As reported in the Journal of Clinical Oncology by Durno et al in the International Replication Repair Deficiency Consortium (IRRDC), use of an IRRDC surveillance protocol was associated with improved overall survival among patients with constitutional mismatch repair deficiency syndrome (CMMRD). As noted by the investigators, CMMRD is a cancer predisposition syndrome associated with inheritance of biallelic pathogenic variants in mismatch repair genes and characterized by early onset synchronous and metachronous multiorgan tumors.

Study Details

The IRRDC surveillance protocol for early tumor detection includes the following components: brain magnetic resonance imaging (MRI) at diagnosis and repeated every 6 months; whole-body MRI beginning at age 6 years and performed annually; abdominal ultrasound and complete blood count at diagnosis and repeated every 6 months; and upper and lower endoscopy annually starting at 4 to 6 years of age. The current analysis included data from patients with confirmed CMMRD who were registered in the IRRDC. Tumor spectrum, effectiveness 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 in 2008.

Key Findings

The study population included 110 patients with a total of 193 malignant tumors. Median age at first cancer diagnosis was 9.2 years (range = 1.7–39.5 years). The most common cancers were central nervous system (CNS; 44%), gastrointestinal (GI; 27%), and hematologic malignancies (19%).

Among 56 patients in the full cohort who underwent surveillance, all 24 GI tumors and each of 5 other solid tumors, 15 (75%) of 20 CNS tumors, and 2 (16%) of 12 hematologic malignancies were identified asymptomatically by surveillance.  

Among the 89 patients followed prospectively, 33 received full surveillance (routine screening using all the recommended modalities), 20 received partial surveillance (did not consistently undergo all screening modalities or were not screened at recommended intervals), and 36 did not receive any routine screening. A total of 139 tumors were detected, with 39 (28%) detected asymptomatically by surveillance and 100 (72%) diagnosed after initial symptoms or signs.

In the prospective cohort, 5-year overall survival was 90% (95% confidence interval [CI] = 78.6%–100%) when cancer was detected asymptomatically and 50% (95% CI = 39.2%–63.7%) when detected symptomatically (P = .001). Overall survival at 4 years was 79% (95% CI = 54.8%–90.9%) in the full-surveillance group (P < .0001 vs no surveillance), 55% (95% CI = 28.5%–74.5%) in the partial-surveillance group (P = .001 vs no surveillance), and 15% (95% CI = 5.2%–28.8%) in the no-surveillance group.

A total of 64 benign and low-grade lesions were detected in 54 patients, with the most common being colorectal polyps and low-grade gliomas. The cumulative likelihood of transformation of colorectal polyps to high-grade dysplastic lesions was 81% within 8 years, and the likelihood of transformation from low-grade to high-grade gliomas was 100% within 6 years.

The investigators concluded, “Surveillance and early cancer detection are associated with improved overall survival for individuals with CMMRD.”

Uri Tabori, MD, of the Division of Haematology-Oncology, The Hospital for Sick Children, Toronto, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by a Stand Up To Cancer-Bristol Meyers Squibb Catalyst Research Grant administered by the American Association for Cancer Research, Canada-Israel Health Research initiative, and others. For full disclosures of the study authors, visit ascopubs.org.