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  1. Article ; Online: Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti-PD-1 Monotherapy: A Report from the International RRD Consortium.

    Das, Anirban / Fernandez, Nicholas R / Levine, Adrian / Bianchi, Vanessa / Stengs, Lucie K / Chung, Jiil / Negm, Logine / Dimayacyac, Jose Rafael / Chang, Yuan / Nobre, Liana / Ercan, Ayse B / Sanchez-Ramirez, Santiago / Sudhaman, Sumedha / Edwards, Melissa / Larouche, Valerie / Samuel, David / Van Damme, An / Gass, David / Ziegler, David S /
    Bielack, Stefan S / Koschmann, Carl / Zelcer, Shayna / Yalon-Oren, Michal / Campino, Gadi Abede / Sarosiek, Tomasz / Nichols, Kim E / Loret De Mola, Rebecca / Bielamowicz, Kevin / Sabel, Magnus / Frojd, Charlotta A / Wood, Matthew D / Glover, Jason M / Lee, Yi-Yen / Vanan, Magimairajan / Adamski, Jenny K / Perreault, Sebastien / Chamdine, Omar / Hjort, Magnus Aasved / Zapotocky, Michal / Carceller, Fernando / Wright, Erin / Fedorakova, Ivana / Lossos, Alexander / Tanaka, Ryuma / Osborn, Michael / Blumenthal, Deborah T / Aronson, Melyssa / Bartels, Ute / Huang, Annie / Ramaswamy, Vijay / Malkin, David / Shlien, Adam / Villani, Anita / Dirks, Peter B / Pugh, Trevor J / Getz, Gad / Maruvka, Yosef E / Tsang, Derek S / Ertl-Wagner, Birgit / Hawkins, Cynthia / Bouffet, Eric / Morgenstern, Daniel A / Tabori, Uri

    Cancer discovery

    2023  Volume 14, Issue 2, Page(s) 258–273

    Abstract: Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy is unknown. We performed an international study on ... ...

    Abstract Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy is unknown. We performed an international study on 75 patients treated with anti-PD-1; 20 are progression free (median follow-up, 3.7 years). After second progression/recurrence (n = 55), continuing ICI-based salvage prolonged survival to 11.6 months (n = 38; P < 0.001), particularly for those with extreme mutation burden (P = 0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and the immune microenvironment. Response to reirradiation was explained by an absence of deleterious postradiation indel signatures (ID8). CTLA4 expression increased over time, and subsequent CTLA4 inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to the reinvigoration of peripheral immune and radiologic responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide a mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology.
    Significance: Hypermutant RRD-HGG are susceptible to checkpoint inhibitors beyond initial progression, leading to improved survival when reirradiation and synergistic immune/targeted agents are added. This is driven by their unique biological and immune properties, which evolve over time. Future research should focus on combinatorial regimens that increase patient survival while limiting immune toxicity. This article is featured in Selected Articles from This Issue, p. 201.
    MeSH term(s) Humans ; CTLA-4 Antigen ; Glioma/drug therapy ; Glioma/genetics ; Brain Neoplasms/drug therapy ; Brain Neoplasms/genetics ; Antineoplastic Agents/therapeutic use ; Immunotherapy ; Tumor Microenvironment
    Chemical Substances CTLA-4 Antigen ; Antineoplastic Agents
    Language English
    Publishing date 2023-10-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2625242-9
    ISSN 2159-8290 ; 2159-8274
    ISSN (online) 2159-8290
    ISSN 2159-8274
    DOI 10.1158/2159-8290.CD-23-0559
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

    Ercan, Ayse Bahar / Aronson, Melyssa / Fernandez, Nicholas R / Chang, Yuan / Levine, Adrian / Liu, Zhihui Amy / Negm, Logine / Edwards, Melissa / Bianchi, Vanessa / Stengs, Lucie / Chung, Jiil / Al-Battashi, Abeer / Reschke, Agnes / Lion, Alex / Ahmad, Alia / Lassaletta, Alvaro / Reddy, Alyssa T / Al-Darraji, Amir F / Shah, Amish C /
    Van Damme, An / Bendel, Anne / Rashid, Aqeela / Margol, Ashley S / Kelly, Bethany L / Pencheva, Bojana / Heald, Brandie / Lemieux-Anglin, Brianna / Crooks, Bruce / Koschmann, Carl / Gilpin, Catherine / Porter, Christopher C / Gass, David / Samuel, David / Ziegler, David S / Blumenthal, Deborah T / Kuo, Dennis John / Hamideh, Dima / Basel, Donald / Khuong-Quang, Dong-Anh / Stearns, Duncan / Opocher, Enrico / Carceller, Fernando / Baris Feldman, Hagit / Toledano, Helen / Winer, Ira / Scheers, Isabelle / Fedorakova, Ivana / Su, Jack M / Vengoechea, Jaime / Sterba, Jaroslav / Knipstein, Jeffrey / Hansford, Jordan R / Gonzales-Santos, Julieta Rita / Bhatia, Kanika / Bielamowicz, Kevin J / Minhas, Khurram / Nichols, Kim E / Cole, Kristina A / Penney, Lynette / Hjort, Magnus Aasved / Sabel, Magnus / Gil-da-Costa, Maria Joao / Murray, Matthew J / Miller, Matthew / Blundell, Maude L / Massimino, Maura / Al-Hussaini, Maysa / Al-Jadiry, Mazin F / Comito, Melanie A / Osborn, Michael / Link, Michael P / Zapotocky, Michal / Ghalibafian, Mithra / Shaheen, Najma / Mushtaq, Naureen / Waespe, Nicolas / Hijiya, Nobuko / Fuentes-Bolanos, Noemi / Ahmad, Olfat / Chamdine, Omar / Roy, Paromita / Pichurin, Pavel N / Nyman, Per / Pearlman, Rachel / Auer, Rebecca C / Sukumaran, Reghu K / Kebudi, Rejin / Dvir, Rina / Raphael, Robert / Elhasid, Ronit / McGee, Rose B / Chami, Rose / Noss, Ryan / Tanaka, Ryuma / Raskin, Salmo / Sen, Santanu / Lindhorst, Scott / Perreault, Sebastien / Caspi, Shani / Riaz, Shazia / Constantini, Shlomi / Albert, Sophie / Chaleff, Stanley / Bielack, Stefan / Chiaravalli, Stefano / Cramer, Stuart Louis / Roy, Sumita / Cahn, Suzanne / Penna, Suzanne / Hamid, Syed Ahmer / Ghafoor, Tariq / Imam, Uzma / Larouche, Valerie / Magimairajan Issai, Vanan / Foulkes, William D / Lee, Yi Yen / Nathan, Paul C / Maruvka, Yosef E / Greer, Mary-Louise C / Durno, Carol / Shlien, Adam / Ertl-Wagner, Birgit / Villani, Anita / Malkin, David / Hawkins, Cynthia / Bouffet, Eric / Das, Anirban / Tabori, Uri

    The Lancet. Oncology

    2024  Volume 25, Issue 5, Page(s) 668–682

    Abstract: Background: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the ...

    Abstract Background: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD.
    Methods: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions.
    Findings: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions.
    Interpretation: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD.
    Funding: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.
    MeSH term(s) Humans ; Male ; Female ; Child ; Child, Preschool ; Neoplastic Syndromes, Hereditary/genetics ; Neoplastic Syndromes, Hereditary/therapy ; Cross-Sectional Studies ; Adolescent ; Brain Neoplasms/genetics ; Brain Neoplasms/therapy ; Brain Neoplasms/mortality ; Brain Neoplasms/pathology ; Brain Neoplasms/epidemiology ; DNA Mismatch Repair ; Longitudinal Studies ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/pathology ; Colorectal Neoplasms/mortality ; Incidence ; MutS Homolog 2 Protein/genetics ; MutL Protein Homolog 1/genetics ; Adult ; Young Adult ; Mutation ; DNA-Binding Proteins
    Chemical Substances MutS Homolog 2 Protein (EC 3.6.1.3) ; MutL Protein Homolog 1 (EC 3.6.1.3) ; MLH1 protein, human ; MSH2 protein, human (EC 3.6.1.3) ; G-T mismatch-binding protein ; DNA-Binding Proteins
    Language English
    Publishing date 2024-03-26
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Multicenter Study
    ZDB-ID 2049730-1
    ISSN 1474-5488 ; 1470-2045
    ISSN (online) 1474-5488
    ISSN 1470-2045
    DOI 10.1016/S1470-2045(24)00026-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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