The Case for Tumor and Germline Testing in Endometrial Cancer Patients


A new study reinforces the need for universal mismatch repair protein immunohistochemistry screening of tumors from endometrial cancer patients, as well as germline genetic testing in accordance with guidelines.

A new study reinforces the need for universal mismatch repair (MMR) protein immunohistochemistry (IHC) screening of tumors from endometrial cancer patients, as well as germline genetic testing in accordance with the guidelines. Proper tumor and germline testing can help identify patients with an increased risk for additional cancers-in particular those with Lynch syndrome, an inherited disease that increases the risk of several cancers, including endometrial, colorectal, and ovarian. The results of the study were published in JCO Precision Oncology.

During an interview with Cancer Network, Aparna Kamat, MD, the director of the division of gynecologic oncology for Houston Methodist, who was not involved with the study research, commented that the study highlights how important it is to do genetic testing for patients who have endometrial cancer and that even patients who are not high risk for additional cancers should have reflex testing of their tumors, which could help identify high-risk patients and lead to prevention strategies.

The study included 156 patients with unselected newly diagnosed endometrial cancer who were scheduled for hysterectomy. Tumor sequencing was performed using the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), which is a panel of 468 genes. Germline testing was performed using an 88-gene panel. Most patients had stage I disease (76%), tumors that were endometrioid (67%), and grade 1 disease (58%).

A total of 24 pathogenic germline variants were found among 22 patients (14%). This included 7 patients (4.5%) with highly penetrant variants, 5 of which had variants for Lynch syndrome, 1 had a known BRCA1 mutation, and 1 had an SMARCA4 deletion. Among the patients with Lynch syndrome variants, 2 had MSH6, 2 had PMS2, and 1 had MLH1. The remaining pathogenic germline variants identified (71%) were in low- and moderate-penetrance or recessive-only genes.

Overall, 6 of the 7 patients with highly penetrant variants met germline testing criteria and would have normally been recommended for germline testing. (The patient with an SMARCA4 deletion did not meet testing criteria.) On the basis of these findings, Kamat said, “I would still recommend sticking with [the guidelines] for the germline testing.”

IHC staining showed that more than a quarter of tumors were absent for MMR, and most of the tumors had MLH1/PMS2 loss with MLH1 hypermethylation. Five tumors indicated Lynch syndrome, which were from the same 5 patients identified via germline testing as having Lynch syndrome. Six tumors were discordant, meaning the MMR absence did not correlate with a germline mutation.

“This is a study that does highlight the need to do a reflex immunohistochemistry for Lynch syndrome, which I think is something that is still lacking in a lot of the centers in the country,” said Kamat. She noted that “all major cancer centers,” including Houston Methodist, perform reflex IHC, but “not everyone is doing it.”

“I think that that would be the best first step, to try to identify as many patients as we can with a genetically proven endometrial cancer,” said Kamat. “It’s definitely a huge benefit if [Lynch syndrome patients] know their genetic status, so we could prevent a second cancer from happening.”

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