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Surveillance and Early Cancer Detection are Associated with Improved Survival in Constitutional Mismatch Repair Deficiency Syndrome

Data from patients with confirmed syndrome registered in the International Replication Repair Deficiency Consortium
01 Sep 2021
Cancer in Special Situations/ Populations

Constitutional mismatch repair deficiency syndrome is a cancer predisposition syndrome associated with inheritance of biallelic pathogenic variants in mismatch repair (MMR) genes leading to deficient MMR during DNA replication. It is characterised by early-onset synchronous and metachronous multiorgan tumours. Surveillance recommendations are effective for early detection and intervention and improve overall survival (OS) in patients with this syndrome according to Dr. Uri Tabori of the Division of Hematology and Oncology, The Hospital for Sick Children in Toronto, Canada, who published the results with colleagues from the International Replication Repair Deficiency Consortium in the Journal of Clinical Oncology.  

The authors wrote in the study background that loss of functional MMR results in a rapid accumulation of mutations and the development of cancers that are highly aggressive and display a hypermutant phenotype. Because of the nature of these tumours, commonly used chemotherapies and radiation are largely ineffective. 

The most common tumours observed in these patients are early-onset central nervous system, gastrointestinal, and haematologic malignancies with higher penetrance than other cancer predisposition syndromes. Although other cancer types have been reported in children and adults with constitutional mismatch repair deficiency syndrome, the frequency and extent of these malignancies are not well characterised.

The International Replication Repair Deficiency Consortium was formed in 2007 and currently includes paediatric and adult patients from more than 45 countries. Since 2008, surveillance recommendations were implemented as part of the management of these patients. However, the recommendations are based on expert opinion and no study has systematically evaluated the efficacy of surveillance and whether adherence affects OS.

The goal of this study was to systematically evaluate the proposed surveillance recommendations for constitutional mismatch repair deficiency syndrome to determine whether current modalities are appropriate to detect the full spectrum of tumours seen and whether detecting asymptomatic tumours results in improved outcome. Tumour spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation.

A total of 193 malignant tumours in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range, 1.7-39.5 years). For patients undergoing surveillance, all gastrointestinal and other solid tumours, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of haematologic malignancies were detected asymptomatically (p < 0.001).

In survival analysis, 89 patients were followed prospectively. Five-year OS was 90% (95% confidence interval [CI] 78.6 to 100) and 50% (95% CI 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (p = 0.001).

Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI 28.5 to 74.5) for partial surveillance, and 15% (95% CI 5.2 to 28.8) for those not under surveillance (p < 0.0001).

Of the 64 low-grade tumours detected, the cumulative likelihood of transformation from low-to high-grade was 81% for gastrointestinal cancers within 8 years and 100% for gliomas in 6 years.

The authors concluded that early presymptomatic detection of constitutional mismatch repair deficiency syndrome cancers by using the current recommended surveillance modalities was associated with improved survival. The OS was significantly better in individuals with the syndrome who fully adhered to surveillance recommendations compared with individuals who did not undergo surveillance. All low-grade brain and most gastrointestinal lesions transformed to malignant cancers during the study period indicating a potential benefit of early detection and intervention.

This study provides justification for the current protocol that can be implemented in most centres around the world and demonstrates a significant survival benefit associated with undergoing surveillance in patients with constitutional mismatch repair deficiency syndrome. Further work is required to enable better detection of some malignancies.

The study was supported by a Stand Up to Cancer—Bristol Meyers Squibb Catalyst Research Grant which is administered by the American Association for Cancer Research. It was also supported by the Canada-Israel Health Research initiative, jointly funded by the Canadian Institutes of Health Research, the Israel Science Foundation, the International Development Research Centre, Canada, and the Azrieli Foundation. Additional financial support was provided by the Canadian Institutes of Health Research, Meagan's Walk, LivWise, The Zane Cohen Center, and BRAINchild.


Durno C, Bahar Ercan A, Bianchi V, et al. Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance. JCO 2021;39(25):2779-2790. DOI: 10.1200/JCO.20.02636. 

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