Screening for Lynch Syndrome: Optimal Strategies and Performance Remain a Moving Target

In the last decade, implementation science has emerged as a transdisciplinary research approach to enhance the systematic uptake and integration of evidence-based guidelines across real-world practice settings. It is estimated that it takes up to 17 years for only 14% of published evidence to be incorporated into clinical practice.^1,2 Given this notable time lag, the barriers and facilitators of implementation have often been explored and found to vary by practice setting, provider and patient characteristics, and overall healthcare systems.

For individuals with colorectal cancer (CRC), universal screening for Lynch syndrome, the most common form of inherited CRC syndrome, involves tumor testing for mismatch repair deficiency (MMRd) by either microsatellite instability (MSI) or immunohistochemistry (IHC) for loss of protein expression of the MMR genes associated with the condition. Universal screening was first recommended in 2009 by the Evaluation of Genomic Applications in Practice and Prevention group (EGAPP)³, followed by the US Multi-Society Task Force on Colorectal Cancer⁴ in 2014, and the National Comprehensive Cancer Network. Results from the implementation of tumor screening programs and their impact have been variable and have often been related to practice setting or type of cancer center.

In the current study, Stone et al. report the outcomes of MMRd tumor testing, notably IHC, in Manitoba, the first Canadian provincial program to implement universal screening of all CRCs diagnosed in patients under the age of 70 years.⁵ Nearly a decade following the recommendations and guidelines to pursue MMRd, Stone et al. provide results from a large study of over 3,000 CRC specimens analyzed between 2018-2020. The investigators evaluated predictors of MMRd testing and referral rates for germline testing.

Stone and colleagues found a high level of compliance with reflex testing, where 89.4% of patients ≤70 years with CRC had tumor IHC testing. This is higher than previous reports of reflex MMRd tumor testing for CRC^6-10 and factors predictive of an increased rate of reflex testing were patient age (<54 years vs 66-70 years), laboratory site, and most notable, individual pathologist. Pathologists with rates of testing higher than the mean (and therefore low miss rates) were 17 times more likely to conduct IHC testing than those with high miss rates. The primary finding that individual pathologist was the most important predictor of universal testing completion has been suggested in prior studies that found variable performance and uptake of tumor MMRd testing based on cancer center.^6,9,10 This finding highlights the potential use of MMRd testing in CRC as a quality performance metric; the investigators are developing a feedback process to alert pathologists of their rates of MMRd testing in order to mitigate the missed opportunities to screen for Lynch syndrome.

However, universal tumor screening for Lynch syndrome is only successful (and cost-effective) if patients who screen positive by tumor MMRd undergo germline genetic testing where the identified carriers, and their family members, can benefit from targeted cancer treatment, screening programs, and other risk-reducing strategies.¹¹ This Canadian province’s healthcare system allowed for a standardized program for genetic counseling referral and testing, provided multigene panel testing through next generation sequencing, and insurance coverage for tumor testing and germline testing and counseling for screen positive cases. Such a system eliminates a number of common barriers related to access-to-care and varied insurance coverage encountered in other healthcare systems. Under these close to ideal conditions, about 76% of patients with MMRd tumors were referred for genetic services, where pathologists were the major driver of referrals in 53.4% of cases and 22.4% by other were referred by other healthcare providers. When offered, uptake of genetics services was high and 84% of patients attended a counseling visit. Unfortunately, 24% of screen positive cases were not referred. While suboptimal, it is a marked improvement from most studies reporting less than 50% referral for genetic evaluation following positive tumor testing. A potential solution to help close this gap relates to the recent paradigm shift in genetic counseling service delivery models; up-front germline genetic testing for some malignancies is performed at time of diagnosis (point-of-care), predominantly to guide treatment options, and genetic referral is reserved for post-test counseling in those with identified pathogenic variants. With a growing appreciation for the benefits of universal germline testing for all solid tumors, screening patients with CRC in this manner would facilitate the potential identification of all individuals with Lynch syndrome.^12,13

Stone and colleagues also report the uptake of cascade testing, the process of offering genetic counseling and testing to at-risk family members of the proband diagnosed with Lynch syndrome. They report that 21.1% of first-degree relatives underwent cascade testing, which is lower than prior reports ranging from 34-52%,¹⁴ despite full insurance coverage of cascade testing for relatives by the provincial universal healthcare plan. Similar to other genetics programs and current practice, probands were provided letters for family members and printed material to facilitate family communication but studies report that the role of the provider is critical in the process of cascade testing, and that the nature of provider engagement with patients and their relatives could be optimized.^15,16 As the investigators conclude, gastroenterologists may facilitate not only genetic referral, but also improve cascade testing and the identification of previvors. Since gastroenterologists are involved in the care continuum of Lynch syndrome carriers with frequent presence during annual/biennial endoscopic surveillance, they have the opportunity to often engage and/or facilitate communication with at-risk family members about cascade testing and its implications. Evaluation of novel strategies to improve the uptake of cascade testing warrant attention and a tracking system and/or other intervention to ensure program success may be an additional, critical component of Lynch syndrome screening.

Clinical practice guidelines for Lynch syndrome screening require continued development and updating, even within healthcare systems or practice settings that have already implemented screening programs, given the rapid pace with which genomic medicine can impact therapeutic decision-making. Manitoba’s program has made an investment in the necessary infrastructure to successfully implement universal tumor MMRd testing for Lynch syndrome screening. It may also be well-poised to assess future strategies for the optimal identification of Lynch syndrome through universal germline testing of all CRC cases and in those eligible for cascade testing, who can benefit most from cancer prevention.