine kinase (RTK)-RA + Sarcoma oncogene homologue (RAS) activation. This subtype of gastric cancer is most closely related to the intestinal subtype. The high rate (∼70%) of TP53 mutations is associated with a high level of somatic copy number variations identified in both focal gene regions as well as at the chromosomal level. The RTK-RAS mutations may offer another opportunity to target. Specifically, it has been demonstrated in other tumor models that high-dose ascorbate may preferentially target RAS-driven tumors.

The EBV type is reported to represent around 10% of gastric cancers and harbors a higher prevalence of DNA hypermethylation than the other subtypes, likely specifically related to EBV infection. This subtype has a high prevalence (∼80%) of mutations in PIK3CA , overexpression of programmed death ligand 1 (PD-L1) and PD-L2, EBV-CpG island methylator phenotype (CIMP) expression, and CDKN2A silencing, as well as altered cytokine signaling.

Patients with microsatellite instable gastric cancer present at an older age; their tumors exhibit moderate genomic hypermutation, gastric CIMP, MLH1 silencing, and varying mitotic pathways. This subtype, as a consequence of defective mismatch repair due to MLH1 silencing secondary to promoter hypermethylation, has a significantly greater number of mutations per megabase than other types of gastric cancer. This circumstance would predict increased efficacy with checkpoint inhibitor immunotherapy ; however, there is no consensus on the definition of microsatellite instability in gastric cancer at this time. A detailed discussion of immunotherapy in gastroesophageal cancers is provided in Drs Adrian G. Murphy and Ronan J. Kelly’s article, “ The Evolving Role of Checkpoint Inhibitors in the Management of Gastroesophageal Cancer ,” in this issue.

Finally, the genomically stable gastric cancer subtype is enriched for Lauren’s diffuse histology, CDH1 and RHOA mutations, cell adhesion, and Claudin-18 – Rho GTPase-activating protein 1 ( CLDN18 -ARHGAP) fusion. Germline mutations in CDH1 are responsible for the genetic predisposition syndrome, hereditary diffuse gastric cancer (HDGC). The lifetime risk of developing HDGC for a CDH1 mutation carrier has recently been estimated at 70% (95% confidence interval [CI], 59%–80%) for men and 56% (95% CI, 44%–69%) for women, and the risk of breast cancer for women was 42% (95% CI, 23%–68%) similar to the risk of developing breast cancer in women who carry some BRCA mutations. Because the risk is so high, prophylactic gastrectomy is recommended by the International Gastric Cancer Linkage Consortium after 20 years of age for people who are known CDH1 mutation carriers. Increased awareness of genetic predisposition syndromes will improve patient outcomes in this disease, though the impact is likely to be low, given that an estimated only 10% to 15% of gastric cancers are thought to be related to a constitutional gene mutation. Another identifiable, and potentially targetable, mutation in the genomically stable gastric cancer subtype is the CLDN18-ARHGAP6 or 26 fusion. This fusion further strengthens the implication of alterations in Rho signaling and the significance of cell adhesion in this subtype of gastric cancer because CLDN18 is involved in intercellular tight junctions and ARHGAP26 is a GTPase-activating protein that activates Rho signaling by facilitating the conversion of Rho GTPases to the GDP state. As reported in Drs Gayathri Anandappa and Ian Chau’s article, “ Emerging Novel Therapeutic Agents in the Treatment of Patients with Gastroesophageal and Gastric Adenocarcinoma ,” in this issue, CLDN18.2 inhibition is a promising new target in treating gastric cancer.

The characterization of gastric cancer into specific disease subtypes is the beginning of the application of precision medicine to gastric and esophageal cancers. It is anticipated that, with improving our ability to subgroup gastric cancer in real time, and by using these data to direct treatment, we will make significant strides in improving patient outcomes.