A diagnosis of gastric (stomach) or esophageal adenocarcinoma brings some questions into sharp focus. How will I treat this disease? What does my future hold?
Although these cancers are still challenging to cure, experts have made a lot of progress in treatment options over the past decade. New targeted therapies, immunotherapies, screening approaches, and clinical trials are improving outcomes.
"We’re better at treating esophageal and stomach cancer now than ever," says Anuj Patel, MD, clinical director of the Center for Esophageal and Gastric Cancer at Dana-Farber Cancer Institute. "We have more options available, better ways of tailoring treatments, and people live longer and do better now than when I started at Dana-Farber, which was only 10 years ago."
Patel discusses some of the most promising advances in the field and what the future of gastric and esophageal adenocarcinoma treatment may hold.
A Shift Toward More Personalized Treatment
Cancer care was more limited in the past. Medication options worked more generally on fast-growing cells (cancers). But as research evolves, cancer drugs are becoming more effective and precise for certain types of tumors.
"One of the most exciting things right now, for both gastric and esophageal cancer, is that we're getting better at understanding the biology of individual patients’ cancers and then tailoring our treatment towards that individual patient and their specific cancer," says Patel.
Doctors now routinely test many tumors for biomarkers, which are specific genetic changes or proteins that may help predict which treatments are most likely to work. For gastric and esophageal cancers, these markers include:
- HER2 (human epidermal growth factor receptor 2)
- PD-L1 (programmed death-ligand 1)
- MSI-H (microsatellite instability-high)
- CLDN18.2 (claudin 18.2)
This approach is called precision medicine. Rather than giving the same treatment to everyone, doctors can increasingly select therapies based on features of your tumor.
"The number of targets, as well as the number of treatments for those targets, has grown over the last few years and is continuing to grow at a good pace," says Patel.
Targeted Therapies Continue to Expand
Targeted therapies work differently from traditional chemotherapy. They’re both systemic, meaning they travel through your bloodstream to your whole body. But unlike chemotherapy, targeted therapy doesn’t attack other normal and healthy fast-growing cells such as hair follicles and bone marrow. They only attack cells with specific biomarkers.
"They often have less side effects because instead of trying to broadly kill things that are growing quickly, they block the pathways that cancer uses to grow and to spread," says Patel.
Trastuzumab (Herceptin) is a targeted treatment that targets HER2-positive cancers. About 15% to 30% of gastric and gastroesophageal junction adenocarcinomas have high levels of HER2. HER2-targeted treatment has helped improve outcomes for many people with this tumor biomarker.
The FDA has approved the targeted treatment zanidatamab-hrii (Ziihera) to treat HER2-positive cancers of the stomach, esophagus, and the area where the stomach and esophagus meet. It may be used as a first-line treatment in combination with standard chemotherapy, either with or without another drug called tislelizumab-jsgr. Zanidatamab is an antibody that targets the HER2 protein that fuels the growth of cancer cells. It stops cancer cells from growing and helps the body's immune system kill them.
Another recent milestone is the approval of zolbetuximab (Vyloy), a treatment for cancers that express CLDN18.2. Patel says these therapies generally work best when combined with chemotherapy rather than replacing it altogether.
“Chemotherapy still plays a pretty big role in the treatment of these types of cancers, but when targeted therapy is effective, it sometimes then lets us back off of the chemotherapy.”
Immunotherapy Is Improving Outcomes
Research shows that a category of drugs called immune checkpoint inhibitors works on advanced gastric and esophageal cancers. Immune checkpoints are natural "brakes" that keep your immune system from attacking healthy cells. Some cancers use these brakes to avoid being attacked. Immune checkpoint inhibitors are drugs that release the brakes, helping immune cells recognize and destroy cancer cells.
For some gastric and esophageal adenocarcinomas, immunotherapy alone can be effective. But Patel says that for most, the combination of immunotherapy plus chemotherapy is better.
Research also shows there can be a benefit to using immunotherapy earlier in treatment. For example, clinical trials showed that using the checkpoint inhibitor durvalumab (Imfinzi) to treatment regimens before and after surgery may lower your chance of cancer recurrence.
"We have found that, for people for whom the goal is surgery, adding immunotherapy to traditional chemotherapy, or sometimes radiation, before and after surgery makes treatment more effective," says Patel. “A lot of what we're trying to figure out is just sort of the way of best optimizing things for specific people.”
New Drug Technologies Are Moving Through Clinical Trials
Antibody-drug conjugates (ADCs) are a new class of cancer drugs. They attach chemotherapy to antibodies that specifically recognize cancer cells.
Patel says ADCs can more precisely deliver treatment to cancer cells while limiting exposure to healthy tissues.
“It still involves chemotherapy, but you're trying to more precisely direct that chemotherapy to just the cancer cells that might have these markers or these targets on them,” says Patel.
Another area of research involves drugs called bispecific antibodies, which bind both cancer cells and immune cells at the same time. Patel says this is similar to the way ADCs work, but without the chemotherapy component.
“Instead they’re trying to pull in your immune cells to these markers on the cancer cells,” says Patel.
Researchers hope this approach will strengthen the body's immune response against tumors. Some are already showing encouraging results in clinical trials.
Focus on Earlier Detection
Many gastric and esophageal adenocarcinomas are diagnosed after symptoms develop, which often means they’re already advanced. Researchers are working on ways to identify these cancers sooner.
Some studies focus on improving endoscopy technology. Others are exploring how artificial intelligence can help doctors detect subtle abnormalities during endoscopic exams.
"There have been techniques looked at to try to improve when patients undergo an endoscopy and the ability to find very early cancer or precancerous lesions," says Patel.
Another route to earlier detection is blood-based screening tests. These tests look for circulating tumor DNA (ctDNA), tiny fragments of DNA cancer cells shed into the bloodstream. Patel says scientists are studying whether these blood tests can identify early signs of cancer in the blood before symptoms appear.
Although these approaches are still in development, they may eventually help find cancer earlier, particularly when you have high risk factors such as Barrett's esophagus or H. pylori infection.
Exploring the Potential of CAR T-Cell Therapy
CAR T-cell therapy has transformed treatment for certain blood cancers such as multiple myeloma. Researchers are now exploring whether it can help with gastric and esophageal cancers.
CAR T treatment involves collecting immune cells from your blood, genetically modifying them in a laboratory, and then returning the cells to your body so they can better recognize and attack cancer.
“This is an area of active research,” says Patel. “It’s a way to take your own immune system, engineer it against a target, and then reintroduce that with the hope that you have then trained the immune system to target the cancer cells.”
Although CAR T therapy for solid tumors is experimental, ongoing studies are exploring whether it can overcome some of the unique challenges of treating gastric and esophageal cancers.
The Importance of Clinical Trials
Researchers continue to study new targets, new drug combinations, and entirely new treatment strategies. The only way they can do this, however, is through clinical trials with real people.
"Clinical trials are both the way that we move forward in the field,” says Patel. “They’re the way we improve outcomes, the way that we develop new treatments, and they are also the way that we most often have access to newer avenues for treatment for people who are actively dealing with cancer.”
If you’re interested in seeing whether you qualify for a clinical trial, talk to your oncologist. Or search databases such as the National Cancer Institute's clinical trials registry or ClinicalTrials.gov.
It’s through these trials that medicine has developed life-extending treatments for those with gastric or esophageal adenocarcinoma.
"The overall survival of patients, how long they live from starting treatment, has gotten longer and longer," says Patel. “And the percentage of patients cured with surgery with these additional treatments is getting higher.”
