Jacob G Scott1, Anders Berglund2, Michael J Schell2, Ivaylo Mihaylov3, William J Fulp2, Binglin Yue2, Eric Welsh2, Jimmy J Caudell4, Kamran Ahmed4, Tobin S Strom4, Eric Mellon4, Puja Venkat4, Peter Johnstone4, John Foekens5, Jae Lee2, Eduardo Moros4, William S Dalton6, Steven A Eschrich2, Howard McLeod6, Louis B Harrison4, Javier F Torres-Roca7. 1. Department of Radiation Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Integrated Mathematical Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA. 2. Department of Integrated Bioinformatics and Biostatistics, Moffitt Cancer Center and Research Institute, Tampa, FL, USA. 3. Department of Radiation Oncology, University of Miami, Miami, FL, USA. 4. Department of Radiation Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA. 5. Department of Medical Oncology and Cancer Genomics, Erasmus Medical Center, Rotterdam, Netherlands. 6. DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center and Research Institute, Tampa, FL, USA. 7. Department of Radiation Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Chemical Biology and Molecular Medicine, Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address: javier.torresroca@moffitt.org.
Abstract
BACKGROUND: Despite its common use in cancer treatment, radiotherapy has not yet entered the era of precision medicine, and there have been no approaches to adjust dose based on biological differences between or within tumours. We aimed to assess whether a patient-specific molecular signature of radiation sensitivity could be used to identify the optimum radiotherapy dose. METHODS: We used the gene-expression-based radiation-sensitivity index and the linear quadratic model to derive the genomic-adjusted radiation dose (GARD). A high GARD value predicts for high therapeutic effect for radiotherapy; which we postulate would relate to clinical outcome. Using data from the prospective, observational Total Cancer Care (TCC) protocol, we calculated GARD for primary tumours from 20 disease sites treated using standard radiotherapy doses for each disease type. We also used multivariable Cox modelling to assess whether GARD was independently associated with clinical outcome in five clinical cohorts: Erasmus Breast Cancer Cohort (n=263); Karolinska Breast Cancer Cohort (n=77); Moffitt Lung Cancer Cohort (n=60); Moffitt Pancreas Cancer Cohort (n=40); and The Cancer Genome Atlas Glioblastoma Patient Cohort (n=98). FINDINGS: We calculated GARD for 8271 tissue samples from the TCC cohort. There was a wide range of GARD values (range 1·66-172·4) across the TCC cohort despite assignment of uniform radiotherapy doses within disease types. Median GARD values were lowest for gliomas and sarcomas and highest for cervical cancer and oropharyngeal head and neck cancer. There was a wide range of GARD values within tumour type groups. GARD independently predicted clinical outcome in breast cancer, lung cancer, glioblastoma, and pancreatic cancer. In the Erasmus Breast Cancer Cohort, 5-year distant-metastasis-free survival was longer in patients with high GARD values than in those with low GARD values (hazard ratio 2·11, 95% 1·13-3·94, p=0·018). INTERPRETATION: A GARD-based clinical model could allow the individualisation of radiotherapy dose to tumour radiosensitivity and could provide a framework to design genomically-guided clinical trials in radiation oncology. FUNDING: None.
BACKGROUND: Despite its common use in cancer treatment, radiotherapy has not yet entered the era of precision medicine, and there have been no approaches to adjust dose based on biological differences between or within tumours. We aimed to assess whether a patient-specific molecular signature of radiation sensitivity could be used to identify the optimum radiotherapy dose. METHODS: We used the gene-expression-based radiation-sensitivity index and the linear quadratic model to derive the genomic-adjusted radiation dose (GARD). A high GARD value predicts for high therapeutic effect for radiotherapy; which we postulate would relate to clinical outcome. Using data from the prospective, observational Total Cancer Care (TCC) protocol, we calculated GARD for primary tumours from 20 disease sites treated using standard radiotherapy doses for each disease type. We also used multivariable Cox modelling to assess whether GARD was independently associated with clinical outcome in five clinical cohorts: Erasmus Breast Cancer Cohort (n=263); Karolinska Breast Cancer Cohort (n=77); Moffitt Lung Cancer Cohort (n=60); Moffitt Pancreas Cancer Cohort (n=40); and The Cancer Genome Atlas GlioblastomaPatient Cohort (n=98). FINDINGS: We calculated GARD for 8271 tissue samples from the TCC cohort. There was a wide range of GARD values (range 1·66-172·4) across the TCC cohort despite assignment of uniform radiotherapy doses within disease types. Median GARD values were lowest for gliomas and sarcomas and highest for cervical cancer and oropharyngeal head and neck cancer. There was a wide range of GARD values within tumour type groups. GARD independently predicted clinical outcome in breast cancer, lung cancer, glioblastoma, and pancreatic cancer. In the Erasmus Breast Cancer Cohort, 5-year distant-metastasis-free survival was longer in patients with high GARD values than in those with low GARD values (hazard ratio 2·11, 95% 1·13-3·94, p=0·018). INTERPRETATION: A GARD-based clinical model could allow the individualisation of radiotherapy dose to tumour radiosensitivity and could provide a framework to design genomically-guided clinical trials in radiation oncology. FUNDING: None.
Authors: Kamran A Ahmed; William J Fulp; Anders E Berglund; Sarah E Hoffe; Thomas J Dilling; Steven A Eschrich; Ravi Shridhar; Javier F Torres-Roca Journal: Int J Radiat Oncol Biol Phys Date: 2015-03-30 Impact factor: 7.038
Authors: Tobin Strom; Sarah E Hoffe; William Fulp; Jessica Frakes; Domenico Coppola; Gregory M Springett; Mokenge P Malafa; Cynthia L Harris; Steven A Eschrich; Javier F Torres-Roca; Ravi Shridhar Journal: Radiother Oncol Date: 2015-07-30 Impact factor: 6.280
Authors: John P Neoptolemos; Deborah D Stocken; Helmut Friess; Claudio Bassi; Janet A Dunn; Helen Hickey; Hans Beger; Laureano Fernandez-Cruz; Christos Dervenis; François Lacaine; Massimo Falconi; Paolo Pederzoli; Akos Pap; David Spooner; David J Kerr; Markus W Büchler Journal: N Engl J Med Date: 2004-03-18 Impact factor: 91.245
Authors: Yudi Pawitan; Judith Bjöhle; Lukas Amler; Anna-Lena Borg; Suzanne Egyhazi; Per Hall; Xia Han; Lars Holmberg; Fei Huang; Sigrid Klaar; Edison T Liu; Lance Miller; Hans Nordgren; Alexander Ploner; Kerstin Sandelin; Peter M Shaw; Johanna Smeds; Lambert Skoog; Sara Wedrén; Jonas Bergh Journal: Breast Cancer Res Date: 2005-10-03 Impact factor: 6.466
Authors: Michael S Lawrence; Petar Stojanov; Paz Polak; Gregory V Kryukov; Kristian Cibulskis; Andrey Sivachenko; Scott L Carter; Chip Stewart; Craig H Mermel; Steven A Roberts; Adam Kiezun; Peter S Hammerman; Aaron McKenna; Yotam Drier; Lihua Zou; Alex H Ramos; Trevor J Pugh; Nicolas Stransky; Elena Helman; Jaegil Kim; Carrie Sougnez; Lauren Ambrogio; Elizabeth Nickerson; Erica Shefler; Maria L Cortés; Daniel Auclair; Gordon Saksena; Douglas Voet; Michael Noble; Daniel DiCara; Pei Lin; Lee Lichtenstein; David I Heiman; Timothy Fennell; Marcin Imielinski; Bryan Hernandez; Eran Hodis; Sylvan Baca; Austin M Dulak; Jens Lohr; Dan-Avi Landau; Catherine J Wu; Jorge Melendez-Zajgla; Alfredo Hidalgo-Miranda; Amnon Koren; Steven A McCarroll; Jaume Mora; Brian Crompton; Robert Onofrio; Melissa Parkin; Wendy Winckler; Kristin Ardlie; Stacey B Gabriel; Charles W M Roberts; Jaclyn A Biegel; Kimberly Stegmaier; Adam J Bass; Levi A Garraway; Matthew Meyerson; Todd R Golub; Dmitry A Gordenin; Shamil Sunyaev; Eric S Lander; Gad Getz Journal: Nature Date: 2013-06-16 Impact factor: 49.962
Authors: Kamran A Ahmed; Prakash Chinnaiyan; William J Fulp; Steven Eschrich; Javier F Torres-Roca; Jimmy J Caudell Journal: Oncotarget Date: 2015-10-27
Authors: Alan Dal Pra; Cedric Panje; Thomas Zilli; Winfried Arnold; Kathrin Brouwer; Helena Garcia; Markus Glatzer; Silvia Gomez; Fernanda Herrera; Khanfir Kaouthar; Alexandros Papachristofilou; Gianfranco Pesce; Christiane Reuter; Hansjörg Vees; Daniel Rudolf Zwahlen; Daniel Engeler; Paul Martin Putora Journal: Strahlenther Onkol Date: 2017-06-27 Impact factor: 3.621
Authors: Elizabeth M Jaffee; Chi Van Dang; David B Agus; Brian M Alexander; Kenneth C Anderson; Alan Ashworth; Anna D Barker; Roshan Bastani; Sangeeta Bhatia; Jeffrey A Bluestone; Otis Brawley; Atul J Butte; Daniel G Coit; Nancy E Davidson; Mark Davis; Ronald A DePinho; Robert B Diasio; Giulio Draetta; A Lindsay Frazier; Andrew Futreal; Sam S Gambhir; Patricia A Ganz; Levi Garraway; Stanton Gerson; Sumit Gupta; James Heath; Ruth I Hoffman; Cliff Hudis; Chanita Hughes-Halbert; Ramy Ibrahim; Hossein Jadvar; Brian Kavanagh; Rick Kittles; Quynh-Thu Le; Scott M Lippman; David Mankoff; Elaine R Mardis; Deborah K Mayer; Kelly McMasters; Neal J Meropol; Beverly Mitchell; Peter Naredi; Dean Ornish; Timothy M Pawlik; Jeffrey Peppercorn; Martin G Pomper; Derek Raghavan; Christine Ritchie; Sally W Schwarz; Richard Sullivan; Richard Wahl; Jedd D Wolchok; Sandra L Wong; Alfred Yung Journal: Lancet Oncol Date: 2017-10-31 Impact factor: 41.316
Authors: David G Kirsch; Max Diehn; Aparna H Kesarwala; Amit Maity; Meredith A Morgan; Julie K Schwarz; Robert Bristow; Sandra Demaria; Iris Eke; Robert J Griffin; Daphne Haas-Kogan; Geoff S Higgins; Alec C Kimmelman; Randall J Kimple; Isabelle M Lombaert; Li Ma; Brian Marples; Frank Pajonk; Catherine C Park; Dörthe Schaue; Phuoc T Tran; Eric J Bernhard Journal: J Natl Cancer Inst Date: 2018-04-01 Impact factor: 13.506
Authors: David M McClatchy; Henning Willers; Aaron N Hata; Zofia Piotrowska; Lecia V Sequist; Harald Paganetti; Clemens Grassberger Journal: Cancer Res Date: 2020-09-09 Impact factor: 12.701
Authors: Kenneth L Pitter; Dana L Casey; Yue C Lu; Margaret Hannum; Zhigang Zhang; Xinmao Song; Isabella Pecorari; Biko McMillan; Jennifer Ma; Robert M Samstein; Isaac X Pei; Atif J Khan; Lior Z Braunstein; Luc G T Morris; Christopher A Barker; Andreas Rimner; Kaled M Alektiar; Paul B Romesser; Christopher H Crane; Joachim Yahalom; Michael J Zelefsky; Howard I Scher; Jonine L Bernstein; Diana L Mandelker; Britta Weigelt; Jorge S Reis-Filho; Nancy Y Lee; Simon N Powell; Timothy A Chan; Nadeem Riaz; Jeremy Setton Journal: J Natl Cancer Inst Date: 2021-03-01 Impact factor: 13.506
Authors: Guillermo Lorenzo; Víctor M Pérez-García; Alfonso Mariño; Luis A Pérez-Romasanta; Alessandro Reali; Hector Gomez Journal: J R Soc Interface Date: 2019-08-14 Impact factor: 4.118