Genome-wide association study of treatment-related toxicity two years following radiotherapy for breast cancer

Càncer de mama; Toxicitat crònica; RadiogenòmicaBreast cancer; Chronic toxicity; RadiogenomicsCáncer de mama; Toxicidad crónica; RadiogenómicaBackground and purpose Up to a quarter of breast cancer patients treated by surgery and radiotherapy experience clinically significant toxicity. If patients at high risk of adverse effects could be identified at diagnosis, their treatment could be tailored accordingly. This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity two years following whole breast radiotherapy. Materials and Methods A genome-wide association study (GWAS) was performed in 1,640 breast cancer patients with complete SNP, clinical, treatment and toxicity data, recruited across 18 European and US centres into the prospective REQUITE cohort study. Toxicity data (CTCAE v4.0) were collected at baseline, end of radiotherapy, and annual follow-up. A total of 7,097,340 SNPs were tested for association with the residuals of toxicity endpoints, adjusted for clinical, treatment co-variates and population substructure. Results Quantile-quantile plots showed more associations with toxicity above the p < 5 × 10-5 level than expected by chance. Eight SNPs reached genome-wide significance. Nipple retraction grade ≥ 2 was associated with the rs188287402 variant (p = 2.80 × 10-8), breast oedema grade ≥ 2 with rs12657177 (p = 1.12 × 10-10), rs75912034 (p = 1.12 × 10-10), rs145328458 (p = 1.06 × 10-9) and rs61966612 (p = 1.23 × 10-9), induration grade ≥ 2 with rs77311050 (p = 2.54 × 10-8) and rs34063419 (p = 1.21 × 10-8), and arm lymphoedema grade ≥ 1 with rs643644 (p = 3.54 × 10-8). Heritability estimates across significant endpoints ranged from 25% to 39%. Our study did not replicate previously reported SNPs associated with breast radiation toxicity at the pre-specified significance level. Conclusions This GWAS for long-term breast radiation toxicity provides further evidence for significant association of common SNPs with distinct toxicity endpoints.REQUITE received funding from the European Union's Seventh Framework Programme for research, technological development, and demonstration under grant agreement no. 601826. We thank all patients who participated in the REQUITE study and all the *members of the REQUITE project consortium in: Belgium: Ghent University Hospital; KU Leuven. France: ICM Montpellier, CHU Nîmes (Department of Radiation Oncology, CHU Nîmes, Nîmes, France). Germany: Zentrum für Strahlentherapie Freiburg (Dr. Petra Stegmaier); Städtisches Klinikum Karlsruhe (Dr. Bernhard Neu); ViDia Christliche Kliniken Karlsruhe (Prof. Johannes Claßen); Klinikum der Stadt Ludwigshafen GmbH (PD Dr. Thomas Schnabel); Universitätsklinikum Mannheim: Anette Kipke, Stefanie Kolb, Anke Keller and Christiane Zimmermann; Strahlentherapie Speyer (Dr. Jörg Schäfer). The researchers at DKFZ also thank Anusha Müller, Irmgard Helmbold, Thomas Heger, and Sabine Behrens. Petra Seibold was supported by ERA PerMed JCT2018 funding (ERAPERMED2018-244, BMBF #01KU1912) and BfS funding (#3619S42261). Italy: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano; Candiolo Cancer Institute – FPO, IRCCS. Tiziana Rancati was partially funded by Fondazione Italo Monzino. Spain: Barcelona: Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus; VHIO acknowledge the Cellex Foundation for providing research facilities and the CERCA Programme/Generalitat de Catalunya for institutional support. Sara Gutiérrez-Enríquez is supported by ERAPerMed JTC2018 funding (ERAPERMED2018-244 and SLT011/18/00005) and the Government of Catalonia (2021SGR01112). Santiago: Complexo Hospitalario Universitario de Santiago. Ana Vega is supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (PI22/00589, PI19/01424, PI16/00046, PI13/ 02030, PI10/00164; INT20/00071, INT17/00133, INT16/00154, INT15/00070), through the Autonomous Government of Galicia (Consolidation and structuring program: IN607B), by ERAPerMed JTC2018 funding (ERAPERMED2018-244) and by the AECC (PRYES211091VEGA). UK: University Hospitals of Leicester NHS Trust: Theresa Beaver, Sara Barrows, Monika Kaushik, Frances Kenny, Jaroslaw Krupa, Kelly V Lambert, Simon M Pilgrim, Sheila Shokuhi, Kalliope Valassidou, Kiran Kancherla, Kufre Sampson, Ahmed Osman and Kaitlin Walker. Harkeran K Jandu is supported by the Wellcome Trust Genetic Epidemiology and Public Health Genomics Doctoral Training Partnership (Grant Number: 218505/Z/19/Z). Tim Rattay was funded by a National Institute of Health Research (NIHR) Clinical Lectureship (CL 2017-11-002). He was previously funded by an NIHR Doctoral Research Fellowship (DRF 2014-07-079). This publication presents independent research funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. University of Manchester: Catharine West and Rebecca Elliott are supported by the NIHR Manchester Biomedical Research Centre and Catharine West is supported by Cancer Research UK (C1094/A18504, C147/A25254). USA: Mount Sinai Hospital, New York

30-Day Mortality Following Palliative Radiotherapy

Indicador clínic; Radiació pal·liativa; PronòsticIndicador clínico: Radiación paliativa; PronósticoClinical indicator; Palliative radiation; PrognosisPurpose: 30-day mortality (30-DM) is a parameter with widespread use as an indicator of avoidance of harm used in medicine. Our objective is to determine the 30-DM followed by palliative radiation therapy (RT) in our department and to identify potential prognosis factors. Material/Methods: We conducted a retrospective cohort study including patients treated with palliative RT in our center during 2018 and 2019. Data related to clinical and treatment characteristics were collected. Results: We treated 708 patients to whom 992 palliative irradiations were delivered. The most frequent primary tumor sites were lung (31%), breast (14.8%), and gastrointestinal (14.8%). Bone was the predominant location of the treatment (56%), and the use of single doses was the preferred treatment schedule (34.4%). The 30-DM was 17.5%. For those who died in the first month the median survival was 17 days. Factors with a significant impact on 30-DM were: male gender (p < 0.0001); Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 2–3 (p = 0.0001); visceral metastases (p = 0.0353); lung, gastrointestinal or urinary tract primary tumors (p = 0.016); and single dose RT (p = <0.0001). In the multivariate analysis, male gender, ECOG PS 2–3, gastrointestinal and lung cancer were found to be independent factors related to 30-DM. Conclusion: Our 30-DM is similar to previous studies. We have found four clinical factors related to 30-DM of which ECOG was the most strongly associated. This data may help to identify terminally ill patients with poor prognosis in order to avoid unnecessary treatments

Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types

Meta-genome; Toxicities; CancerMetagenoma; Toxicidades; CáncerMetagenoma; Toxicitats; CàncerBackground This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung). Methods A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standardized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic variants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV—formerly SNP)–based heritability of rSTATacute in all patients and for each cancer type. Results Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for prostate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10‒8 < P < 1.0 × 10‒5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size ‒0.17; P = 1.7 × 10‒7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified ‘RNA splicing via endonucleolytic cleavage and ligation’ (P = 5.1 × 10‒6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected). Conclusions There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta–genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.E.N. was supported by a scholarship for a PhD from the University of Groningen, Groningen, The Netherlands. T.D. is funded as an Academic Clinical Fellow by the National Institute for Health Research, UK. D.J.T. is supported by a grant from The Taylor Family Foundation and Cancer Research UK [C19941/A30286]. M.L.K.C. is supported by the National Medical Research Council Singapore Clinician Scientist Award (NMRC/CSA-INV/0027/2018), National Research Foundation Proton Competitive Research Program (NRF-CRP17-2017-05), Ministry of Education Tier 3 Academic Research Fund (MOE2016-T3-1-004), the Duke-NUS Oncology Academic Program Goh Foundation Proton Research Programme, NCCS Cancer Fund, and the Kua Hong Pak Head and Neck Cancer Research Programme. G.C.B. is supported by Cancer research UK RadNet Cambridge [C17918/A28870]. RADIOGEN research was supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (INT20/00071, INT15/00070, INT17/00133, INT16/00154; PI19/01424; PI16/00046; PI13/02030; PI10/00164); by AECC grant PRYES211091VEGA and through the Autonomous Government of Galicia (Consolidation and structuring program: IN607B). C.N.A. and L.M.H.S. received funding from the Danish Cancer Society (grant R231-A14074-B2537). T.R. was funded by a National Institutes of Health Research (NIHR) Clinical Lectureship (CL 2017-11-002) and is supported by the NIHR Leicester Biomedical Research Centre. This publication presents independent research funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. REQUITE received funding from the European Union’s Seventh Framework Programme for research, technological development, and demonstration under grant agreement No. 601826. S.G.E. is supported by the government of Catalonia 2021SGR01112. L.D. was supported by the European Union Horizon 2020 research and innovation programs BRIDGES (grant No. 634935)

External Validation of a Predictive Model for Acute Skin Radiation Toxicity in the REQUITE Breast Cohort

Càncer de mama; Model de predicció; RadioteràpiaCáncer de mama; Modelo de predicción; RadioterapiaBreast cancer: Prediction model; RadiotherapyBackground: Acute skin toxicity is a common and usually transient side-effect of breast radiotherapy although, if sufficiently severe, it can affect breast cosmesis, aftercare costs and the patient's quality-of-life. The aim of this study was to develop predictive models for acute skin toxicity using published risk factors and externally validate the models in patients recruited into the prospective multi-center REQUITE (validating pREdictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve QUalITy of lifE in cancer survivors) study. Methods: Patient and treatment-related risk factors significantly associated with acute breast radiation toxicity on multivariate analysis were identified in the literature. These predictors were used to develop risk models for acute erythema and acute desquamation (skin loss) in three Radiogenomics Consortium cohorts of patients treated by breast-conserving surgery and whole breast external beam radiotherapy (n = 2,031). The models were externally validated in the REQUITE breast cancer cohort (n = 2,057). Results: The final risk model for acute erythema included BMI, breast size, hypo-fractionation, boost, tamoxifen use and smoking status. This model was validated in REQUITE with moderate discrimination (AUC 0.65), calibration and agreement between predicted and observed toxicity (Brier score 0.17). The risk model for acute desquamation, excluding the predictor tamoxifen use, failed to validate in the REQUITE cohort. Conclusions: While most published prediction research in the field has focused on model development, this study reports successful external validation of a predictive model using clinical risk factors for acute erythema following radiotherapy after breast-conserving surgery. This model retained discriminatory power but will benefit from further re-calibration. A similar model to predict acute desquamation failed to validate in the REQUITE cohort. Future improvements and more accurate predictions are expected through the addition of genetic markers and application of other modeling and machine learning techniques.TRat is currently an NIHR Clinical Lecturer. He was previously funded by a National Institute of Health Research (NIHR) Doctoral Research Fellowship (DRF 2014-07-079). This publication presents independent research funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. The REQUITE study received funding from European Union's 7th Framework Programme for research, technological development and demonstration under grant agreement no. 601826. The ISE study was supported by the German Office for Radiation Protection, project number St. Sch. 4116 and 4233. The LeND study received funding from Breast Cancer Now (formerly Breast Cancer Campaign) under grant ref. 2007NovPR45