Understanding Lynch Syndrome and Associated Cancer Risk: Identification

In this third episode of OncChats: Understanding Lynch Syndrome and Cancer Risk, Fay Kastrinos, MD, MPH, of Columbia University Herbert Irving Comprehensive Cancer Center, discusses testing guidance for identifying Lynch syndrome.

Universal testing with MSI or immunohistochemistry [IHC] in all newly diagnosed colorectal cancer [CRC] is a firm guideline, and that’s regardless of the age of cancer diagnosis or family history of CRC. Multiple studies have consistently proven it to be clinically feasible to take this approach on. This approach is more sensitive than existing clinical criteria, as many individuals with Lynch syndrome are diagnosed at older ages and may have less striking family histories than what was previously appreciated. [As such,] universal testing of CRC, as well as endometrial tumors with MSI and IHC have been recommended by many professional organizations and they’re still widely being adopted.

However, these days, tumor testing is far more often used to advance treatment decision-making in a more personalized approach, particularly in individuals with metastatic disease. Tumor testing for decision making, as it relates to treatment, most often includes MSI testing, as well as tumor DNA testing and sequencing. MSI testing across all tumor types has really been an important screening tool to select patients who may have a favorable response to immune checkpoint inhibitor therapy. These results may potentially be also used to screen for Lynch syndrome in tumors beyond CRC, and this is relevant because there are a number of additional cancers beyond colon cancer that are associated with Lynch syndrome.

A recent study evaluated MSI across a wide variety of malignancies and [examined] its use as a potential means to identify Lynch syndrome regardless of tumor type. In this study, data from over 15,000 individuals with more than 50 types of cancer were evaluated and were used to determine MSI and germline status from the tumor, as well as DNA sequencing. CRC and endometrial cancer comprised the majority of cancers [that were] MSI high in this study, but 38% of MSI-high tumors were of other types. Germline testing across the board confirmed a diagnosis of Lynch syndrome in 16.3% [of patients.] Among those who had Lynch syndrome[–associated] cancers other than colon and endometrial cancer, nearly half failed to meet clinical criteria for testing on the basis of the cancer type or family cancer history. These individuals would not have been identified with Lynch syndrome.

Another means in directing treatment options relies on next-generation tumor sequencing, particularly for CRC. [The] detection of Lynch syndrome amongst those who undergo next-generation sequencing of CRC has also been compared with protocols that include MSI testing, IHC staining, as well as germline testing. [As such,] when correlating the results from next-generation tumor sequencing to that of germline DNA testing, 100% of individuals identified with Lynch syndrome [from] tumor sequencing were also identified by germline DNA testing. This suggests that we might be able to use tumor sequencing as an effective method [to also identify] Lynch syndrome in addition to guiding treatment options. However, whether this is cost effective as a strategy remains to be determined.

Germline testing is the gold standard for identifying Lynch syndrome but extends beyond just looking at Lynch syndrome–associated genes through multigene panel testing. In evaluating multigene panel testing results in all colon cancers unselected for age at diagnosis, personal or family cancer history, or tumor testing results, pathogenic variants in cancer susceptibility genes are identified in up to 10% of patients. [Although] 3% of individuals with unselected colon cancer cases have Lynch syndrome, 7% of pathogenic variants [are] in non-Lynch syndrome–associated genes, all of which have specialized screening protocols that these patients would benefit from.

Check back next Wednesday for the next episode in this series.