PURPOSE: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor 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. RESULTS: A total of 193 malignant tumors 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 GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .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 < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Aga Khan University Hospital Karachi Pakistan

Akron Children's Hospital Akron OH

Ann and Robert H Lurie Children's Hospital of Chicago Chicago IL

Children's Hospital of Eastern Ontario Genetics Ottawa ON Canada

Children's Hospital of Pittsburgh of UPMC Pittsburgh PA

Children's National Medical Center Brain Tumor Institute Washington DC

Coliseum Medical Centers Macon GA

Dana Farber Children's Hospital Cancer Center Pediatric Oncology Boston MA

Deparments of Oncology and Human Genetics McGill University Health Centre Cancer Genetics Program Montreal QC Canada

Department of Biostatistics Princess Margaret Cancer Centre University of Toronto Toronto ON Canada

Department of Clinical Cancer Genetics Banner MD Anderson Cancer Center Gilbert AZ

Department of Hematology and Oncology Cleveland Clinic Cleveland OH

Department of Hematology Medical Oncology Medical University of South Carolina Charleston SC

Department of Hematology Oncology CHU de Quebec Universite Laval Quebec QC Canada

Department of Internal Medicine The Ohio State University Comprehensive Cancer Center Columbus OH

Department of Medical Oncology and Hematology CancerCare Manitoba Winnipeg MB Canada

Department of Neurosurgery Taipei Veterans General Hospital Taipei Taiwan

Department of Oncology Hadassah Medical Center Jerusalem Israel

Department of Oncology Saint Jude Children's Research Hospital Memphis TN

Department of Pediatric Haematology and Oncology Hospital of the Goethe University Frankfurt Frankfurt am Main Hessen Germany

Department of Pediatric Hemato Oncology Tel Aviv Sourasky Medical Center Tel Aviv Israel

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine University Hospital Motol Charles University Prague Czechia

Department of Pediatric Hematology and Oncology Atrium Health Charlotte NC

Department of Pediatric Hematology and Oncology Hannover Medical School Hannover Niedersachsen Germany

Department of Pediatric Hematology and Oncology Universite Catholique de Louvain Louvain la Neuve Walloon Brabant Belgium

Department of Pediatric Hematology and Oncology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Pediatric Hematology Oncology CancerCare Manitoba Winnipeg MB Canada

Department of Pediatric Hematology Oncology Children's Hospital Colorado Aurora CO

Department of Pediatric Hematology Oncology Children's Hospitals and Clinics of Minnesota Minneapolis MN

Department of Pediatric Hematology Oncology Hospital Infantil Universitario Nino Jesus Madrid Spain

Department of Pediatric Hematology Oncology Istanbul University Fatih Istanbul Turkey

Department of Pediatric Hematology Oncology King Fahad Medical City Riyadh Saudi Arabia

Department of Pediatric Hematology Oncology Nicklaus Children's Hospital Miami FL

Department of Pediatric Hematology Oncology NYU Langone Health New York NY

Department of Pediatric Hematology Oncology Schneider Children's Medical Center of Israel Petah Tikva Israel

Department of Pediatric Hematology Oncology Sheba Medical Center Tel Hashomer Israel

Department of Pediatric Hematology Oncology Sutter Health Sacramento CA

Department of Pediatric Hematology Oncology University of Michigan Medical School Ann Arbor MI

Department of Pediatric Laboratory Medicine The Hospital for Sick Children Toronto ON Canada

Department of Pediatric Neurology Medical College of Wisconsin Milwaukee WI

Department of Pediatric Neurosurgery Tel Aviv Sourasky Medical Center Tel Aviv Israel

Department of Pediatrics Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute Mumbai Maharashtra India

Department of Pediatrics London Health Sciences Centre London ON Canada

Department of Pediatrics Oregon Health and Science University Portland OR

Department of Pediatrics Stanford Medicine Stanford CA

Department of Pediatrics University of Gothenburg Sahlgrenska Academy Goteborg Sweden

Department of Pediatrics University of Padua Padova Veneto Italy

Department of Pediatrics West Virginia University Morgantown WV

Department of Surgery Mount Sinai Hospital Toronto ON Canada

Division of Clinical and Metabolic Genetics The Hospital for Sick Children Toronto ON Canada

Division of Gastroenterology Hepatology and Nutrition The Hospital for Sick Children Toronto ON Canada

Division of Hematology and Oncology The Hospital for Sick Children Toronto ON Canada

Division of Hematology Oncology IWK Health Centre Halifax NS Canada

Division of Medical Oncology University of Ottawa Ottawa ON Canada

Division of Oncology McGill University Health Centre Montreal QC Canada

IWK Health Centre Halifax NS Canada

Johns Hopkins All Children's Hospital Cancer and Blood Disorders Institute Saint Petersburg FL

Lebanese American University Medical Center Rizk Beirut Lebanon

MAHAK Pediatric Cancer Treatment and Research Center Tehran Iran

McGill University Health Centre Montreal QC Canada

Medical College of Wisconsin Pediatrics Milwaukee WI

Michigan State University College of Human Medicine Center for Bleeding and Clotting Disorders East Lansing MI

Ministry of Health Oman Child Health Specialist Muscat Muscat Oman

Motol University Hospital Praha Czechia

Mount Sinai Hospital The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease Toronto ON Canada

Oncology Division Tel Aviv University Sackler Faculty of Medicine Tel Aviv Israel

Oregon Health and Science University Portland OR

Paediatric Haematology Womens and Childrens Hospital North Adelaide South Australia Australia

Pediatric Hematology Oncology and Stem Cell Transplant Columbia University Irving Medical Center New York NY

Pediatric Unit Fondazione IRCCS Istituto Nazionale dei Tumori Milano Lombardia Italy

Rambam Health Care Campus The Genetics Institute Haifa Israel

Saint Jude Children's Research Hospital Memphis TN

Sheba Medical Center at Tel Hashomer Tel Hashomer Israel

Sheba Medical Center Cancer Research Center Tel Hashomer Israel

Sutter Health Cancer Risk Program Sacramento CA

Sydney Children's Hospital Randwick Kids Cancer Centre Randwick New South Wales Australia

Tel Aviv Sourasky Medical Center Genetic Institute Tel Aviv Israel

The Hospital for Sick Children The Arthur and Sonia Labatt Brain Tumour Research Centre Toronto ON Canada

The Indus Hospital Karachi Sindh Pakistan

The Ohio State University Comprehensive Cancer Center Internal Medicine Columbus OH

The Royal Children's Hospital Melbourne Children's Cancer Centre Parkville Victoria Australia

UH Rainbow Babies and Children's Hospital Division of Pediatrics Pediatric Neuro oncology Cleveland OH

Universite Catholique de Louvain La Faculte de Medecine Bruxelles Belgium

University Hospital Dusseldorf Dusseldorf Nordrhein Westfalen Germany

University of California San Francisco San Francisco CA

University of Toronto Institute of Medical Science Toronto ON Canada

Valley Children's Hospital Madera CA

Wayne State University Detroit MI

West Virginia University Cancer Institute Morgantown WV

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