Overview

The stomach is an organ that is part of the gastrointestinal system. It has a variety of functions, including digestion, and is part of the innate immune system. The stomach produces enzymes to digest the food that it temporarily stores before it passes into the intestines.  It also produces hydrochloric acid to kill pathogens that have entered the body after eating or drinking. ¹

The majority of cells in the stomach produce mucus, and the most common stomach cancer, stomach adenocarcinoma, usually arises from mucus-producing cells. This article will explore how stomach cancer can arise and the mechanisms by which therapeutic targets can mitigate this disease.

What is stomach cancer?

There are two main types of stomach cancer (gastric cancer): the “intestinal type”, which comprises 70% of gastric adenocarcinomas, and the “diffuse type”, which is characterised by the disruption of the stomach’s glands. 

The intestinal type is mainly a product of chronic gastritis. High-salt diets or bacteria such as H. pylori can lead to chronic gastritis, which in turn can cause the death of the most common type of cell in the stomach - parietal cells. As a result, there is less hydrochloric acid produced in the stomach, leading to chronic atrophic gastritis (CAG). CAG initiates chronic inflammation in the stomach, which worsens cells within CAG-affected tissue, causing cancer.²

Causes and risk factors for stomach cancer:³

There is no single cause for each individual’s case of stomach cancer. However, there are several risk factors that can aggravate the health of your stomach and contribute to the risk of developing stomach cancer:³

• High salt diets
• Smoking
• Obesity
• Radiation exposure
• H. pylori infection
• Increased calorie consumption
• Gastritis
• Alcohol use
• Family history (for diffuse-type gastric adenocarcinoma) 
• Lack of exercise
• Advanced age

Signs and symptoms of stomach cancer⁴

• Abdominal pain
• Problems swallowing
• Nausea
• Unexpected weight loss
• Fatigue
• Vomiting
• Indigestion

These symptoms are nonspecific, which decreases the likelihood that medical testing would be prompted. Consequently, around 60% of patients are not suitable for treatment due to late diagnosis or other comorbidities. Therefore, it is important that you know these symptoms, schedule regular check-ups with your doctor, and maintain a healthy lifestyle to catch potential issues early and lower your risk.⁴

Current standard treatments for stomach cancer

Gastrectomy

The most common treatment for stomach cancer is surgery, gastrectomy. A total gastrectomy refers to the removal of the entire stomach,  the nearby lymph nodes and other tissues near the tumour, to control the cancer and lower the chance of the cancer returning. The oesophagus is then attached to the small intestine, but the patient must eat smaller and more nutritious meals.

A subtotal gastrectomy is when the part of the stomach that contains cancer is surgically removed, along with lymph nodes and other tissues near the tumour. The spleen can also be removed (splenectomy).⁵

Radiation therapy

This treatment method aims to damage the DNA of cancer cells so that they cannot replicate and function. It can also be used to damage the blood supply to the tumour, preventing it from receiving adequate nutrients to continue to grow. In a study of stomach cancer patients, 20% of patients who received this treatment alongside surgery lived for over 10 years, compared to 13% of patients in another group who only had surgery.

However, this is an intense procedure and causes side effects such as fatigue, nausea, and changes in appetite and bowel function.⁶

Chemotherapy

This attempts to attack cancer cells directly by targeting specific proteins that allow cancer cells to evade the immune system. However, the toxicity of this drug often causes healthy cells to be destroyed too, causing patients to experience side effects such as hair loss, weight loss, and diarrhea.⁷

Targeted therapies

This treatment strategy allows for a more personalised approach to each patient. Molecular profiling and biomarker testing is required to validate particular mutations which are associated with stomach cancer. By targeting the specific mutations which are driving cancer, the patient can be given medicine that prevents further tumour growth. This increased precision enables a substantial anti-tumour response and can minimise toxicity to normal tissues. Furthermore, targeted therapies can be administered in combination with surgery or radiotherapy to further increase overall survival.

Trastuzumab

All chemotherapy candidates must have their tumour checked for the overexpression of HER2, a protein that is frequently expressed in several cancers to cause uncontrolled cell growth. This allows for a more personalised treatment, such as trastuzumab, which has proven to significantly increase the survival of gastric cancer patients, minimising the risk of death by 26%. This drug binds to HER2 proteins to prevent cancer cells from growing and stimulates the patient’s immune system to destroy the cancer cells.⁸

Ramucirumab

This drug, like trastuzumab, is also approved for use on its own or in combination with chemotherapy for gastric cancer patients. This drug aims to bind to VEGFR-2, a receptor that is stimulated on cancer cells to increase their proliferation and survival. Ramucirumab therefore reduces the ability of cancer cells to stimulate new blood vessel formation (angiogenesis), weakening the tumour’s growth. This drug has demonstrated significant use, reducing the risk of disease progression or death by 52%. ⁹

Nivolumab

Some cancer cells can overexpress PD-L1, a protein that binds to its receptor on immune cells. Normally, this process occurs in healthy cells to prevent the immune system from attacking your own body. However, cancer cells can also acquire this behaviour, allowing them to evade the immune system. The role of Nivolumab is to bind to PD-1 on immune cells, activating them to attack cancer cells while also preventing those cancer cells from evading the immune system by interfering with immune cell interactions. While this treatment has been shown to be successful for other types of cancer, a study found that a 4-year survival rate was just 17% combined with chemotherapy. ¹⁰

https://www.onclive.com/view/updated-checkmate-649-data-reinforce-nivolumab-plus-chemo-as-frontline-soc-in-advanced-gastric-cancers

Summary

Gastric cancer remains one of the leading causes of cancer deaths worldwide but is mainly associated with lifestyle factors such as diet, obesity, and smoking. Maintaining a healthy lifestyle reduces the risk of developing this disease and can favour a better prognosis. 

It is important to see a doctor as soon as possible if you experience abdominal pain, nausea or weight loss, since late diagnoses comprise ~60% of patients, which contributes to an unfavourable prognosis. 

Standard treatment, including surgery, radiation therapy and chemotherapy, can improve survival rates but are accompanied by adverse effects. 

Targeted therapies allow for precision medicine and can significantly improve the survival rates of patients, but are mainly used in patients who have advanced cancer. This reinforces the importance of attending regular screenings for early detection.