Mismatch Repair Screening of Gastrointestinal Cancers: The Impact on Lynch Syndrome Detection and Immunotherapy

Abstract

Introduction: Mismatch repair immunohistochemistry (MMR IHC) or microsatellite instability (MSI) testing is now routinely performed in patients with colorectal cancer (CRC) to select those requiring Lynch syndrome testing. MMR IHC is also carried out on CRC and upper gastrointestinal (GI) cancers to select patients for immunotherapy. We review the Royal Marsden Hospital's pathway of molecular to germline testing for Lynch syndrome in the context of NICE guidance and the National Test Directory.

Methods: We conducted (i) a retrospective audit of adherence to NICE guidance DG27 for patients diagnosed with CRC March 2017-August 2018 and (ii) a retrospective service evaluation of MMR IHC/Lynch syndrome testing in patients diagnosed with upper GI cancers January 2019-2020.

Results: Of 394 patients with CRC, 346 (87.8%) had MMR IHC testing. Thirty-eight of 346 (10.9%) were MMR deficient (MMR-D) and 5 (1.4%) were found to have pathogenic germline variants causing Lynch syndrome. Of 405 patients with upper GI cancers, 221 (54.6%) had MMR IHC testing. Ten of 221 (4.5%) were MMR-D and 1 (0.5%) had a pathogenic germline variant causing Lynch syndrome.

Discussion: This study highlights the small but significant number of patients, with CRC or upper GI cancers, which were caused by Lynch syndrome. It also highlights weaknesses in our testing pathway that limit access to germline testing. As MMR testing increases, it is important that clinicians are aware that patients with MMR-D tumours require reflex somatic testing or referral for germline testing. We have incorporated the guidelines into a pathway for use in clinics and multidisciplinary teams.

Keywords: Colorectal cancer; Gastrointestinal cancer; Immunotherapy; Lynch syndrome; Microsatellite instability; Mismatch repair.

Fig. 1

Consort diagram showing MMR IHC testing for CRC. Including subsequent investigation and referral to clinical genetics, and evaluation of audit standards

Fig. 2

Summary of MMR IHC and genetic testing of patients with upper GI cancers

Fig. 3

Proposed management workflow for referral to clinical genetics for Lynch syndrome testing. Including separate assessment of CRC and upper GI malignancies. *No referral indicated for Lynch syndrome testing; however, pancreatic cancer age < 60; personal/family history of cancers; or personal history of bowel polyps may still warrant clinical genetics referral. † Amsterdam criteria: ≥ 3 cases over ≥ 2 generations with ≥ 1 case affected at < 50 years