Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance

Abstract

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.

Immune Checkpoint Inhibition as Single Therapy for Synchronous Cancers Exhibiting Hypermutation: An IRRDC Study

“…Clinical data (cancer incidence and time) were collected from 106 patients with CMMRD registered in the International Replication Repair Deficiency Consortium [6][7][8][9]12 between 2008 and 2019. Metachronous (arising sequentially and after completion of treatment for the first primary tumor) and synchronous tumors (distinct cancers that either coexist at the time of the original diagnosis or develop during the treatment of the original cancer and/or , 6 months from the primary diagnosis) were identified, and whole-exome sequencing (WES) was preformed from their paired tumor and germline samples to determine TMB, COSMIC mutational signatures, 13 neoantigen burden, and microsatellite (MS)-indels 14 using established tools (Data Supplement).…”

Challenges in the diagnosis of neurofibromatosis type 1 (NF1) in young children facilitated by means of revised diagnostic criteria including genetic testing for pathogenic NF1 gene variants

“…Constitutive mismatch repair deficiency (CMMRD, MIM#276300) is a rare autosomal recessive inherited disease caused by pathogenic variants in one of the mismatch repair genes MLH1 , MSH2 , MSH6 or PMS2 (Bakry et al 2014 ; Wimmer et al 2014 , 2017 ; Suerink et al 2019 ; Perez-Valencia et al 2020 ; Aronson et al 2021 ; Duorno et al 2021 ). Children with CMMRD often have multiple CALM that are similar to those seen in patients with NF1 or Legius syndrome.…”

“…Some patients with CMMRD even meet the clinical NIH diagnostic criteria for NF1 (Wimmer et al 2014 ). It is important to distinguish between these conditions because CMMRD is associated with a high risk of childhood malignancy unlike NF1 and Legius syndrome (Bakry et al 2014 ; Wimmer et al 2014 , 2017 ; Suerink et al 2019 ; Perez-Valencia et al 2020 ; Aronson et al 2021 ; Duorno et al 2021 ).…”

Could the immune checkpoint inhibitor against colorectal cancer in constitutional mismatch repair deficiency syndrome prevent new cancer formation?

“…12 Cancer surveillance is essential to improving long-term prognosis, as it promotes early cancer detection and prevention. 13 To prevent carcinogenesis in patients with CMMRD, methodologies such as aspirin intake, which was reportedly effective against LS, and ICI, neoantigen vaccine or a combination thereof have been considered. 4,8,[12][13][14] Chang et al reported that immunoprofiling of premalignant lesions with LS suggested the effectiveness of ICIs.…”

“…13 To prevent carcinogenesis in patients with CMMRD, methodologies such as aspirin intake, which was reportedly effective against LS, and ICI, neoantigen vaccine or a combination thereof have been considered. 4,8,[12][13][14] Chang et al reported that immunoprofiling of premalignant lesions with LS suggested the effectiveness of ICIs. 15 This report suggested the efficacy of ICI for the prevention of carcinogenesis from polyps.…”