A Positive Outlook for Lynch Syndrome-Related Cancers

As more patients undergo genomic sequencing, researchers are discovering that Lynch syndrome is more common than they originally thought.

The good news, however, is that vaccines may eventually be a promising cancer prevention for this patient population, according to Steven M. Lipkin, MD, PhD, professor of medicine and genetic medicine and the vice chair for basic and translational research at Weill Cornell Medicine.

“Lynch syndrome confers and approximately 70% to 80% lifetime risk for developing colorectal cancer, and approximately 50% to 60% lifetimes risk for women to develop cancer of the endometrium,” he said in an interview with OncLive, a sister publication of CURE. “There are also other sites that are involved. These include gastric, ovarian, pancreatic, biliary, renal, bladder cancer, and a few others.”

While treatment options continue to expand for patients with certain genetic mutations, once it is determined that someone has Lynch syndrome, the first goal is to prevent cancer from developing in the first place. For most patients this means more screening, while others may opt for prophylactic surgeries.

“The cornerstone for management of Lynch syndrome currently is colonoscopies. Surveillance (with colonoscopies) is an important way to try to detect cancers early,” Lipkin said, noting that most individuals with Lynch syndrome get colonoscopies every 2 years. “We also recommend the use of aspirin, which is a nonsteroidal anti-inflammatory agent (NSAID).”

Colonoscopies can find colorectal cancer before they occur or in the earliest stages, but there are no proven methods to prevent other types of Lynch syndrome-related malignancies.

“At the moment, we don’t have very effective ways of preventing some of the cancers [located at] the other sites. So, there are a lot of women who will actually choose, after childbearing, to have surgery, similar to women with the BRCA1 or BRCA2 mutation who have a hysterectomy.”

If patients do develop cancer, there may be more options available to them, depending on the genomic profile of the tumor.

Lynch syndrome is caused by a germline mutation in 1 of several DNA mismatch repair (dMMR) genes, which are responsible for correcting any errors that occur during the DNA replication process. With these genes not working properly, there may be a long strand of faulty DNA — a condition called microsatellite instability.

Tumors that are classified as microsatellite instability-high (MSI-H) tend to respond well to immune checkpoint inhibitors. In fact, in 2017, pembrolizumab (Keytruda) was approved for patients with unresectable or metastatic, MSI-H or dMMR deficient solid tumors. Later, in 2018, nivolumab (Opdivo) plus ipilumumab (Yervoy) was approved for MSI-H or dMMR-deficient metastatic colorectal that progressed on prior therapy.

Looking ahead, cancer vaccines may be added to the toolbox of preventing Lynch syndrome-related cancers.

“Lynch syndrome patients not only have high rates of developing cancers, but they also [can] develop tumor mutations that are most immunogenic,” Lipkin said.

Lipkin mentioned a preclinical study where a neoantigen vaccine was tested in mice with Lynch syndrome. The vaccine, which generated antigen-specific responses, reduced intestinal tumors and improved survival. When given with naproxen, overall survival was improved even more.

“If you think of the idea of having a cancer vaccine as potentially attractive, Lynch syndrome is probably the paradigm place to start. If this is ever going to work, this would be the syndrome,” he added.