RAPPER: The Radiogenomics of Radiation Toxicity
2013; Elsevier BV; Volume: 25; Issue: 7 Linguagem: Inglês
10.1016/j.clon.2013.04.001
ISSN1433-2981
AutoresN.G. Burnet, Gillian C. Barnett, Rebecca Elliott, David P. Dearnaley, Paul D.P. Pharoah, Alison M. Dunning, Catharine West,
Tópico(s)Cancer Genomics and Diagnostics
ResumoRAPPER (Radiogenomics: Assessment of Polymorphisms for Predicting the Effects of Radiotherapy) is a large multicentre collaborative study, funded by Cancer Research UK. RAPPER addresses the hypothesis that normal genetic variation (common polymorphisms, rather than rare mutations) is responsible for most of the variation in toxicity between patients receiving the same dose of radiotherapy. Successful identification of genetic determinants will allow predictive testing for normal tissue radiosensitivity, and should contribute to better outcomes through biological individualisation of radiotherapy [1Norman A. Kagan A.R. Chan S.L. The importance of genetics for the optimization of radiation therapy. A hypothesis.Am J Clin Oncol. 1988; 11: 84-88Crossref PubMed Scopus (78) Google Scholar, 2Ågren A. Brahme A. Turesson I. Optimization of uncomplicated control for head and neck tumors.Int J Radiat Oncol Biol Phys. 1990; 19: 1077-1085Abstract Full Text PDF PubMed Scopus (142) Google Scholar, 3West C.M. Hendry J.H. Intrinsic radiosensitivity as a predictor of patient response to radiotherapy.Br J Radiol Suppl. 1992; 24: 146-152Google Scholar, 4Burnet N.G. Wurm R. Nyman J. Peacock J.H. Normal tissue radiosensitivity – how important is it?.Clin Oncol. 1996; 8: 25-34Abstract Full Text PDF PubMed Scopus (55) Google Scholar, 5Barnett G.C. West C.M. Dunning A.M. et al.Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype.Nat Rev Cancer. 2009; 9: 134-142Crossref PubMed Scopus (493) Google Scholar]. The advent of modern technologies of image-guided radiotherapy and intensity-modulated radiotherapy allows doses to normal tissue structures to be further reduced, achieving physical individualisation. The combination of these two methods of individualisation will be synergistic in improving outcomes.The RAPPER StudyRAPPER collects blood samples from radiotherapy patients for DNA extraction and genotyping [[6]RAPPER website: www.RAPPER-study.org/ [last accessed 08.07.13].Google Scholar]. RAPPER accesses toxicity data collected from patients in clinical trials, which avoids duplication and is a more efficient approach for research staff, patients and funders. One additional RAPPER questionnaire gathers information on potential non-genetic factors (age, body mass index, co-morbid conditions, ethnicity), which must be accounted for in genotyping studies. The core activities of RAPPER include organisation of blood sample collection, collaboration with the relevant clinical trials for access to and collation of the toxicity data, and the subsequent genotyping and analysis of correlations with toxicity.RAPPER started in 2006, and over 5000 blood samples have now been collected, with the rate of accrual proceeding ahead of target (Figure 1a). This makes RAPPER the first and largest nationally integrated radiogenomics programme in the world. At present, 40 of the 67 UK radiotherapy centres (including devolved nations) are involved in RAPPER (either open or in set-up), plus there are 14 additional centres open where patients are seen in follow-up. Collecting samples from 60% of UK radiotherapy centres is a major achievement, which reflects the enthusiastic support of a large number of individual clinicians and their teams. Furthermore, as the RAPPER portfolio of trials continues to grow there will be new opportunities to target the remaining radiotherapy centres. Although samples are predominantly from patients with breast and prostate cancer, other sites are also of interest (Figure 1b, Table 1) (see below).Table 1Clinical trials that have recruited, are currently recruiting, or are about to start recruiting to RAPPER, with associated sample numbersClinical trialTumour siteSample number collected (trial target accrual)FunderCambridge IMRTBreast1052 (1052)Breast Cancer CampaignCHHiPProstate2141 (3180)CR-UKPIVOTALProstate43 (110)CR-UKRT01Prostate265 (800)MRCRADICALSProstate195 (4000)CR-UKSTAMPEDEProstate0 (5000)CR-UKPelvic IMRTProstate143 (500)ICRDose EscalationProstate58 (100)ICRHDR Brachy BoostProstate9 (300)Audit (no funds)PRECIOUSProstate/gynaecological23 (100)CR-UKVoxToxProstate/head and neck/central nervous system0 (1700)CR-UKART-DECOHead and neck16 (354)CR-UKDe-ESCALATEHead and neck0 (330)CR-UKCOSTARHead and neck0 (84)CR-UKVORTEXSarcoma180 (400)CR-UKRICERectal97 (142)Roche/ PfizerEXCITERectal76 (82)CR-UKPACEProstate0 (200)Accuray Inc.Some additional patients are also recruited prospectively from breast, prostate and gynaecology patients (309) and from small Christie Hospital studies with prospective collection of toxicity data (281). Open table in a new tab Individual Variation in Normal Tissue ResponseIndividual variation in radiotherapy toxicity is well established, although the individual response can be modified by extrinsic factors, including dose, age, additional treatment and co-morbidities [5Barnett G.C. West C.M. Dunning A.M. et al.Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype.Nat Rev Cancer. 2009; 9: 134-142Crossref PubMed Scopus (493) Google Scholar, 8Turesson I. Individual variation and dose dependency in the progression rate of skin telangiectasia.Int J Radiat Oncol Biol Phys. 1990; 19: 1569-1574Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 9Tucker S.L. Turesson I. Thames H.D. Evidence of individual differences in the radiosensitivity of human skin.Eur J Cancer. 1992; 28A: 1783-1791Abstract Full Text PDF PubMed Scopus (167) Google Scholar, 10Bentzen S.M. Overgaard J. Patient-to-patient variability in the expression of radiation-induced normal tissue injury.Semin Radiat Oncol. 1994; 4: 68-80Abstract Full Text PDF PubMed Scopus (188) Google Scholar, 11Turesson I. Nyman J. Holmberg E. Odén A. Prognostic factors for acute and late skin reactions in radiotherapy patients.Int J Radiat Oncol Biol Phys. 1996; 36: 1065-1075Abstract Full Text PDF PubMed Scopus (266) Google Scholar, 12Burnet N.G. Johansen J. Turesson I. Nyman J. Peacock J.H. Describing patients' normal tissue reactions: concerning the possibility of individualising radiotherapy dose prescriptions based on potential predictive assays of normal tissue radiosensitivity. Steering Committee of the BioMed2 European Union Concerted Action Programme on the Development of Predictive Tests of Normal Tissue Response to Radiation Therapy.Int J Cancer. 1998; 79: 606-613Crossref PubMed Scopus (91) Google Scholar, 13Holscher T. Bentzen S.M. Baumann M. Influence of connective tissue diseases on the expression of radiation side effects: a systematic review.Radiother Oncol. 2006; 78: 123-130Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 14Barnett G.C. De Meerleer G. Gulliford S.L. Sydes M.R. Elliott R.M. Dearnaley D.P. The impact of clinical factors on the development of late radiation toxicity: results from the Medical Research Council RT01 trial (ISRCTN47772397).Clin Oncol. 2011; 23: 613-624Abstract Full Text Full Text PDF Scopus (79) Google Scholar]. The use of accurate and reproducible dosimetry together with adjustment for extrinsic factors were key features of a set of studies that showed individual differences in skin response [8Turesson I. Individual variation and dose dependency in the progression rate of skin telangiectasia.Int J Radiat Oncol Biol Phys. 1990; 19: 1569-1574Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 9Tucker S.L. Turesson I. Thames H.D. Evidence of individual differences in the radiosensitivity of human skin.Eur J Cancer. 1992; 28A: 1783-1791Abstract Full Text PDF PubMed Scopus (167) Google Scholar]. In fact, 80% of individual variation was unexplained after allowing for the extrinsic factors [11Turesson I. Nyman J. Holmberg E. Odén A. Prognostic factors for acute and late skin reactions in radiotherapy patients.Int J Radiat Oncol Biol Phys. 1996; 36: 1065-1075Abstract Full Text PDF PubMed Scopus (266) Google Scholar, 12Burnet N.G. Johansen J. Turesson I. Nyman J. Peacock J.H. Describing patients' normal tissue reactions: concerning the possibility of individualising radiotherapy dose prescriptions based on potential predictive assays of normal tissue radiosensitivity. Steering Committee of the BioMed2 European Union Concerted Action Programme on the Development of Predictive Tests of Normal Tissue Response to Radiation Therapy.Int J Cancer. 1998; 79: 606-613Crossref PubMed Scopus (91) Google Scholar], raising the possibility of underlying genetic differences as a cause for this variation. In the same period, cellular radiosensitivity, in lymphocytes, was shown to have a high inherited component [[15]Roberts S.A. Spreadborough A.R. Bulman B. Barber J.B. Evans D.G. Scott D. Heritability of cellular radiosensitivity: a marker of low-penetrance predisposition genes in breast cancer?.Am J Hum Genet. 1999; 65: 784-794Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar], confirmed in several independent studies [[16]West C.M. Barnett G.C. Genetics and genomics of radiotherapy toxicity: towards prediction.Genome Med. 2011; 3: 52Crossref PubMed Scopus (137) Google Scholar], and supporting the hypothesis of a link to underlying genetic variation.Predicting Individual VariationIn early efforts at predictive testing, cellular sensitivity correlated with tissue response in small series [17Burnet N.G. Nyman J. Turesson I. Wurm R. Yarnold J.R. Peacock J.H. Prediction of normal tissue tolerance to radiotherapy from in vitro cellular radiation sensitivity.Lancet. 1992; 339: 1570-1571Abstract PubMed Scopus (146) Google Scholar, 18Brock W.A. Tucker S.L. Geara F.B. et al.Fibroblast radiosensitivity versus acute and late normal skin responses in patients treated for breast cancer.Int J Radiat Oncol Biol Phys. 1995; 32: 1371-1379Abstract Full Text PDF PubMed Scopus (128) Google Scholar, 19Johansen J. Bentzen S.M. Overgaard J. Overgaard M. Relationship between the in vitro radiosensitivity of skin fibroblasts and the expression of subcutaneous fibrosis, telangiectasia, and skin erythema after radiotherapy.Radiother Oncol. 1996; 40: 101-109Abstract Full Text PDF PubMed Scopus (151) Google Scholar], but larger studies had variable results [20Peacock J. Ashton A. Bliss J. et al.Cellular radiosensitivity and complication risk after curative radiotherapy.Radiother Oncol. 2000; 55: 173-178Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 21West C.M. Davidson S.E. Elyan S.A. et al.Lymphocyte radiosensitivity is a significant prognostic factor for morbidity in carcinoma of the cervix.Int J Radiat Oncol Biol Phys. 2001; 51: 10-15Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar].Initial investigations of possible genetic variation underlying individual sensitivity were, of necessity, focussed on candidate genes considered to have some potential biological role in radiation response [[22]Carlomagno F. Burnet N.G. Turesson I. et al.Comparison of DNA repair protein expression and activities between human fibroblast cell lines with different radiosensitivities.Int J Cancer. 2000; 85: 845-849Crossref PubMed Scopus (31) Google Scholar] (reviewed in [5Barnett G.C. West C.M. Dunning A.M. et al.Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype.Nat Rev Cancer. 2009; 9: 134-142Crossref PubMed Scopus (493) Google Scholar, 23Andreassen C.N. Alsner J. Overgaard M. Sørensen F.B. Overgaard J. Risk of radiation-induced subcutaneous fibrosis in relation to single nucleotide polymorphisms in TGFB1, SOD2, XRCC1, XRCC3, APEX and ATM – a study based on DNA from formalin fixed paraffin embedded tissue samples.Int J Radiat Biol. 2006; 82: 577-586Crossref PubMed Scopus (94) Google Scholar]). RAPPER was conceived as a candidate gene study. A power calculation suggested that a sample of 2000 patients had 90% power at a significance level of 0.001 to detect an allele present in 20% of the population that conferred an increased risk of toxicity of 50%. A target accrual of 2200 was therefore set. This number was larger than any previous study, but still partly pragmatic. However, it became clear that the candidate gene approach, the only practicable method at the time, was unlikely to succeed. The approach is based on the premise that the biology of the relevant processes is understood. The demonstration that some areas of genetic variation linked to breast cancer susceptibility lay in gene deserts underlined our superficial understanding of the molecular genetics of cancer [[24]Easton D.F. Pooley K.A. Dunning A.M. et al.Genome-wide association study identifies novel breast cancer susceptibility loci.Nature. 2007; 447: 1087-1093Crossref PubMed Scopus (1916) Google Scholar], and showed unequivocally that a different methodology was required.The technology for high throughput genotyping became available and affordable comparatively recently. RAPPER was therefore redesigned as a genome-wide association study (GWAS). A GWAS has a higher chance of finding associations, does not assume that the biology is understood, but requires much larger numbers of patients. Funding was obtained for a GWAS in 2000 patients, with this seen as the first stage of a multistage project. In this design, the 'top' 5% of single nucleotide polymorphisms (SNPs), i.e. those with the most significant P values for association, are taken into a much larger validation study, to provide greater power. This very large study size is needed in order to find genetic variations with modest effects on toxicity. Additional value is probably from meta-analysis using data from even larger numbers of patients, and the recent establishment of an international Radiogenomics Consortium is key for the success of such a collaboration [[25]West C. Rosenstein B.S. Alsner J. et al.Establishment of a Radiogenomics Consortium.Int J Radiat Oncol Biol Phys. 2010; 76: 1295-1296Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar]. The very large RAPPER resource allows significant influence in the Radiogenomics Consortium, allowing the considerable UK expertise to contribute at the international level.Generalised or Tissue-specific Sensitivity?At present it is not yet clear to what extent genetic variation links to an overall measure of toxicity rather than tissue-specific toxicity end points. The former would be most convenient, and an element of generalised sensitivity is plausible. However, tissue-specific factors are also likely and indicate the need to collect samples from multiple tumour types (relating to multiple normal tissues).Evidence is emerging, for at least some toxicity end points, that SNP profiles are tissue specific [[26]Kerns S.L. Stock R. Stone N. et al.A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of erectile dysfunction following radiation therapy for prostate cancer.Int J Radiat Oncol Biol Phys. 2013; 85: e21-e28Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar]. Therefore, there may not be a single SNP profile that can be used for any radiotherapy side-effect. As radiogenomics is relevant for any tumour where radiotherapy toxicity limits curative potential, a UK collaborative effort is essential, especially for less common cancers.Early Results from the RAPPER Genotyping WorkThe RAPPER study has shown that genetic variation in the two most widely studied SNPs in the TGFB1 gene are not linked with variation in 2 year radiotherapy toxicity in breast cancer patients, despite early reports of a possible association [[27]Barnett G.C. Coles C.E. Burnet N.G. et al.No association between SNPs regulating TGF-β1 secretion and late radiotherapy toxicity to the breast: results from the RAPPER study.Radiother Oncol. 2010; 97: 9-14Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar]. This definitive result was possible because of the large number of samples in the study. Although it shows that these two SNPs in TGFB1 are not responsible for variation in toxicity, it is still biologically plausible that alteration of gene function, for example by variation in regulatory regions, may modulate toxicity via the TGFB1 gene. The absence of a link with toxicity has just been confirmed for one of these SNPs in an international meta-analysis involving 2782 breast patients [[28]Barnett G.C. Elliott R.M. Alsner J. et al.on behalf of the Radiogenomics Consortium. Individual patient data meta-analysis shows no association between the SNP rs1800469 in TGFB and late radiotherapy toxicity.Radiother Oncol. 2012; 105: 289-295Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar]. A number of other SNPs potentially implicated in variations in toxicity have also been shown to have individual effect sizes too small to have individual clinical relevance [[29]Barnett G.C. Coles C.E. Elliott R.M. et al.Independent validation of genes and polymorphisms reported to be associated with radiation toxicity: a prospective analysis study.Lancet Oncol. 2012; 13: 65-77Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar].Above all, these findings underline the need for a deeper understanding of the biology of radiation response at a tissue and organism level. They also endorse using GWAS methodology rather than a candidate gene approach to identify SNPs, although there is a risk of false negatives (i.e. missing real associations).The phase I RAPPER GWAS is now complete; analysis is proceeding, and final results are anticipated in 2013.Continuing Work of RAPPERWe are seeking to further expand the patient numbers in RAPPER. It is hoped that funding can be obtained to increase the total number to 12 000.There is a particular need for follow-up on patients in the RT01 prostate study, who have not yet been enrolled in RAPPER. This is a cohort of patients with detailed dose-volume data, highly relevant to the analysis of outcomes, who are not yet part of the study, but would provide substantial additional value per patient because of the detailed dosimetry available. A specific effort to target this patient group is being developed, in the hope of collecting these precious data.Continuing collection of toxicity data is essential for biological studies as side-effects may continue to develop for up to 5 years and sometimes beyond. The collection of late toxicity data, typically requiring 5 years of follow-up but sometimes benefitting from 10 year data, presents a tension with efforts to reduce oncology-specific follow-up by moving this into the community [[30]Coles C.E. Faivre-Finn C. Radiotherapy research trials in the UK: secrets of success.Clin Oncol (R Coll Radiol). 2012; 24: 229-231Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar]. As well as being invaluable for radiogenomics, this information is also essential for clinical outcome measures to define the therapeutic ratio.RAPPER is continuing to collect samples and we thank our multicentre collaborators, and their patients, for their contribution. It is only by expanding the number of patients, typically to at least an order of magnitude larger than randomised clinical trials, that genetic questions can be answered. In order to achieve success, the recording of toxicity is crucial, and the value of clinical toxicity data is substantially advanced if the same toxicity recording systems are used, associated with information on the pre-treatment status of the patient and on potential modifiers and confounders of response.The ultimate goal of radiogenomics is to add an additional element of personalised medicine to the radiotherapy planning and prescription, to improve the outcome for the patient. Such individualisation, combined with the very best radiotherapy treatment planning and delivery techniques, will also allow for more imaginative combination with pharmaceutical agents and should achieve both lower toxicity and higher cure rates. RAPPER (Radiogenomics: Assessment of Polymorphisms for Predicting the Effects of Radiotherapy) is a large multicentre collaborative study, funded by Cancer Research UK. RAPPER addresses the hypothesis that normal genetic variation (common polymorphisms, rather than rare mutations) is responsible for most of the variation in toxicity between patients receiving the same dose of radiotherapy. Successful identification of genetic determinants will allow predictive testing for normal tissue radiosensitivity, and should contribute to better outcomes through biological individualisation of radiotherapy [1Norman A. Kagan A.R. Chan S.L. The importance of genetics for the optimization of radiation therapy. A hypothesis.Am J Clin Oncol. 1988; 11: 84-88Crossref PubMed Scopus (78) Google Scholar, 2Ågren A. Brahme A. Turesson I. Optimization of uncomplicated control for head and neck tumors.Int J Radiat Oncol Biol Phys. 1990; 19: 1077-1085Abstract Full Text PDF PubMed Scopus (142) Google Scholar, 3West C.M. Hendry J.H. Intrinsic radiosensitivity as a predictor of patient response to radiotherapy.Br J Radiol Suppl. 1992; 24: 146-152Google Scholar, 4Burnet N.G. Wurm R. Nyman J. Peacock J.H. Normal tissue radiosensitivity – how important is it?.Clin Oncol. 1996; 8: 25-34Abstract Full Text PDF PubMed Scopus (55) Google Scholar, 5Barnett G.C. West C.M. Dunning A.M. et al.Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype.Nat Rev Cancer. 2009; 9: 134-142Crossref PubMed Scopus (493) Google Scholar]. The advent of modern technologies of image-guided radiotherapy and intensity-modulated radiotherapy allows doses to normal tissue structures to be further reduced, achieving physical individualisation. The combination of these two methods of individualisation will be synergistic in improving outcomes. The RAPPER StudyRAPPER collects blood samples from radiotherapy patients for DNA extraction and genotyping [[6]RAPPER website: www.RAPPER-study.org/ [last accessed 08.07.13].Google Scholar]. RAPPER accesses toxicity data collected from patients in clinical trials, which avoids duplication and is a more efficient approach for research staff, patients and funders. One additional RAPPER questionnaire gathers information on potential non-genetic factors (age, body mass index, co-morbid conditions, ethnicity), which must be accounted for in genotyping studies. The core activities of RAPPER include organisation of blood sample collection, collaboration with the relevant clinical trials for access to and collation of the toxicity data, and the subsequent genotyping and analysis of correlations with toxicity.RAPPER started in 2006, and over 5000 blood samples have now been collected, with the rate of accrual proceeding ahead of target (Figure 1a). This makes RAPPER the first and largest nationally integrated radiogenomics programme in the world. At present, 40 of the 67 UK radiotherapy centres (including devolved nations) are involved in RAPPER (either open or in set-up), plus there are 14 additional centres open where patients are seen in follow-up. Collecting samples from 60% of UK radiotherapy centres is a major achievement, which reflects the enthusiastic support of a large number of individual clinicians and their teams. Furthermore, as the RAPPER portfolio of trials continues to grow there will be new opportunities to target the remaining radiotherapy centres. Although samples are predominantly from patients with breast and prostate cancer, other sites are also of interest (Figure 1b, Table 1) (see below).Table 1Clinical trials that have recruited, are currently recruiting, or are about to start recruiting to RAPPER, with associated sample numbersClinical trialTumour siteSample number collected (trial target accrual)FunderCambridge IMRTBreast1052 (1052)Breast Cancer CampaignCHHiPProstate2141 (3180)CR-UKPIVOTALProstate43 (110)CR-UKRT01Prostate265 (800)MRCRADICALSProstate195 (4000)CR-UKSTAMPEDEProstate0 (5000)CR-UKPelvic IMRTProstate143 (500)ICRDose EscalationProstate58 (100)ICRHDR Brachy BoostProstate9 (300)Audit (no funds)PRECIOUSProstate/gynaecological23 (100)CR-UKVoxToxProstate/head and neck/central nervous system0 (1700)CR-UKART-DECOHead and neck16 (354)CR-UKDe-ESCALATEHead and neck0 (330)CR-UKCOSTARHead and neck0 (84)CR-UKVORTEXSarcoma180 (400)CR-UKRICERectal97 (142)Roche/ PfizerEXCITERectal76 (82)CR-UKPACEProstate0 (200)Accuray Inc.Some additional patients are also recruited prospectively from breast, prostate and gynaecology patients (309) and from small Christie Hospital studies with prospective collection of toxicity data (281). Open table in a new tab RAPPER collects blood samples from radiotherapy patients for DNA extraction and genotyping [[6]RAPPER website: www.RAPPER-study.org/ [last accessed 08.07.13].Google Scholar]. RAPPER accesses toxicity data collected from patients in clinical trials, which avoids duplication and is a more efficient approach for research staff, patients and funders. One additional RAPPER questionnaire gathers information on potential non-genetic factors (age, body mass index, co-morbid conditions, ethnicity), which must be accounted for in genotyping studies. The core activities of RAPPER include organisation of blood sample collection, collaboration with the relevant clinical trials for access to and collation of the toxicity data, and the subsequent genotyping and analysis of correlations with toxicity. RAPPER started in 2006, and over 5000 blood samples have now been collected, with the rate of accrual proceeding ahead of target (Figure 1a). This makes RAPPER the first and largest nationally integrated radiogenomics programme in the world. At present, 40 of the 67 UK radiotherapy centres (including devolved nations) are involved in RAPPER (either open or in set-up), plus there are 14 additional centres open where patients are seen in follow-up. Collecting samples from 60% of UK radiotherapy centres is a major achievement, which reflects the enthusiastic support of a large number of individual clinicians and their teams. Furthermore, as the RAPPER portfolio of trials continues to grow there will be new opportunities to target the remaining radiotherapy centres. Although samples are predominantly from patients with breast and prostate cancer, other sites are also of interest (Figure 1b, Table 1) (see below). Some additional patients are also recruited prospectively from breast, prostate and gynaecology patients (309) and from small Christie Hospital studies with prospective collection of toxicity data (281). Individual Variation in Normal Tissue ResponseIndividual variation in radiotherapy toxicity is well established, although the individual response can be modified by extrinsic factors, including dose, age, additional treatment and co-morbidities [5Barnett G.C. West C.M. Dunning A.M. et al.Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype.Nat Rev Cancer. 2009; 9: 134-142Crossref PubMed Scopus (493) Google Scholar, 8Turesson I. Individual variation and dose dependency in the progression rate of skin telangiectasia.Int J Radiat Oncol Biol Phys. 1990; 19: 1569-1574Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 9Tucker S.L. Turesson I. Thames H.D. Evidence of individual differences in the radiosensitivity of human skin.Eur J Cancer. 1992; 28A: 1783-1791Abstract Full Text PDF PubMed Scopus (167) Google Scholar, 10Bentzen S.M. Overgaard J. Patient-to-patient variability in the expression of radiation-induced normal tissue injury.Semin Radiat Oncol. 1994; 4: 68-80Abstract Full Text PDF PubMed Scopus (188) Google Scholar, 11Turesson I. Nyman J. Holmberg E. Odén A. Prognostic factors for acute and late skin reactions in radiotherapy patients.Int J Radiat Oncol Biol Phys. 1996; 36: 1065-1075Abstract Full Text PDF PubMed Scopus (266) Google Scholar, 12Burnet N.G. Johansen J. Turesson I. Nyman J. Peacock J.H. Describing patients' normal tissue reactions: concerning the possibility of individualising radiotherapy dose prescriptions based on potential predictive assays of normal tissue radiosensitivity. Steering Committee of the BioMed2 European Union Concerted Action Programme on the Development of Predictive Tests of Normal Tissue Response to Radiation Therapy.Int J Cancer. 1998; 79: 606-613Crossref PubMed Scopus (91) Google Scholar, 13Holscher T. Bentzen S.M. Baumann M. Influence of connective tissue diseases on the expression of radiation side effects: a systematic review.Radiother Oncol. 2006; 78: 123-130Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 14Barnett G.C. De Meerleer G. Gulliford S.L. Sydes M.R. Elliott R.M. Dearnaley D.P. The impact of clinical factors on the development of late radiation toxicity: results from the Medical Research Council RT01 trial (ISRCTN47772397).Clin Oncol. 2011; 23: 613-624Abstract Full Text Full Text PDF Scopus (79) Google Scholar]. The use of accurate and reproducible dosimetry together with adjustment for extrinsic factors were key features of a set of studies that showed individual differences in skin response [8Turesson I. Individual variation and dose dependency in the progression rate of skin telangiectasia.Int J Radiat Oncol Biol Phys. 1990; 19: 1569-1574Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 9Tucker S.L. Turesson I. Thames H.D. Evidence of individual differences in the radiosensitivity of human skin.Eur J Cancer. 1992; 28A: 1783-1791Abstract Full Text PDF PubMed Scopus (167) Google Scholar]. In fact, 80% of individual variation was unexplained after allowing for the extrinsic factors [11Turesson I. Nyman J. Holmberg E. Odén A. Prognostic factors for acute and late skin reactions in radiotherapy patients.Int J Radiat Oncol Biol Phys. 1996; 36: 1065-1075Abstract Full Text PDF PubMed Scopus (266) Google Scholar, 12Burnet N.G. Johansen J. Turesson I. Nyman J. Peacock J.H. Describing patients' normal tissu
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