Lynch Syndrome Testing Results Conflict Among Women with Endometrial Cancer

Compared with recommended screening for Lynch syndrome, additional testing may yield conflicting results in determining mismatch repair status among women with endometrial cancer, according to study results presented at the 49th Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancers held in New Orleans March 24-27.

Microsatellite instability (MSI) testing and immunohistochemistry screening for mismatch repair proteins are two of the recommended methods of screening for hereditary nonpolyposis colorectal cancer, also known as Lynch syndrome. While these testing methods can help oncologists determine if targeted therapy would be beneficial for women with endometrial cancer, their sensitivity and specificity are each less than 90 percent, according to the study abstract.

For example, a recent study showed that 8.1 percent of MSI and immunohistochemistry results in mismatch repair mutation carriers conflicted with results found by multigene panel testing, “but the concordance of MSI and immunohistochemistry gene testing overall is not well understood,” the researchers wrote.

Therefore, the researchers evaluated multigene panel testing results among women with endometrial cancer with prior MSI and/or immunohistochemistry testing to assess concordance between results.

Patients who had multigene testing panel testing between 2012 and 2016 were classified in to three groups: concordant if tumor testing matched multigene panel testing results, discordant if they did not match multigene panel testing results, and atypical if they had both concordant and discordant features.

Of the 789 eligible cases of endometrial cancer, 50 percent were concordant, 47 percent were discordant and 3 percent were atypical.

In total, 739 cases had immunohistochemistry results, of which concordance appeared high among those with normal results (96 percent) and low in the abnormal results (19.8 percent). The largest percentage of cases with abnormal results appeared discordant with cases for which MLH1 methylation – a genetic mutation common in endometrial cancer – had not been ruled out (43.3 percent).

However, an additional 31.6 percent of abnormal cases conflicted with results where MLH1 methylation was ruled out or not necessary, while 5.3 percent of cases were classified as atypical.

Lastly, the researchers noted that ten cases with concordant, normal immunohistochemistry results had a germline mutation in a non-mismatch repair gene, while seven of 11 discordant cases with normal immunohistochemistry results did have a mismatch repair mutation.

The researchers found that nearly half of MSI and/or immunohistochemistry results were discordant with mismatch repair gene results, however, these findings may be explained by: MLH1 promoter methylation not being ruled out in testing, two somatic mismatch repair mutations, unclassified variants that are pathogenic, inaccurate testing, and mutations that may go undetected by current technology.

“These result provide guidance on what to expect from multigene panel testing results in a patient with given MSI and immunohistochemistry results, suggest scenarios where somatic gene testing may be useful, and highlight several opportunities for further study,” the researchers wrote.