Esophageal cancer

Esophageal cancer is cancer of the esophagus, the tube that moves food and liquid from the throat to the stomach. Esophageal cancer has two main types: adenocarcinoma and squamous cell carcinoma. These two types of esophageal cancer are categorized based on their histology or microscopic anatomy. Adenocarcinoma and squamous cell carcinoma also differ in epidemiology and the location of the esophagus from which they typically arise. Adenocarcinoma begins in cells of mucus-secreting glands and usually occurs in the lower part of the esophagus. Squamous cell carcinoma begins in squamous cells, which are flat, thin cells lining the surface of the esophagus and usually develops in the upper and middle parts of the esophagus. Worldwide, squamous cell carcinoma is the most prevalent esophageal cancer. In the United States, adenocarcinoma is the most prevalent type of esophageal cancer and affects mostly white men. Other rare types of esophageal cancer include small-cell carcinoma, sarcoma, lymphoma, melanoma, and choriocarcinoma.

• Pain or difficulty swallowing

• Weight loss

• Pain behind the breastbone

• Hoarseness and cough

• Indigestion and heartburn

• A lump under the skin

Esophageal cancer has a five-year survival above 20% in some parts of the world. High mortality for this cancer is due to typical late diagnosis after the cancer has advanced or metastasized. At diagnosis, only 18% of esophageal cancers are confined to the primary site, and in 40% of cases, there is distant metastasis. Surgery alone has led to poor outcomes due to complex anatomy and high rates of recurrence.

When esophageal cancer is minimally invasive, surgery offers a potential cure. Multimodal therapy involving surgery, chemotherapy, and radiation is the standard care.

Targeted therapy options for esophageal cancer include human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and phosphoinositide 3-kinase mammalian target of rapamycin (PI3K/mTOR).

Pembrolizumab (Keytruda) and Nivolumab (Opdivo) are immunotherapy drugs used to treat esophageal cancer. Pembrolizumab is given as a first-line treatment along with the chemotherapy drugs cisplatin and fluorouracil in patients with locally advanced or metastatic ESCC or EAC tumors at the gastroesophageal junction that are HER-2 negative. Nivolumab may be given if cancer remains after neoadjuvant therapy with chemoradiation and surgery or in combination with cisplatin and fluorouracil or carboplatin and fluorouracil for advanced or metastatic AEC or tumors at the gastroesophageal junction.

At the time of esophageal cancer diagnosis, patients have dysphagia (difficulty swallowing) and have typically lost more than 10% of body weight. 79% of patients with esophageal cancer develop malnutrition. People with esophageal cancer that have trouble swallowing can benefit from a soft diet of high-protein and high-calorie foods if they have trouble maintaining normal weight.

When recovering from surgery, a feeding tube may be used to help patients get sufficient nutrients. A feeding tube can go through the nose to the stomach or through the skin into the stomach or small intestine. Nutrition given by intravenous (IV) drip, called parenteral nutrition, may be given after surgery to deliver proteins, fats, and vitamins.

Incidence of esophageal cancer varies greatly between regions of the world with a 56-fold difference in age-standardized incidence rate between Malawi, Southeastern Africa with the highest rate of 18.7 per 100,000 people and Guinea, West Africa with the lowest rate of 0.42 per 100,000. The incidence rate reported for Eastern Asia was 12.2 per 100,000, compared with 5.5 per 100,000 in Northern Europe. The worldwide incidence rate of esophageal cancer is 9.3 per 100,000, and in the US it is 5.6 per 100,000.

The incidence of esophageal cancer was estimated to be 3.2% of all cancer diagnoses. About 87% of cases are esophageal squamous cell carcinoma (ESCC), and 11% are esophageal adenocarcinoma (EAC) globally. In the US, the distribution is 31% ESCC and 64% EAC. Among histology-confirmed cases of esophageal cancer in the US, 85% of affected individuals were reported to be Caucasian. Caucasians accounted for 94% of esophageal adenocarcinomas (EAC) and 66% of esophageal squamous cell carcinomas (ESCC) in the US.

The Asian Esophageal Cancer Belt refers to a geographical region that includes Iran, parts of China, Turkey, and Kazakhstan with a high incidence of ESCC. EAC is the more common form of esophageal cancer in North America and Europe. The incidence of ESCC has decreased with improvements in diet and drinking water, but EAC has increased in over recent decades in economically well-developed countries.

Esophageal cancer has a higher incidence in men than women, with 70% of esophageal cancers worldwide occurring in men. Men have a three to four times greater risk than women for developing ESCC and a seven to ten times higher risk for developing EAC. 60% of esophageal cancers occur in people older than sixty-five years of age. The incidence rate increase with age for both men and women.

While gastroesophageal reflux disease (GERD) and Barrett’s esophagus increase the risk of EAC, ESCC is more strongly related to environmental risk factors, such as smoking, alcohol consumption, and zinc deficiency. Other risk factors for esophageal cancer are listed below.

• Chronic inflammation in the esophagus

• Heavy alcohol use (for ESCC)

• Barrett’s esophagus (for EAC)

• Tobacco smoking or chewing

• Obesity is associated with an increased risk of EAC

• Obesity is associated with a reduced risk of ESCC

• Low income

• Deficiency of vitamins A, C, and zinc

• Hot drinks

• Infections such as human papillomavirus

• Esophageal diseases
• Family history of lung, prostate, breast, cervical, oral, and pharyngeal cancers
• Family history of hiatal hernia (EAC)
• Consumpton of red, salty, or processed meat (ESCC)

The risk of esophageal cancer is 0.5% per year in patients with Barrett’s esophagus. Barrett’s esophagus is a complication of gastroesophageal reflux disease (GERD) in which the lining of the esophagus changes to resemble that of the lining of the intestine. The normal squamous epithelium changes to a columnar-lined intestinal metaplasia. Barrett’s esophagus is a precancerous condition, meaning it has abnormal cells that have an increased risk of becoming cancerous.

Chronic inflammation in the esophagus disrupts cell signaling and growth. Exposure to environmental factors can contribute to chronic inflammation, which can lead to epithelial cell transformation in both types of esophageal cancer. Smoking causes tissue damage and inflammation. Chronic exposure of the distal epithelium to stomach and bile acids can trigger inflammation and Barrett’s esophagus (intestinal metaplasia), which can lead to the development of EAC. Acid reflux can cause esophageal injury directly or secondary to the recruitment of inflammatory cells to the site in the response to damage. Inflammatory cells can cause the generation of reactive oxygen species (ROS) that can damage tissues and cells. Inflammation induces cell growth and invasion, mutagenesis, and angiogenesis and may also suppress immune function. Persistent stimulation of inflammation can lead to tumor formation.

The following genetic mutations are common in esophageal cancer.

• TP53 mutations

• EGFR overexpression

• CCND1 overexpression

• CDK4/CDK6 overexpression

• MDM2 overexpression

• CCNE1 amplification

• MGST1 mutation

High intake of fruit and vegetables was shown to be protective against ESCC and EAC, which is thought to be due to antioxidant properties. Antioxidants from fruits and vegetables are thought to help reduce oxidative stress and inflammation. Folate and Vitamin C have been shown to reduce the risk of esophageal cancer, and there is evidence that high-fiber diets reduce the risk of esophageal cancer.

Evidence from clinical studies and animal research shows that zinc is important for the health of cells on the surface of the esophagus that make up the esophageal epithelium. Zinc deficiency causes abnormal cell proliferation of esophageal cells, which promotes tumor development. Zinc performs many functions. Zinc is a cofactor of more than 300 enzymes, plays a role in protein 3-dimensional structure, and modulates the functions of L-type Ca 2+ and K+ ion channels. Zinc may also cross-communicate with Ca2+ signaling pathways.

The store-operated Ca2+ entry (SOCE) channel, Orai1, shows increased expression in tumor tissue from patients with ESCC with poor prognosis. Increased expression of Orai1 contributes to hyperactive intracellular Ca2+ oscillations and faster cell proliferation of human ESCC cells. Zinc supplementation was shown to inhibit the proliferation of ESCC cell lines through the inhibition of Orai1-mediated SOCE. Non-tumorigenic esophageal epithelial cells and ESCC cells with Orai1 knocked down showed less sensitivity to zinc treatment.

Chemoprevention is the use of substances to prevent cancer from developing. Chemoprevention can be used to lower a person’s risk of developing cancer in people with an inherited cancer syndrome or a family history of cancer. People that have had cancer may take chemoprevention agents to lower the risk of cancer recurrence. Research is ongoing for the use of aspirin and acid-reducing medications for the prevention of EAC in people with Barrett’s esophagus.

Proton pump inhibitors (PPI) decrease stomach acid secretion by inhibiting H+/K+ATPase. PPI treatment is associated with a decreased risk of high-grade dysplasia and adenocarcinoma in clinic-based cohort studies for patients with Barrett’s esophagus. However, there is some evidence that prolonged PPI use, causing increased gastric pH associated bile salt toxicity, may promote progression to EAC. High-dose PPI was shown to protect against the composite endpoint of all-cause mortality, esophageal adenocarcinoma, and grade-dysplasia in the AspECT randomized trial. The group in the study who took high-dose PPI with aspirin showed the strongest benefit.

Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductases designed to treat lipid disorders such as hypercholesterolemia to prevent heart disease. Statins have been shown to have anti-tumor properties with a preventative role in esophageal cancer. Statins have been shown to have an inhibitory effect on the growth of human esophageal adenocarcinoma cells in culture. Statin use prior to diagnosis of esophageal cancer was found to be associated with a 19% decrease in cancer-specific mortality. A UK-based cohort study found benefits of statin use after diagnosis of esophageal cancer on esophageal cancer-specific mortality and all-cause mortality for EAC but not ESCC. A meta-analysis found that statin use reduced all-cause mortality and cancer-specific mortality by 16% in esophageal cancer patients.

The microbiome of the esophagus can be classified into the type I microbiome, which are mainly Gram-positive bacteria, and the type II microbiome, which is enriched with Gram-negative bacteria. The type I microbiome is more associated with a normal esophagus and type II with an abnormal esophagus. Acidic gastric juice can convert the type I microbiome into the abnormal type II microbiome through the killing of acid-sensitive bacteria.

Reflux esophagitis and Barrett’s esophagus are associated with a decrease in the abundance of Streptococcus species. A reduction in microbial diversity, decrease of Firmicutes (also known as Bacill), and increase of Proteobacteria and Lactobacillus fermentum have been reported for EAC. ESCC is associated with a reduction in Streptococcus species and an increase in Fusobacterium nucleatum. Limited research suggests that the esophageal microbiota may influence patient response to chemotherapy and surgery complications. In the future, the esophageal microbiome screen could be used for treatment decisions. Treatments such as targeted antibiotics, probiotics, or prebiotics could potentially be used to favor beneficial microbes in the esophagus.

Gram-negative bacteria contain lipopolysaccharide (LPS) as a major part of their cell walls. LPS is thought to activate an innate immune response. It is thought that an altered microbiome in Barrett’s esophagus could trigger chronic inflammation. The shift toward gram-negative bacteria has been reported to lead to LPS-mediated inflammation through Toll-like receptor-4 (TLR-4) and NF-κB. The shift to gram-negative bacteria is also thought to cause relaxation of the esophageal sphincter and increased reflux through a mechanism involving nitric oxide synthase (NOS).

• Nicotine-induced VEGF-C production
• IL-6
• STAT3
• IL-1β
• NF-kB
• dickkopf-1 protein
• claudin 18 isoform 2
• fibroblast growth factor receptor 2b
• NFE2L2/KEAP1/CUL3 pathway
• CDK4/6 inhibition
• PIK3CA inhibition

Curcumin is a plant-derived anti-NF-kB compound that inhibits the inflammatory response to bile and acid in Barrett’s esophagus and EAC.

Lactis NCC 2287 is a probiotic that improves esophageal inflammation in experimental eosinophilic esophagitis.

PVR (Poliovirus receptor) is a transmembrane protein overexpressed on cancer cells (including esophageal cancer) associated with resistance to PD-1 and PDL1 immune checkpoint inhibitors. Tumor cells that express PVR cause immune cells that interact with them to lose DNAM-1 from their surface, reducing their anti-tumor activity. NTX1088 is a monoclonal antibody developed by Nectin Therapeutics that blocks PVR and aims to restore DNAM-1 (CD226), on the surface of immune cells. The treatment is expected to increase anti-tumor activity in T cells and NK cells. The anti-PVR treatment also stimulates an anti-tumor response by preventing immune suppression through checkpoint receptors TIGIT and CD96.

Capsulomics developed a swallowable sponge sampling device for early detection of individuals with Barrett’s esophagus with a high risk of developing esophageal cancer. PCR-based epigenetic tests for esophageal cancer and Barrett’s esophagus are in development.

CDx Diagnostics sponsored Sachin Wani, MD at University of Colorado Cancer Center to test the diagnostic platform WATS3D, Wide-Area Transepithelial Sampling with computer-assisted three-dimensional analysis. WATS3D will be compared to the standard Seattle biopsy protocol. The WATS3D system used a brush device rather than forceps and synthesized 3D images and neural network analyses, a method of AI, is used to identify abnormal cells for pathologists to assess.

Cyted is using its analysis platform together with Metronic’s cytosponge biopsy collection device to screen patients for esophageal cancer. The sponge is swallowed as a capsule and then pulled out through the mouth by string.

Lucid Diagnostics developed EsoCheck, a cell collection device, and EsoGuard, a methylated DNA test for Barrett's esophagus, a precancer condition. Lucid is a subsidiary of PAVmed. In early 2023, it was reported that Lucid would pause further development of the EsoCure Esophageal Ablation device. The device is a single-use thermal balloon ablation catheter used with a standard endoscope to allow clinicians to treat dysplastic Barrett’s Esophagus before it can progress to EAC.

Natera, a cell-free DNA testing company, tested its tumor-informed molecular residual disease (MRD) assay called Signatera in resected EAC patients, and it was shown to detect recurrence.

NinePoint Medical collaborated with the consulting firm Farm Design to develop the NvisionVLE Imaging System for evaluating the tissue of the esophagus during endoscopy. NvisionVLE uses the ultrasound technology optical coherence tomography (OCT) to generate cross-sectional scans with tissue layers at a depth of 3mm.

Proteomics International Laboratories (PIL) signed an agreement with the Australian medical research institute QIMR Berghofer for the right to use biomarkers discovered by researchers at QIMR Berghofer for a blood test to screen patients with Barrett’s esophagus for pre-cancerous cells and early-stage EAC.

EndoGastric Solutions has an FDA-approved transoral incisionless fundoplication device for the reconstruction of the valve between the stomach and esophagus.

EndoStim is a Dutch medical device start-up developing a neurostimulation device to treat GERD. The device is intended to restore long-term reflux control and esophageal function by applying neurostimulation impulses to the esophageal sphincter.

EsoCap, a company based in Switzerland, designed a drug delivery system for the esophagus, where drugs normally remain only for a few seconds. The delivery system entered clinical trials for the treatment of eosinophilic esophagitis, a condition not associated with the development of esophageal cancer. EsoCap entered a licensing agreement with Upadia to use its monoclonal antibodies to develop therapies for Barrett’s esophagus using the thin film drug delivery system. Upadia, based in the Netherlands, was founded by Professor Sheila Krishnadath, who has demonstrated that antibodies against bone morphogenetic proteins (anti-BMP antibodies) inhibit the development of Barrett’s esophagus.

Restech, a medical engineering company, markets Stretta for the treatment of GERD. Stretta uses low-power radiofrequency energy to remodel the sphincter muscle. Restech acquired Mederi Therapeutics, the company that developed Stretta.

Torax Medical developed an FDA-approved magnetic ring implant that sits at the base of the esophagus.The LINX Reflux Management System is intended to keep the esophageal sphincter closed to treat GERD. Johnson & Johnson’s Ethicon unit agreed to acquire Torax Medical in 2017.

Biostage developed a lab-grown esophageal implant comprised of a biocompatible scaffold seeded with the patient’s cells. The implant is planned to be tested in clinical trials and will be tested in patients that require six centimeters of their esophagus to be removed due to esophageal cancer, trauma, or a birth defect.

Isola Therapeutics is developing a drug delivery platform for esophageal cancer and lung cancer.