Lynch Syndrome Linked with More Cancers

Findings from a large prospective genomic analysis indicate that Lynch syndrome may be linked with more tumor types than previously thought (J Clin Oncol 36, 2018 [suppl; abstr LBA1509]). The data were presented on June 4 by Zsofia Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, during the 2018 American Society of Clinical Oncology Annual Meeting in Chicago, IL.

Either sporadic defects in DNA mismatch repair (MMR) proteins—chiefly MLH1, MSH2, MSH6, PMS2, and EPCAM—or Lynch syndrome, which arises from germline mutations in these MMR genes, compromises the ability to fix DNA replication errors and results in microsatellite instability (MSI). This phenotype, which may increase neoantigen production and thereby sensitivity to immunotherapy, is classically associated with colorectal cancer, as well as with endometrial and stomach cancers. However, with pembrolizumab (Keytruda; Merck) and nivolumab (Opdivo; Bristol-Myers Squibb) earning tissue-agnostic approvals last year for tumors that exhibit high MSI, clinicians are increasingly assessing patients' MSI status regardless of cancer type, Stadler observed, to determine their likelihood of benefiting from PD-1 blockade.

“Until now, the prevalence of germline MMR gene mutations across all tumors with MSI has been unknown, so we made that the goal of our study,” Stadler said. She and her colleagues used MSK-IMPACT, an FDA-authorized next-generation sequencing platform that incorporates MSI detection, to evaluate 15,045 tissue samples representing more than 50 tumor types. Germline analyses to identify MMR gene mutations were then carried out on blood samples from study participants.

Stadler reported that 93.2% of tumor samples were MSI-stable, 4.6% were MSI-indeterminate, and 2.2% were MSI-high. The distribution of germline MMR mutations across these three groups was 0.3%, 1.9%, and 16.3%, respectively. For the MSI-stable patients, Stadler noted, “this prevalence is essentially equivalent to the general population's risk of Lynch syndrome.”

Focusing on the MSI-indeterminate and MSI-high cohorts, the investigators used immunohistochemistry to confirm MMR deficiency in these tumors. They also determined that 88% displayed a dominant pattern of tumor mutational signatures consistent with defective DNA repair. “It's further evidence that the tumors in these two groups were likely caused by Lynch syndrome,” Stadler said. By contrast, 89% of tumors in the MSI-stable cohort did not feature such mutational signatures, she added.

Stadler pointed out that among the patients in both the MSI-indeterminate and MSI-high groups who were found to have Lynch syndrome, fully half had tumor types other than colorectal or endometrial cancers—for instance, prostate cancer, urothelial carcinoma, and soft-tissue sarcoma. Importantly, of this half, 45% did not meet current clinical testing criteria for Lynch syndrome.

“We believe our study shows that MSI-high or MSI-indeterminate status, regardless of tumor type, should prompt a germline assessment for Lynch syndrome,” she said. “This will increase our ability to recognize it in not only patients but their families too, who may well benefit from genetic counseling and increased cancer surveillance.”

Kim Reiss Binder, MD, of the University of Pennsylvania in Philadelphia, agreed that “evaluating MSI status in more patients, which is already starting to happen, and finding more with Lynch syndrome this way, has major implications downstream for family members.”

“This study is absolutely practice-changing,” added Shannon Westin, MD, of The University of Texas MD Anderson Cancer Center in Houston. “We've been testing just the tip of the [Lynch syndrome] iceberg; given that this is a straightforward process, it can and should be implemented more broadly in the clinic.” –Alissa Poh

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