Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance
Authors: Durno Carol , Ercan Ayse Bahar , Bianchi Vanessa , Edwards Melissa , Aronson Melyssa , Galati Melissa , Atenafu Eshetu G. , Abebe-Campino Gadi , Al-Battashi Abeer , Alharbi Musa , Azad Vahid Fallah , Baris Hagit N. , Basel Donald , Bedgood Raymond , Bendel Anne , Ben-Shachar Shay , Blumenthal Deborah T. , Blundell Maude , Bornhorst Miriam , Bronsema Annika , Cairney Elizabeth , Rhode Sara , Caspi Shani , Chamdin Aghiad , Chiaravalli Stefano , Constantini Shlomi , Crooks Bruce , Das Anirban , Dvir Rina , Farah Roula , Foulkes William D. , Frenkel Zehavit , Gallinger Bailey , Gardner Sharon , Gass David , Ghalibafian Mithra , Gilpin Catherine , Goldberg Yael , Goudie Catherine , Hamid Syed Ahmer , Hampel Heather , Hansford Jordan R. , Harlos Craig , Hijiya Nobuko , Hsu Saunders , Kamihara Junne , Kebudi Rejin , Knipstein Jeffrey , Koschmann Carl , Kratz Christian , Larouche Valerie , Lassaletta Alvaro , Lindhorst Scott , Ling Simon C. , Link Michael P. , Loret De Mola Rebecca , Luiten Rebecca , Lurye Michal , Maciaszek Jamie L. , MagimairajanIssai Vanan , Maher Ossama M. , Massimino Maura , McGee Rose B. , Mushtaq Naureen , Mason Gary , Newmark Monica , Nicholas Garth , Nichols Kim E. , Nicolaides Theodore , Opocher Enrico , Osborn Michael , Oshrine Benjamin , Pearlman Rachel , Pettee Daniel , Rapp Jan , Rashid Mohsin , Reddy Alyssa , Reichman Lara , Remke Marc , Robbins Gabriel , Roy Sumita , Sabel Magnus , Samuel David , Scheers Isabelle , Schneider Kami Wolfe , Sen Santanu , Stearns Duncan , Sumerauer David , Swallow Carol , Taylor Leslie , Thomas Gregory , Toledano Helen , Tomboc Patrick , Van Damme An , Winer Ira , Yalon Michal , Yen Lee Yi , Zapotocky Michal , Zelcer Shayna , Ziegler David S. , Zimmermann Stefanie , Hawkins Cynthia , Malkin David , Bouffet Eric , Villani Anita , Tabori Uri 
Published: May 2021

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.