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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.

Background The MAPK pathway, is a signal transduction pathway involved in the oncogenesis of a variety of pediatric tumors. The clinical use of BRAF inhibitors and MEK inhibitors is increasingly used in oncology practice. The toxicity profile of these drugs in the pediatric population, particularly in relation to development, growth and sexual maturation remains insufficiently studied. Procedure This study includes 22 pediatric patients with molecularly confirmed MAPK pathway driven tumors treated with MEK or BRAF between August 2014 and March 2020. Throughout treatment they underwent regular laboratory, endocrine, cardiac, ophthalmic and dermatologic evaluation. Toxicity was recorded and evaluated according to CTCA v4. Results Overall an adverse event frequency of 86% was encountered. Dermatological disorders accounted for 68% of the adverse events. Overall 8 patients suffered from severe adverse events including Erythema Nodosum, PLEVA-like rash, osteoporosis, Sarcoid-like massive lymphadenopathy, retinal toxicity and elevated liver enzymes & CPK. Four patients discontinued treatment as a result of adverse events. In this cohort we did not encounter any treatment-related abnormalities of sexual maturation or gonadal function nor statistically significant growth retardation, however a slower than expected growth rate was observed in one patient. In addition dose-dependent, non-symptomatic and within normal range for age decreased cardiac SF% was noted in two patients treated with MEK inhibitor. Conclusion Treatment with BRAF and MEK inhibitors was shown to be generally safe, we report drug tolerability of 82%. However, further prospective studies should be preformed to are characterize the full scope of side effects in the pediatric population.

BACKGROUND Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome resulting in early onset central nervous system (CNS) and other cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. METHODS We surveyed all confirmed CMMRD patients in the International Replication Repair Deficiency Consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging (CNS and total body MRI) studies were employed. Survival analyses and efficacy of each method were assessed. RESULTS Surveillance data were collected from 105 CMMRD individuals from 41 countries. Of the 193 malignant tumors, CNS malignancies were the most common (44%). The surveillance protocol uncovered 49 asymptomatic tumors including 16 glioblastomas and medulloblastomas. Five-year overall survival was 89% for tumors discovered by surveillance, and 61% for symptomatic tumors (p6 months as per protocol. Finally, of the low grade tumors identified asymptomatically, 5 were low grade gliomas. All of the low grade gliomas, which were not resected transformed to high grade tumors at a median of 1.6 ± 0.9 years. CONCLUSION These data support a survival benefit in CMMRD patients undergoing a surveillance protocol. Adherence to protocol and resection of lower grade lesions may improve survival for patients with CNS tumors.