Emerging therapeutic strategies in Lynch syndrome-associated colorectal cancer and the role of MMR testing

Abstract

Lynch syndrome is the most common hereditary cancer predisposition, accounting for 1-5% of colorectal cancer cases, and is driven by germline mutations in DNA mismatch repair genes. Despite established diagnostic criteria, such as the Amsterdam guidelines, Lynch syndrome remains largely underdiagnosed. To address this gap, universal tumour screening has been introduced for all newly diagnosed cases of colorectal cancer and endometrial cancer, significantly improving early detection. The surgical management of colorectal cancer in patients with Lynch syndrome remains controversial. While extended colectomy reduces the risk of metachronous colorectal cancer, surgical strategies must be carefully individualised based on patient-specific factors. Chemoprevention with aspirin has shown promise in reducing the risk of colorectal cancer, with ongoing trials investigating optimal dosing. Immunotherapy, particularly immune checkpoint inhibitors, has revolutionised the treatment of Microsatellite Instability-High/deficient Mismatch Repair colorectal cancer, offering durable responses and significant survival benefits. In addition, the neoadjuvant use of immune checkpoint inhibitors is paving the way for non-surgical interventions, potentially transforming the management of colorectal cancer in patients with Lynch syndrome. A multidisciplinary approach and continued research are essential to optimise cancer prevention, treatment and quality of life for people with Lynch syndrome.

Keywords: DNA mismatch repair; Lynch syndrome; colorectal cancer; immunotherapy; universal tumour screening.