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. 2021 Sep 1;39(25):2779-2790.
doi: 10.1200/JCO.20.02636. Epub 2021 May 4.

Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance

Carol Durno  1   2 , Ayse Bahar Ercan  3   4 , Vanessa Bianchi  3 , Melissa Edwards  3 , Melyssa Aronson  2 , Melissa Galati  3   4 , Eshetu G Atenafu  5 , Gadi Abebe-Campino  6 , Abeer Al-Battashi  7 , Musa Alharbi  8 , Vahid Fallah Azad  9 , Hagit N Baris  10 , Donald Basel  11 , Raymond Bedgood  12 , Anne Bendel  13 , Shay Ben-Shachar  14 , Deborah T Blumenthal  15 , Maude Blundell  16 , Miriam Bornhorst  17 , Annika Bronsema  18 , Elizabeth Cairney  19 , Sara Rhode  20 , Shani Caspi  21 , Aghiad Chamdin  22 , Stefano Chiaravalli  23 , Shlomi Constantini  24 , Bruce Crooks  25 , Anirban Das  26 , Rina Dvir  27 , Roula Farah  28 , William D Foulkes  29 , Zehavit Frenkel  30 , Bailey Gallinger  31 , Sharon Gardner  32 , David Gass  33 , Mithra Ghalibafian  9 , Catherine Gilpin  34 , Yael Goldberg  35 , Catherine Goudie  36 , Syed Ahmer Hamid  37 , Heather Hampel  38 , Jordan R Hansford  39 , Craig Harlos  40 , Nobuko Hijiya  41 , Saunders Hsu  42 , Junne Kamihara  43 , Rejin Kebudi  44 , Jeffrey Knipstein  45 , Carl Koschmann  46 , Christian Kratz  47 , Valerie Larouche  48 , Alvaro Lassaletta  49 , Scott Lindhorst  50 , Simon C Ling  1 , Michael P Link  51 , Rebecca Loret De Mola  52 , Rebecca Luiten  53 , Michal Lurye  30 , Jamie L Maciaszek  54 , Vanan MagimairajanIssai  55 , Ossama M Maher  56 , Maura Massimino  23 , Rose B McGee  54 , Naureen Mushtaq  57 , Gary Mason  58 , Monica Newmark  59 , Garth Nicholas  60 , Kim E Nichols  61 , Theodore Nicolaides  32 , Enrico Opocher  62 , Michael Osborn  63 , Benjamin Oshrine  64 , Rachel Pearlman  65 , Daniel Pettee  66 , Jan Rapp  67 , Mohsin Rashid  68 , Alyssa Reddy  69 , Lara Reichman  70 , Marc Remke  71 , Gabriel Robbins  32 , Sumita Roy  72 , Magnus Sabel  73 , David Samuel  74 , Isabelle Scheers  75 , Kami Wolfe Schneider  76 , Santanu Sen  77 , Duncan Stearns  78 , David Sumerauer  79 , Carol Swallow  80 , Leslie Taylor  54 , Gregory Thomas  81 , Helen Toledano  82 , Patrick Tomboc  83 , An Van Damme  84 , Ira Winer  72 , Michal Yalon  6 , Lee Yi Yen  85 , Michal Zapotocky  86 , Shayna Zelcer  19 , David S Ziegler  87 , Stefanie Zimmermann  88 , Cynthia Hawkins  89 , David Malkin  26 , Eric Bouffet  26 , Anita Villani  26 , Uri Tabori  26
Affiliations

Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance

Carol Durno et al. J Clin Oncol. .

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.

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Conflict of interest statement

Hagit N. BarisConsulting or Advisory Role: Sanofi, Igentify LtdSpeakers' Bureau: Sanofi, Takeda, Pfizer Donald BaselHonoraria: BioMarinConsulting or Advisory Role: iQvia Deborah T. BlumenthalConsulting or Advisory Role: AstraZeneca, Novocure, Takeda Miriam BornhorstConsulting or Advisory Role: AstraZeneca/MedImmune Sara RhodeHonoraria: Myriad GeneticsSpeakers' Bureau: Myriad GeneticsTravel, Accommodations, Expenses: Myriad Genetics Roula FarahHonoraria: Novo NordiskConsulting or Advisory Role: Novo Nordisk William D. FoulkesResearch Funding: AstraZeneca David GassEmployment: X4 PharmaceuticalsHonoraria: X4 PharmaceuticalsSpeakers' Bureau: Precisionscientia Heather HampelStock and Other Ownership Interests: Genome MedicalConsulting or Advisory Role: InVitae, Genome Medical, Promega, 23andMe Jordan R. HansfordConsulting or Advisory Role: Bayer Craig HarlosTravel, Accommodations, Expenses: GlaxoSmithKline Nobuko HijiyaHonoraria: NovartisConsulting or Advisory Role: Novartis, IncyteResearch Funding: Pfizer Junne KamiharaStock and Other Ownership Interests: PanTher Therapeutics, ROME Therapeutics, TellBioHonoraria: Pfizer, NanoString Technologies, Third Rock Ventures, Foundation MedicineConsulting or Advisory Role: ROME Therapeutics, Third Rock VenturesResearch Funding: PureTech, Ribon Therapeutics, ACD BiotechnePatents, Royalties, Other Intellectual Property: Patent on drug delivery device licensed to PanTher Therapeutics, Patents on Repeat RNA biomarkers and therapeutics licensed to Rome Therapeutics, Patents on Circulating Tumor Cell Biomarkers Licensed to TellBio Inc Jeffrey KnipsteinEmployment: PRA Health SciencesConsulting or Advisory Role: Atheneum Alvaro LassalettaStock and Other Ownership Interests: Gilead SciencesConsulting or Advisory Role: Shire, Jazz Pharmaceuticals, Roche, ServierTravel, Accommodations, Expenses: Shire, Gilead Sciences Simon C. LingHonoraria: AbbvieResearch Funding: Abbvie, Gilead Sciences Michael P. LinkConsulting or Advisory Role: Incyte, ADC Therapeutics, Lilly, Steba Biotech, Mesoblast, GlaxoSmithKline, SyndaxResearch Funding: Seattle Genetics, Janssen Oncology Rebecca Loret de MolaEmployment: Huron Consulting Maura MassiminoConsulting or Advisory Role: Oncoscience, Novartis Gary MasonEmployment: Janssen Research & Development, MerckStock and Other Ownership Interests: Johnson & Johnson, MerckTravel, Accommodations, Expenses: Janssen Research & Development Kim E. NicholsStock and Other Ownership Interests: IncyteResearch Funding: Incyte/Novartis, Alpine Immune Sciences Enrico OpocherConsulting or Advisory Role: AstraZenecaTravel, Accommodations, Expenses: AstraZeneca Michael OsbornTravel, Accommodations, Expenses: Amgen, Pfizer Benjamin OshrineHonoraria: Mesoblast Alyssa ReddyConsulting or Advisory Role: Novartis, AstraZeneca Lara ReichmanResearch Funding: Illumina Marc RemkeStock and Other Ownership Interests: Bayer, BB Biotech Ventures, BioNTech AG, InVitae, IDEXX Laboratories Kami Wolfe SchneiderOther Relationship: Journal of Genetic Counseling Duncan StearnsConsulting or Advisory Role: AstraZenecaOpen Payments Link: https://openpaymentsdata.cms.gov/physician/792397 Patrick TombocHonoraria: Unicare Health PlanConsulting or Advisory Role: UniCare Health Plan An Van DammeConsulting or Advisory Role: Octapharm, Pfizer, BayerResearch Funding: Johnson & JohnsonTravel, Accommodations, Expenses: Pfizer, Sobi, Shire, Roche Ira WinerResearch Funding: Oncoceutics David S. ZieglerConsulting or Advisory Role: Bayer, AmgenTravel, Accommodations, Expenses: Bayer Cynthia HawkinsConsulting or Advisory Role: BayerPatents, Royalties, Other Intellectual Property: IP for low-grade glioma and sarcoma fusion panels as well as medulloblastoma subgrouping panel David MalkinConsulting or Advisory Role: Bayer Eric BouffetConsulting or Advisory Role: NovartisResearch Funding: Roche, Bristol Myers SquibbNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Study overview. CMMRD, constitutional mismatch repair deficiency; IRRDC, International Replication Repair Deficiency Consortium.
FIG 2.
FIG 2.
Tumor spectrum and efficacy of the surveillance modalities to detect asymptomatic malignant tumors in the full study cohort. (A) Distribution of malignant tumors from individuals with CMMRD. (B) Tumors detected during surveillance per tumor type. *P = .03 (brain) compared with literature cohort (brain) determined using “N–1” chi-squared test. ALL, acute lymphoblastic leukemia; AML, acute myelomonocytic leukemia; CMMRD, constitutional mismatch repair deficiency; IRRDC, International Replication Repair Deficiency Consortium.
FIG 3.
FIG 3.
Survival for individuals with constitutional mismatch repair deficiency according to surveillance status. (A) Survival for all tumors stratified by symptomatic and asymptomatic detection. (B) Survival for brain tumors stratified by symptomatic and asymptomatic detection. (C) Survival for GI tumors stratified by symptomatic and asymptomatic detection. (D) Survival for patients stratified by surveillance adherence. P values were calculated by log-rank test. OS, overall survival.
FIG 4.
FIG 4.
Low-grade tumors detected in patients with constitutional mismatch repair deficiency undergoing surveillance. (A) Distribution of low-grade tumors in the full study cohort (n = 64). (B) Percentage of polyps with high-grade dysplasia and the frequency of preventative surgery. (C) Magnetic resonance imaging scans showing tumor transformation and time to transformation of six nonresected low-grade gliomas. (D) Cumulative likelihood of high-grade transformation over time for brain (red) and GI (blue) tumors.
See this image and copyright information in PMC

References

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