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MSK Team Finds Immunotherapy May Lessen Visceral Tumor Risk After Lynch Syndrome-Linked Cancer


The headline and this article have been updated to clarify that the study found immunotherapy may lessen the risk of new neoplasias, not the risk of recurrence of the same cancer.

NEW YORK – Research from Memorial Sloan Kettering Cancer Center suggests that immune checkpoint inhibitors may prevent some patients with Lynch syndrome-associated cancers from developing new cancers in vital organs and poor outcomes.

The retrospective study, published in Nature Medicine this month, analyzed data from 172 patients with Lynch syndrome who had received checkpoint inhibitors at MSK and compared their rates of new neoplasia to Lynch syndrome patients who only received chemotherapy. The findings suggest that "visceral subsequent primary malignancies," which are tumors that occur in major organs in the body, "may be decreased by immune checkpoint blockade exposure or that there is a shift in the type of subsequent primary malignancy that occurs," authors led by Zsofia Stadler, a gastrointestinal oncologist and clinical geneticist at MSK, wrote in the paper. "This may impact survival because visceral tumors can be lethal if not successfully treated."

Lynch syndrome is an inherited condition that increases a patient's risk for developing cancer; these patients have a 70 percent risk of developing cancer in their lifetime. Lynch syndrome-associated cancers include colon, rectal, gastric, uterine, ovarian, and urinary tract tumors. These tumors also typically have DNA mismatch repair deficiency (dMMR) because the genetic mutations associated with Lynch syndrome prevent cells from being able to repair DNA damage.

Among patients in this study, colorectal cancer was the most common primary tumor, occurring in 42 percent of patients, followed by endometrial cancer in 16 percent. More than 60 percent of patients in the study harbored germline variants in MSH2 and MLH1, two common genes mutated in Lynch syndrome. Most patients (66 percent) received immunotherapy for metastatic disease and 82 percent received immunotherapy for a dMMR tumor. After treatment, 12 percent of patients developed a subsequent primary malignancy.

While the patients in the immunotherapy and chemo treatment groups had similar rates of new cancers, fewer patients developed new visceral tumors after immunotherapy. While immunotherapy did not entirely prevent new cancers from forming, it appeared to reduce the severity of the tumors that did occur.

Across three cohorts of Lynch syndrome patients who received different treatments, the average rates of a subsequent primary malignancy per year of follow up were similar: 3.2 percent for the MSK immunotherapy-treated cohort, 4.1 percent for the MSK chemotherapy-treated group, and 4.9 percent for an external dataset of Lynch syndrome patients.

However, about half of the new neoplasias (48 percent) in the immunotherapy treatment group at MSK were cutaneous tumors and half were visceral tumors in key organs. In the chemo-treated group, however, only 12 percent of new tumors were cutaneous, and 88 percent were visceral tumors.

"[These findings] open up the broader idea of whether immunotherapy may be a potential way of preventing certain Lynch-associated tumors, especially the visceral ones, which are the ones that are potentially life threatening," Stadler said.

Stadler and colleagues conducted their study encouraged by an earlier analysis of nearly 47,000 cancer patients, which found that less than 1 percent of around 1,200 patients on immune checkpoint inhibitors for their first primary cancer developed second primary cancers. In comparison, nearly 3 percent of around 17,000 patients on chemotherapy, but no immunotherapy, developed a second primary cancer.

Going forward, Stadler and her colleagues are hoping to conduct a prospective clinical trial to test immunotherapy's potential as a preventive treatment in Lynch syndrome-associated cancers.

The findings also had more immediate clinical implications for surveillance of patients with Lynch syndrome. Because a large proportion of these patients developed Lynch-associated skin cancers after treatment with both immunotherapy and chemo, Stadler and her colleagues recommended dermatological screenings alongside regular surveillance for cancer.

She pointed out that most of the patients included in this study received immunotherapy for metastatic, dMMR tumors. There are three immunotherapies approved for solid tumors with dMMR: Merck's Keytruda (pembrolizumab) and GlaxoSmithKline's Jemperli (dostarlimab) have tissue-agnostic approvals in this setting; and Bristol Myers Squibb's immunotherapy combination Opdivo (nivolumab) and Yervoy (ipilimumab) is approved for dMMR or microsatellite instability-high (MSI-high) metastatic colorectal cancer.

"Previously, in the metastatic setting, we wouldn't routinely continue high-risk surveillance because patients oftentimes succumbed to their cancer," Stadler said. "Immunotherapy has completely shifted that, as many of these patients do great with long-term complete and durable responses to immunotherapy."

However, Stadler emphasized that this study highlights that these patients do remain at high risk of new cancer development, adding "as we expand the use of immunotherapy in these Lynch populations to earlier-stage settings, we absolutely need to be on top of post-immunotherapy surveillance."

MSK's study also provides insight into the biology of Lynch-associated tumors that develop after immunotherapy and these insights could inform cancer vaccines. When the researchers delved into next-generation sequencing data on the study participants' tumors before and after immunotherapy, they found that the MSISensor score, a measure of MSI levels, was significantly lower in post-immunotherapy tumors and these tumors exhibited fewer frameshift mutations.

The post-treatment tumors also harbored fewer mutation-associated neoantigens, which Stadler flagged as a measure of tumor immunogenicity. "This is suggesting that those post-immunotherapy tumors that developed weren't as immunogenic, potentially reflecting the selective pressures these tumors may be facing with prior immunotherapy exposure," she explained.

These insights could inform development of neoantigen cancer vaccines for Lynch syndrome, she added, since Lynch-associated tumors in the study appeared to have some differences in neoantigens and frameshift peptides after immunotherapy. Cancer vaccines typically target specific neoantigens and frameshift peptides to prevent the formation of tumors.

"There's a lot of excitement about the potential effectiveness of vaccines in Lynch syndrome, but the impact that immunotherapy has on Lynch-associated tumors may help inform optimal vaccine development," she explained. "For example, if new neoplasia after immunotherapy have completely different frameshift peptides, then it brings up the question of whether using recurrent neoantigens will be an effective mechanism for all or perhaps only for certain subsets of cancer types."