Mark A Applebaum1, Zalman Vaksman2, Sang Mee Lee3, Eric A Hungate1, Tara O Henderson1, Wendy B London4, Navin Pinto5, Samuel L Volchenboum1, Julie R Park5, Arlene Naranjo6, Barbara Hero7, Andrew D Pearson8, Barbara E Stranger9, Susan L Cohn1, Sharon J Diskin10. 1. Department of Pediatrics, University of Chicago, Chicago, IL, USA. 2. Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 3. Department of Public Health Sciences, University of Chicago, Chicago, IL, USA. 4. Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. 5. Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. 6. Children's Oncology Group Statistics and Data Center, Department of Biostatistics, University of Florida, Gainseville, FL, USA. 7. Children's Hospital, Department of Pediatric Oncology and Hematology, University of Cologne, Cologne, Germany. 8. Divisions of Cancer Therapeutics and Clinical Studies, Institute of Cancer Research and Children and Young People's Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK - Retired. 9. Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA; Institute for Genomics and Systems Biology, Center for Data Intensive Science, University of Chicago, Chicago, IL, USA. 10. Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, Philadelphia, PA, USA. Electronic address: diskin@email.chop.edu.
Abstract
BACKGROUND: The incidence of second malignant neoplasm (SMN) within the first ten years of diagnosis in high-risk neuroblastoma patients treated with modern, intensive therapy is unknown. Further, the underlying germline genetics that contribute to SMN in these survivors are not known. METHODS: The International Neuroblastoma Risk Group (INRG) database of patients diagnosed from 1990 to 2010 was analysed. SMN risk was accessed by cumulative incidence, standardised incidence ratios (SIRs) and absolute excess risk. A candidate gene-based association study evaluated genetic susceptibility to SMN in neuroblastoma survivors. RESULTS: Of the 5987 patients in the INRG database with SMN data enrolled in a clinical trial, 43 (0.72%) developed a SMN. The 10-year cumulative incidence of SMN for high-risk patients was 1.8% (95% confidence interval [CI] 1.0-2.6%) compared with 0.38% (95% CI: 0.22-0.94%) for low-risk patients (P = 0.01). High-risk patients had an almost 18-fold higher incidence of SMN compared to age- and sex-matched controls (SIR = 17.5 (95% CI: 11.4-25.3), absolute excess risk = 27.6). For patients treated on high- and intermediate-risk clinical trials, the SIR of acute myelogenous leukaemia was 106.8 (95% CI: 28.7-273.4) and 127.7 (95%CI: 25.7-373.3), respectively. Variants implicating DNA repair genes XRCC3 (rs861539: P = 0.006; odds ratio: 2.04, 95%CI: 1.19-3.46) and MSH2 (rs17036651: P = 0.009; odds ratio: 0.26, 95% CI: 0.08-0.81) were associated with SMN. CONCLUSION: The intensive multi-modality treatment strategy currently used to treat high-risk neuroblastoma is associated with a significantly increased risk of secondary acute myelogenous leukaemia. Defining the interactions of treatment exposures and genetic factors that promote the development of SMN is critical for optimising survivorship care.
BACKGROUND: The incidence of second malignant neoplasm (SMN) within the first ten years of diagnosis in high-risk neuroblastomapatients treated with modern, intensive therapy is unknown. Further, the underlying germline genetics that contribute to SMN in these survivors are not known. METHODS: The International Neuroblastoma Risk Group (INRG) database of patients diagnosed from 1990 to 2010 was analysed. SMN risk was accessed by cumulative incidence, standardised incidence ratios (SIRs) and absolute excess risk. A candidate gene-based association study evaluated genetic susceptibility to SMN in neuroblastoma survivors. RESULTS: Of the 5987 patients in the INRG database with SMN data enrolled in a clinical trial, 43 (0.72%) developed a SMN. The 10-year cumulative incidence of SMN for high-risk patients was 1.8% (95% confidence interval [CI] 1.0-2.6%) compared with 0.38% (95% CI: 0.22-0.94%) for low-risk patients (P = 0.01). High-risk patients had an almost 18-fold higher incidence of SMN compared to age- and sex-matched controls (SIR = 17.5 (95% CI: 11.4-25.3), absolute excess risk = 27.6). For patients treated on high- and intermediate-risk clinical trials, the SIR of acute myelogenous leukaemia was 106.8 (95% CI: 28.7-273.4) and 127.7 (95%CI: 25.7-373.3), respectively. Variants implicating DNA repair genes XRCC3 (rs861539: P = 0.006; odds ratio: 2.04, 95%CI: 1.19-3.46) and MSH2 (rs17036651: P = 0.009; odds ratio: 0.26, 95% CI: 0.08-0.81) were associated with SMN. CONCLUSION: The intensive multi-modality treatment strategy currently used to treat high-risk neuroblastoma is associated with a significantly increased risk of secondary acute myelogenous leukaemia. Defining the interactions of treatment exposures and genetic factors that promote the development of SMN is critical for optimising survivorship care.
Authors: Mark A Applebaum; Tara O Henderson; Sang Mee Lee; Navin Pinto; Samuel L Volchenboum; Susan L Cohn Journal: Pediatr Blood Cancer Date: 2014-09-23 Impact factor: 3.167
Authors: Veronica Moroz; David Machin; Andreas Faldum; Barbara Hero; Tomoko Iehara; Veronique Mosseri; Ruth Ladenstein; Bruno De Bernardi; Hervé Rubie; Frank Berthold; Katherine K Matthay; Tom Monclair; Peter F Ambros; Andrew D J Pearson; Susan L Cohn; Wendy B London Journal: Eur J Cancer Date: 2010-11-26 Impact factor: 9.162
Authors: Alberto Garaventa; Claudio Gambini; Giampiero Villavecchia; Andrea Di Cataldo; Luigi Bertolazzi; Maria Rosa Pizzitola; Bruno De Bernardi; Riccardo Haupt Journal: Cancer Date: 2003-03-01 Impact factor: 6.860
Authors: Brian H Kushner; Kim Kramer; Shakeel Modak; Li-Xuan Qin; Karima Yataghena; Suresh C Jhanwar; Nai-Kong V Cheung Journal: Pediatr Blood Cancer Date: 2009-07 Impact factor: 3.167
Authors: Claire Seedhouse; Rowena Faulkner; Nadia Ashraf; Emma Das-Gupta; Nigel Russell Journal: Clin Cancer Res Date: 2004-04-15 Impact factor: 12.531
Authors: Susan L Cohn; Andrew D J Pearson; Wendy B London; Tom Monclair; Peter F Ambros; Garrett M Brodeur; Andreas Faldum; Barbara Hero; Tomoko Iehara; David Machin; Veronique Mosseri; Thorsten Simon; Alberto Garaventa; Victoria Castel; Katherine K Matthay Journal: J Clin Oncol Date: 2008-12-01 Impact factor: 44.544
Authors: Susan G Kreissman; Robert C Seeger; Katherine K Matthay; Wendy B London; Richard Sposto; Stephan A Grupp; Daphne A Haas-Kogan; Michael P Laquaglia; Alice L Yu; Lisa Diller; Allen Buxton; Julie R Park; Susan L Cohn; John M Maris; C Patrick Reynolds; Judith G Villablanca Journal: Lancet Oncol Date: 2013-07-25 Impact factor: 41.316
Authors: F J Hosking; D Feldman; R Bruchim; B Olver; A Lloyd; J Vijayakrishnan; P Flint-Richter; P Broderick; R S Houlston; S Sadetzki Journal: Br J Cancer Date: 2011-03-01 Impact factor: 7.640
Authors: Caroline Laverdière; Qi Liu; Yutaka Yasui; Paul C Nathan; James G Gurney; Marilyn Stovall; Lisa R Diller; Nai-Kong Cheung; Suzanne Wolden; Leslie L Robison; Charles A Sklar Journal: J Natl Cancer Inst Date: 2009-07-31 Impact factor: 11.816
Authors: Ferro Nguyen; Ivan Alferiev; Peng Guan; David T Guerrero; Venkatadri Kolla; Ganesh S Moorthy; Michael Chorny; Garrett M Brodeur Journal: Clin Cancer Res Date: 2018-03-07 Impact factor: 12.531
Authors: Danielle Novetsky Friedman; Patrick Hilden; Chaya S Moskowitz; Suzanne L Wolden; Emily S Tonorezos; Zoltan Antal; Dean Carlow; Shakeel Modak; Nai-Kong Cheung; Kevin C Oeffinger; Charles A Sklar Journal: Pediatr Blood Cancer Date: 2018-07-15 Impact factor: 3.167
Authors: Lin Xiao; Klaartje Somers; Murray D Norris; Michelle Haber; Jayne Murray; Ruby Pandher; Mawar Karsa; Emma Ronca; Angelika Bongers; Rachael Terry; Anahid Ehteda; Laura D Gamble; Natalia Issaeva; Katerina I Leonova; Aisling O'Connor; Chelsea Mayoh; Pooja Venkat; Hazel Quek; Jennifer Brand; Frances K Kusuma; Jessica A Pettitt; Erin Mosmann; Adam Kearns; Georgina Eden; Stephanie Alfred; Sophie Allan; Lei Zhai; Alvin Kamili; Andrew J Gifford; Daniel R Carter; Michelle J Henderson; Jamie I Fletcher; Glenn Marshall; Ricky W Johnstone; Anthony J Cesare; David S Ziegler; Andrei V Gudkov; Katerina V Gurova Journal: Clin Cancer Res Date: 2021-05-16 Impact factor: 12.531
Authors: Brittany J Poelaert; Svetlana Romanova; Shelby M Knoche; Madeline T Olson; Bailee H Sliker; Kaitlin Smits; Brittney L Dickey; Alexandra E J Moffitt-Holida; Benjamin T Goetz; Nuzhat Khan; Lynette Smith; Hamid Band; Aaron M Mohs; Donald W Coulter; Tatiana K Bronich; Joyce C Solheim Journal: J Control Release Date: 2020-07-22 Impact factor: 9.776
Authors: Sounak Gupta; Chad M Vanderbilt; Bradley C Leibovich; Loren Herrera-Hernandez; Aditya Raghunathan; William R Sukov; Jesse S Voss; Emily G Barr Fritcher; Katelyn A Reed; Christine M Lohse; Victor E Reuter; Rafael E Jimenez; R Houston Thompson; John C Cheville Journal: Hum Pathol Date: 2020-07-15 Impact factor: 3.466