From gaps to compliance: a 12-year retrospective cohort study of trends in mismatch repair protein testing and Lynch syndrome identification in colorectal cancer in Central Switzerland.

Study aim: Alongside an analysis of incidence trends in colorectal cancer and Lynch syndrome over time, the study sought to evaluate the implementation and trends of reflex testing for mismatch repair proteins and key mutations in relevant genes (BRAF, KRAS, NRAS) in colorectal cancer in Central Switzerland from 2011 to 2022, specifically assessing adherence to the Swiss Academy for Quality in Medicine (SAQM) guidelines, in order to identify any gaps or inconsistencies in testing practices that may hinder the diagnosis of Lynch syndrome or microsatellite instability, highlighting areas requiring improvements for optimal patient care.

Methods: This retrospective study enrolled 2602 patients with 2673 histologically confirmed colorectal cancers. Data collection from the Central Switzerland Cancer Registry included demographic, molecular and immunohistochemical profiles of all histologically confirmed colorectal cancers over the analysed 12-year period. Statistical analyses were performed using R (v4.3.1) with the tidyverse package. Normality was assessed with the Shapiro-Wilk test and non-parametric comparisons were made using the Wilcoxon rank-sum test. Chi-square and Fisher's exact tests were used for categorical variables, while Poisson and binomial regression models were used to evaluate temporal trends.

Results: Of 2673 tumours analysed, 76% were tested for mismatch repair proteins, with testing rates improving significantly from 58% in 2011 to >99% in 2022. Among these, 14% showed a mismatch repair protein deficiency, with 77% being MLH1-related and 23% non-MLH1-related, categorising them as Lynch-suspected. 73% (n = 257) of the MLH1-deficient tumours underwent further molecular testing for BRAF mutations. Among these, 33% showed no mutation, also categorising them as Lynch-suspected, while the remaining 67% were categorised as sporadic. In total, 6% of the tested tumours were categorised as Lynch-suspected and required further testing and/or genetic counselling. Statistical estimates suggest that among the non-tested tumours, 88 cases could potentially harbour a microsatellite instability, including approximately 5 Lynch-suspected cases. Additionally, in 44 cases, incorrect mismatch repair proteins were tested, potentially leading to missed microsatellite instability. Among the 59 tumours that did not undergo BRAF testing, approximately 20 may have been Lynch-suspected and missed due to insufficient testing. Tumour incidence and the proportion of Lynch-suspected tumours among all tumours remained stable over time, without cantonal hotspots.

Conclusions: Remarkable progress in colorectal cancer diagnostics across Central Switzerland could be demonstrated, leading to a near-complete compliance with guidelines for mismatch repair proteins and molecular testing by 2022. This high adherence to guidelines provides a solid foundation for better personalised surveillance and treatment, ultimately improving the quality of care for colorectal cancer patients in the region. However, during the early years of the study some gaps existed, particularly in testing practices for rectal cancers and incomplete molecular follow-up, potentially missing some patients with a microsatellite instability, who could have benefited from different therapies, and Lynch syndrome patients, who together with their families could have benefited from tighter surveillance.