ASCO 2018-TEST ALL MSI-H TUMORS FOR LYNCH SYNDROME

Patients found to have tumors with high microsatellite instability (MSI-H) should be tested and screened for Lynch syndrome, regardless what type of cancer they have, says an expert commenting on a new study.

The new study was presented here at American Society of Clinical Oncology (ASCO) 2018.

In a cohort of individuals with MSI-H tumors, 16% were subsequently found to have Lynch syndrome.

Among this group, 25% had colorectal or endometrial cancers, the most common types of malignancies associated with Lynch syndrome.

However, almost half of patients with MSI-H and MSI-indeterminate (MSI-I) tumors identified as having Lynch syndrome had cancer types that have not previously or were only rarely linked to the syndrome. These include mesothelioma, sarcoma, adrenocortical cancer, melanoma, prostate, and ovarian germ cell cancer. Within this group, 45% did not meet the criteria for Lynch syndrome genetic testing criteria based on family or personal cancer history.

"MSI-H is predictive of Lynch syndrome across tumor types and suggests a more heterogenous phenotype than previously expected," said senior study author Zsofia Kinga Stadler, MD, clinic director of the Clinical Genetics Service and a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City.

"An MSI-H tumor signature, regardless of cancer subtype, should prompt germline genetic assessment for the evaluation of Lynch syndrome," she said.

This is an absolutely practice-changing study Dr Shannon Westin

"This is an absolutely practice-changing study, which indicates that patients with [MSI-H] tumors should be tested and [screened] for Lynch syndrome, regardless of their cancer type," said Shannon Westin, MD, associate professor, Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas. Westin is an ASCO expert who was not involved in the study.

Testing the Tip of the Iceberg 

Westin pointed out that with "the rise of precision medicine, more and more patients will undergo testing for [MSI], but what we're learning [is] that among those tumors with high MSI status, 16% had Lynch syndrome."

"What is important is that 50% of patients had tumors that are not typically associated with Lynch syndrome," she reiterated.

This study shows that MSI not only has therapeutic implications but also has cancer prevention implications, Westin explained. "We are only testing the tip of the iceberg of patients who may be affected by Lynch syndrome. And what we now know [is] that under the surface, there are a larger number of patients with specific cancer types that should be tested for Lynch syndrome."

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"This is a straightforward testing strategy that can be immediately implemented and will not only affect patients but their family members," she added. "The impact of that cannot be understated."

Richard Schilsky MD, chief medical officer of ASCO, also emphasized this point. This study shows that many of the MSI-H tumors "are coming from individuals in families with hereditary Lynch syndrome that was not previously diagnosed. That's where [the] take-home message is: Doctors and patients have to recognize the possibility that when these test results come in, they may show a familial cancer tendency that was previously unknown, and it's important not only to patients but also to their family," he commented to Medscape Medical News.

Changes in Treatment Paradigm 

Last year, two drug approvals by the US Food and Drug Administration changed the paradigm of cancer treatment, as the new indication specifies a genetic defect without any mention of tumor types. The first was pembrolizumab (Keytruda, Merck) in May 2017, approved to treat any tumor associated with a high risk for MSI (MSI-H), and in August 2017, nivolumab (Opdivo, Bristol-Myers Squibb) was approved for use in patients with colorectal cancer and mismatch repair (MMR)/MSI defects.

The approval of pembrolizumab increased the rate of testing in metastatic cancers, and MSI testing of tumors has become broadly used to identify patients who may benefit from pembrolizumab. However, a recent study found that testing in colorectal cancer remains low. This is despite recent guidelines recommending that all patients with colorectal cancer be tested for deficient DNA MMR (MMR-D). Among 152,993 adults with colorectal cancer, however, the rate of testing rate was just 28.2%, and only 43.1% of younger patients were tested for MMR/MSI status.

MSI-H/I Tumors Linked to Lynch 

In an introduction to her new study, Stadler explained that an estimated 1 in 300 (0.3%) people in the general population has Lynch syndrome, but the characterization of Lynch syndrome across heterogeneous MSI-H/MMR-D tumors is unknown. For their study, the authors analyzed 15,045 tumor samples collected from patients with more than 50 different types of advanced cancer, using MSK-IMPACT, a next-generation sequencing platform authorized by the US Food and Drug Administration.

MSI status was determined via MSIsensor: a score lower than 3 designated microsatellite stable (MSS), a score of 3 or more to less than 10 was MSI-I, and a score of at least 10 was MSI-H status. Germline mutations were assessed in MLH1, MSH2, MSH6, PMS2, and EPCAM, which are associated with Lynch syndrome, and MMR-D status was evaluated with immunohistochemical staining.

Of 15,045 tumors tested, 93.2% were MSS, 4.6% MSI-I, and 2.2% MSI-H. Germline mutations were identified in 0.3% (37/14,020) of MSS tumors, 1.9% (13/699) of MSI-I, and 16.3% (53/326) of MSI-H (P < .001).

Not surprisingly, 25% of 1025 MSI-H/MSI-I tumors were either colorectal or endometrial, but 50% (33/66) of patients with Lynch syndrome had MSI-H/MSI-I tumors that are less commonly or not previously associated with the syndrome (mesothelioma, sarcoma, adrenocortical, melanoma, ovarian germ cell).

However, patients with MSI-H/MSI-I who had cancers other than colorectal or endometrial met testing criteria in only 63.6% of cases. They had lower MSIsensor scores and were more likely to be MSI-I compared with patients with colorectal/endometrial cancer (MSI-I: 30.3% (10/33) vs 9.1% (3/33); P = .03).

"Noncolorectal and endometrial Lynch-associated tumors are less likely to meet the criteria for genetic risk assessment," said Stadler.

Immunohistochemical staining was completed in 86.4% (57/66) of patients with Lynch syndrome with MSI-H/MSI-I tumors, with 98.3% MMR-D concordance. Among patients with Lynch syndrome with MSS tumors, 78% had MSH6/PMS2 mutations, whereas 71% with MSI-H/MSI-I tumors had MLH1/MSH2/EPCAM mutations (P < .001). In addition, 89.2% (33/37) of MSS tumors showed non-MMR-D signatures.