ESTRO 2020 Abstract book

S4 ESTRO 2020

predict benefit from the addition of hypoxia-targeted treatment to radiotherapy in a seventh (BCON trial). The signature is progressing to final testing in a biomarker driven trial. A sarcoma signature has been validated in four independent cohorts including a randomised trial (VorteX) and is being taken forward using the NanoString platform. A prostate signature was validated in nine cohorts and is also progressing using NanoString. A number of key elements in developing genomic signatures are highlighted. (1) Multiple cohorts are obtained for validation in silico , via collaboration and/or by obtaining funding to build unique cohorts involving patients treated with radiotherapy and generating transcriptomic data. (2) Signatures are tested to show independence from existing and emerging prognostic factors, e.g. CINSARC and sarculator (sarcoma); Decipher and a 31 risk loci classifier reflecting genomic instability (prostate). (3) Considerable effort is put into identifying platforms for clinical application that involves testing gene probes, choosing suitable endogenous reference genes, and assessing assay performance. Within the rapidly changing field of biomarkers for oncology the radiation oncology community need to catalyse competitiveness and accelerate progress. A change in culture is needed to improve biomarker development, evaluation, translation and implementation. There is a need to identify “what we do best and finding more ways of doing less of it better”. SP-0018 Genome-scale and systematic variant profiling delineates the radiogenomic landscape of cancer B. Yard 1 , A. Petty 1 , J. Castrillon 1 , P. Gopal 2 , M. Abazeed 2 1 cleveland Clinic, Thor, Cleveland, Usa ; 2 northwestern University, Radiation Oncology, Cleveland, Usa Abstract text BACKGROUND: The impact of the preponderance of common or rare cancer genetic alterations on the sensitivity of cells to ionizing radiation remain unknown. We conducted a systematic, large-scale profiling effort to identify genetic variants that alter cellular sensitivity to radiation. METHODS: Candidate variants were prioritized on the basis of their location within conserved protein domains (UniProt), predicted functional impact (MutationAssessor), and genotype-phenotype associations from large-scale cancer cell line irradiation efforts. We used site-directed mutagenesis to generate mutant clones and transferred the ORFs into lentiviral vectors for stable expression under a PGK and/or EF-1a promoter in SV40 or hTERT immortalized cells, or the NCI-H1299 cancer cell line. For variants predicted to confer loss of gene function, the endogenous loci were deleted using a novel intro-exon junctional CRISPR method (J-CRISPR). The effect of individual variants on radiation responses were benchmarked using the cyto- and radio-protective NFE2L2 E79K gain-of-function mutation (resistance) or the deletion of the DNA repair gene TP53BP1 (sensitivity). Candidate variants that effected sensitivity or resistance were selected using a Gaussian mixture model and were validated by colony formation assays. RESULTS: Over 1600 replicates were tested, comprising 91 genes and 560 variants. Variants that were nominated by our in silico enrichment methods, are evolutionary conserved, or those under somatic oncogenic selection were significantly more likely to result in a variant that conferred changes in the vulnerability of cells to radiation. The vast majority of common cancer variants did not alter the radio- phenotype; several rare cancer variants did. We annotated known and new radioresistant and radiosensitive variants involved in several cellular functional categories including cellular signaling, cytoskeleton, cell cycle, apoptosis, DNA methylation, and DNA repair. Phenotypic impact profiling reveals distinct metabolic and gene expression pathways that, upon modulation, alter the sensitivity of cells to irradiation CONCLUSION: Determining the impact of

like eyes give advantage to interstitial BT due to the rapid fall-off of dose outside the target. Cavities like ear, orbit, nostrils, if included in the target offer the chance of making personalized molds to adapt the isodose to these irregular surfaces. And exophytic tumors need to be radiated with a maximum dose to the skin, what is possible through interstitial needles or plastic tubes fixed with templates, adding extra needles outside of the body with excellent dosimetry and outcome, like lip carcinomas. Brachytherapy is a good alternative to external radiation procedures, and in some situations can become the best option to get better dose distributions and protect organs at risk. Moreover, total treatment time can be reduced to 5-10 days compared with external beam radiation schemes lasting several weeks, what is desirable in elder patients. SP-0014 How do different radiotherapy techniques affect the patient? L. Mills Radiotherapy department, The Christie Hospital NHS Foundation Trust, Manchester, United Kingdom

Abstract not received

Symposium: Cutting-edge genomics in radiation oncology

SP-0015 Genome wide association studies in radiation oncology TBC

Abstract not available

SP-0016 The use of genomics in radiation oncology C. Hiley Cancer Institute|Genome Instability and Cancer Evolution, London, United Kingdom

Abstract not received

SP-0017 Development and validation of genetic signatures in radiation oncology C. West 1 1 The University of Manchester, Translational Radiobiology, Manchester, United Kingdom Abstract text The biomarker development pipeline is fraught with failure. The plethora of published predictors and prognosticators for radiation oncology provide biological insight but lack practical application. The development of tumour genomic signatures addresses some of the limitations associated with other approaches for biomarker development. Accessible and expanding online resources allow for validation in multiple cohorts. There are multiple methods for signature implementation that have proven accuracy and have entered the clinical arena. The use of a signature versus a single marker can reduce intra-tumour heterogeneity and improve performance. The most widely developed signatures in radiation oncology are those that assess tumour hypoxia. Work in Manchester focused on developing tumour type specific signatures for assessing hypoxia. Our head and neck signature developed with Oxford was validated in four cohorts, taken forward for application using customised Taqman arrays and shown to predict benefit from the addition of hypoxia-targeted treatment to radiotherapy in a fourth cohort (ARCON trial). The signature was assessed prospectively in the UK NIMRAD trial, which closed to recruitment in May 2019. Hypoxia signature scores were generated for most of the 338 patients recruited into the NIMRAD trial. A bladder signature was validated in four of six cohorts and shown to

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