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