title: A genome-based model for adjusting radiotherapy dose (GARD): a retrospective, cohort-based study.
abstract: 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.
  
  
  
  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).
  
  
  
  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).
  
  
  
  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.
  
  
  
  None.
authors.affiliation: 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.
authors.forename: Jacob G
authors.initials: JG
authors.lastname: Scott
authors.affiliation: Department of Integrated Bioinformatics and Biostatistics, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Anders
authors.initials: A
authors.lastname: Berglund
authors.affiliation: Department of Integrated Bioinformatics and Biostatistics, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schell
authors.affiliation: Department of Radiation Oncology, University of Miami, Miami, FL, USA.
authors.forename: Ivaylo
authors.initials: I
authors.lastname: Mihaylov
authors.affiliation: Department of Integrated Bioinformatics and Biostatistics, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Fulp
authors.affiliation: Department of Integrated Bioinformatics and Biostatistics, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Binglin
authors.initials: B
authors.lastname: Yue
authors.affiliation: Department of Integrated Bioinformatics and Biostatistics, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Welsh
authors.affiliation: Department of Radiation Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Jimmy J
authors.initials: JJ
authors.lastname: Caudell
authors.affiliation: Department of Radiation Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Kamran
authors.initials: K
authors.lastname: Ahmed
authors.affiliation: Department of Radiation Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Tobin S
authors.initials: TS
authors.lastname: Strom
authors.affiliation: Department of Radiation Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Mellon
authors.affiliation: Department of Radiation Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Puja
authors.initials: P
authors.lastname: Venkat
authors.affiliation: Department of Radiation Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Johnstone
authors.affiliation: Department of Medical Oncology and Cancer Genomics, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: John
authors.initials: J
authors.lastname: Foekens
authors.affiliation: Department of Integrated Bioinformatics and Biostatistics, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Jae
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Radiation Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Moros
authors.affiliation: DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Dalton
authors.affiliation: Department of Integrated Bioinformatics and Biostatistics, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Eschrich
authors.affiliation: DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: McLeod
authors.affiliation: Department of Radiation Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Louis B
authors.initials: LB
authors.lastname: Harrison
authors.affiliation: 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.
authors.forename: Javier F
authors.initials: JF
authors.lastname: Torres-Roca
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015894:Genome, Human; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D011379:Prognosis; D011446:Prospective Studies; D011836:Radiation Tolerance / Q000235:genetics*; D011879:Radiotherapy Dosage; D011880:Radiotherapy Planning, Computer-Assisted / Q000379:methods; D012189:Retrospective Studies; D015996:Survival Rate; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor