Preventing Lynch Syndrome Cancers: New Study Suggests Immunotherapy Could Work

Dr. Zsofia Stadler

Dr. Zsofia Stadler is an expert in Lynch syndrome, an inherited condition that increases the risk of several types of cancer, especially tumors of the gastrointestinal tract.

Immunotherapy drugs called checkpoint inhibitors may prevent serious tumors from forming in some people with an increased risk of cancer due to a condition called Lynch syndrome, according to new research published October 16, 2023, in Nature Medicine by Memorial Sloan Kettering Cancer Center (MSK).

“This opens the door to a very big idea, which is that immunotherapy could be used to prevent cancer,” says gastrointestinal oncologist Luis Diaz Jr., MD, head of MSK’s Division of Solid Tumor Oncology and a co-author of the paper. “This analysis was based on past data about patients, but the initial findings suggest this is something that should be tested in future clinical trials.”

What Is Lynch Syndrome?

Lynch syndrome is one of the most common genetic conditions that raises someone’s risk for developing cancer. According to gastrointestinal oncologist and clinical geneticist Zsofia Stadler, MD, the paper’s corresponding author, people who have inherited Lynch syndrome have a 70% risk of developing at least one cancer in their lifetime.

Lynch syndrome is linked to cancers of the gastrointestinal tract, including colon cancerrectal cancer, and stomach (gastric) cancer, and cancers of the small intestine.

It also increases the risk of uterine (endometrial) cancer, ovarian cancer, and some cancers of the upper urinary tract.

Studying Immunotherapy Versus Chemotherapy for Lynch Syndrome Cancers

The new study analyzed data from 172 people with Lynch syndrome who had been treated with checkpoint inhibitors at MSK and initially noted that 12% of these patients developed a new cancer after immunotherapy. Next, these patients were compared with patients who also had the syndrome but were treated with chemotherapy — not immunotherapy. Researchers looked at how many patients in each group developed another cancer over the next three years.

At first, the findings were disappointing: Rates of new cancer were the same in both groups pre-treatment and post-treatment, suggesting no protective benefit from the immunotherapy. But when the investigators took a closer look at the data, they found something much more promising.

A wave carrying crabs crashes against a brick wall

An illustration representing this research was selected by Nature Medicine for its cover. The risk of cancer is represented by the waves carrying crabs (cancer) toward land (patients). The immunotherapy treatment is represented by a wall preventing the crabs from reaching land. Illustration by Samantha Welker.

About 50% of the cancers that developed in the Lynch patients receiving immunotherapy were small skin cancers — not serious cancers. In contrast, for the patients receiving only chemotherapy, the majority of new cancers were more serious tumor types.

The incidence of visceral tumors — those arising deep in the internal organs — was actually much lower in those who had received immunotherapy.

“We don’t know why the patients were more likely to get skin cancer, but these skin cancers have limited clinical implications,” Dr. Stadler says. “They were easy to detect and easy to treat. What’s important is that the rate of visceral tumors — like those in the gastrointestinal tract and other vital organs — were so much lower. These visceral tumors are the ones that cause serious problems.”

Based on these findings, Dr. Diaz and Dr. Stadler plan to conduct a forward-looking clinical trial following patients to determine whether giving checkpoint inhibitors may protect against cancer in people with Lynch syndrome. A cautionary note: These drugs have side effects, which must be considered when weighing risks and benefits of using them as a preventive treatment.

Why Does Lynch Syndrome Cause Cancer? The Tumors Have an MMRd Mutation

People with Lynch syndrome have such a high risk of developing cancer because they carry a gene mutation that prevents their cells from being able to repair genetic damage. This leads to a condition called DNA mismatch repair deficiency (MMRd).

This opens the door to a very big idea, which is that immunotherapy could be used to prevent cancer.
Luis Diaz Jr. gastrointestinal oncologist

These MMRd cancers have a lot of mutations, which makes them visible to the immune system. Therefore, drugs that enlist the immune system to fight cancer cells are particularly effective. Past research from Dr. Diaz and others found that tumors with MMRd are more likely to respond to checkpoint inhibitors. Thanks to that discovery, these drugs are now widely used to treat patients whose tumors have MMRd, including those whose cancers are due to Lynch syndrome.

Why It’s Important To Get Tested for Lynch Syndrome

“This research demonstrates why it’s important for patients to have the genetics of their tumors analyzed,” Dr. Stadler says. She and her team have previously demonstrated the importance of testing patients for Lynch syndrome if their tumor is found to be MMRd, regardless of what type of cancer they have. These genetic tests not only match patients with the best treatment but they also provide crucial information to patients and their families about the risk of future cancers.

“We think that up to 90% of people with Lynch syndrome don’t know they have it,” Dr. Stadler adds. “It’s grossly under-tested in the population, even in families whose cancer history suggests there could be a possible link.”

Those most at risk are people in families with a high number of Lynch-associated cancers diagnosed in people before the age of 50.

MSK Has Programs for People With Lynch Syndrome and Other Cancer Genes

For people who know they have Lynch syndrome or another hereditary cancer syndrome, MSK has a program called CATCH (which stands for Comprehensive Assessment, Treatment, and Prevention of Cancers With Hereditary Predispositions), led by clinical geneticist and family medicine doctor Alicia Latham, MD.

The program provides close surveillance and regular screenings, including:

  • Frequent colonoscopies
  • Endoscopies to look for cancers in the upper gastrointestinal tract
  • Urinalysis to look for genitourinary tumors
  • Regular screenings for skin cancer
  • Other cancer screenings based on family history

Because no good screening methods exist for gynecologic cancers, women with Lynch syndrome and certain other hereditary syndromes often decide to have their uteruses and ovaries removed after having children.

“This program has helped many families and helps to fulfill an important part of our mission at MSK,” Dr. Stadler says. “Our ultimate goal is to prevent people from developing cancer in the first place.”