Tumor-based screening for Lynch Syndrome: Check Every Colorectal Cancer

Swati G. Patel, MD, MS

Associate Professor of Medicine

University of Colorado Anschutz Medical Center; Rocky Mountain Regional Veterans Affairs Medical Center,  Denver, Colorado

This summary reviews Stone JK, Winter R, Khan D, et al. A Canadian Provincial Screening Program for Lynch Syndrome. American Journal of Gastroenterology 2023;118:345-53.

Correspondence to Swati G. Patel, MD, MS. Associate Editor. Email: EBGI@gi.org

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COMMENTARY

Why Is This Important?
Lynch syndrome is the most common hereditary cancer syndrome with an estimated prevalence of 1/279          individuals,¹ accounting for 3-5% of all colorectal cancers. It also increases risk of multiple other cancers. There are effective cancer risk reduction strategies for Lynch Syndrome  patients, including more intensive   endoscopic surveillance, chemoprevention and risk reduction surgery that can significantly decrease the burden of cancer in these patients and their family members.² Unfortunately, Lynch Syndrome is grossly under-diagnosed with less than 10% of Lynch Syndrome patients being aware of their diagnosis in the United States.³ An approach to improving identification of these patients is to screen all CRC patients for dMMR or microsatellite instability (MSI), the hallmarks of Lynch. Though this has been recommended by multiple professional societies, a minority of health systems in the US have successful universal screening programs.^4-7 Successful population-based implementation of a LS screening program can be an example to other health systems.

Key Study Findings
This study demonstrates that a protocolized universal tumor screening program where there is clear designation of who is responsible for ordering, performing, interpreting and  conducting follow up on testing results in high adherence to tumor-based screening for Lynch Syndrome where 88% of eligible specimens are screened.

Unfortunately, there is successive drop off in appropriate referral to genetics, patient acceptance of referral, and patient acceptance of  genetic testing, such that only 55% of patients who qualify for genetic testing based on tumor screening complete germline testing. Even when offered as a covered benefit, only 21% of family members of those with newly diagnosed syndromes complete germline genetic testing. The individual pathologist responsible for ordering the tumor-based IHC screening was the strongest predictor of whether the screening was completed.

Caution
Though health systems can use the  results of this study to model programs within their systems, it is important to acknowledge several limitations to tumor-based screening. It requires multiple steps: (1) ordering/completing dMMR or MSI testing, (2) conducting any follow up tests (for instance braf or hypermethylation testing to exclude sporadic cancers in those with absence of MLH1/PMS2 on IHC0, (3) interpreting results, (4) placing referral to genetics, (5) completion of genetic testing, and (6) disclosure of results to patients and clinical providers. Even when there is clear designation of who is responsible for completing, interpreting and following up on the testing, there is drop off at each level. This study also reinforced how these programs are still vulnerable to variabilities in practice among individual clinicians. Furthermore, the tumor testing approach does not screen for other hereditary syndromes, which account for 50% of all pathogenic/likely pathogenic variants among CRC patients,⁸ and can even miss patients with Lynch Syndrome⁹. Thus, to try to simplify the process and optimize yield, there is movement in the field towards offering all CRC patients direct multigene panel germline genetic testing with the National Comprehensive Cancer Network asking clinicians to consider this approach for the first time in 2022.

My Practice
I recommend all CRC patients undergo hereditary risk assessment with three simple steps. First, we should be thinking about a possible hereditary syndrome in all patients we diagnose with CRC, regardless of age at diagnosis, family history or tumor characteristics. Second, I recommend ensuring that our pathology colleagues are performing tumor-based screening for dMMR on our CRC biopsy specimens instead of waiting until resection, since surgical management can change based on presence of a hereditary syndrome. Third, and finally, I recommend all patients with CRC be referred to a genetic counselor who can interpret tumor-based testing, collect multi-generation cancer family history and review the indications, benefits and expected yield of multi-gene panel testing for all CRC patients. I always emphasize the importance of communicating genetic testing results to all family members so they may benefit from relevant cancer risk reduction interventions.

For Future Research
As we move towards direct germline genetic testing in CRC patients, more research will need to be done to determine exactly which genes should be included on a panel and how best to ensure equitable access to genetic testing and appropriate follow up care for newly diagnosed patients and their family members.

Conflict of Interest
Dr. Patel has no disclosures.

REFERENCES

1. Win AK, Jenkins MA, Dowty JG, et al. Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer. Cancer Epidemiol Biomarkers Prev 2017;26:404-412.
2. NCCN. Genetic/Familial High-Risk Assessment: Colorectal. National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/default.aspx, 2021.
3. Hampel H, de la Chapelle A. The search for unaffected individuals with Lynch syndrome: do the ends justify the means? Cancer Prev Res (Phila) 2011;4:1-5.
4. Mittal C, Dang D, Stoffel E, et al. Underutilization of Lynch Syndrome Screening at Two Large Veterans Affairs Medical Centers. Dig Dis Sci 2020.
5. Beamer LC, Grant ML, Espenschied CR, et al. Reflex immunohistochemistry and microsatellite instability testing of colorectal tumors for Lynch syndrome among US cancer programs and follow-up of abnormal results. J Clin Oncol 2012;30:1058-63.
6. Cross DS, Rahm AK, Kauffman TL, et al. Underutilization of Lynch syndrome screening in a multisite study of patients with colorectal cancer. Genet Med 2013;15:933-40.
7. Karlitz JJ, Hsieh MC, Liu Y, et al. Population-Based Lynch Syndrome Screening by Microsatellite Instability in Patients </=50: Prevalence, Testing Determinants, and Result Availability Prior to Colon Surgery. Am J Gastroenterol 2015;110:948-55.
8. Yurgelun MB, Kulke MH, Fuchs CS, et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol 2017;35:1086-95.
9. Pearlman R, Frankel WL, Swanson BJ, et al. Prospective Statewide Study of Universal Screening for Hereditary Colorectal Cancer: The Ohio Colorectal Cancer Prevention Initiative. JCO Precis Oncol 2021;5.

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