5 research outputs found

    REQUITE: A prospective multicentre cohort study of patients undergoing radiotherapy for breast, lung or prostate cancer

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    Purpose: REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data. Methods: An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially curable radiotherapy. Radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Pre-treatment blood samples were collected. Patients were followed for a minimum of 12 (lung) or 24 (breast/prostate) months and summary descriptive statistics were generated. Results: The study recruited 2069 breast (99% of target), 1808 prostate (86%) and 561 lung (51%) cancer patients. The centralised, accessible database includes: physician-(47,025 forms) and patient-(54,901) reported outcomes; 11,563 breast photos; 17,107 DICOMs and 12,684 DVHs. Imputed genotype data are available for 4223 patients with European ancestry (1948 breast, 1728 prostate, 547 lung). Radiation-induced lymphocyte apoptosis (RILA) assay data are available for 1319 patients. DNA (n = 4409) and PAXgene tubes (n = 3039) are stored in the centralised biobank. Example prevalences of 2-year (1-year for lung) grade >= 2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung). Conclusion: The comprehensive centralised database and linked biobank is a valuable resource for the radiotherapy community for validating predictive models and biomarkers. Patient summary: Up to half of cancer patients undergo radiation therapy and irradiation of surrounding healthy tissue is unavoidable. Damage to healthy tissue can affect short-and long-term quality-of-life. Not all patients are equally sensitive to radiation "damage" but it is not possible at the moment to identify those who are. REQUITE was established with the aim of trying to understand more about how we could predict radiation sensitivity. The purpose of this paper is to provide an overview and summary of the data and material available. In the REQUITE study 4400 breast, prostate and lung cancer patients filled out questionnaires and donated blood. A large amount of data was collected in the same way. With all these data and samples a database and biobank were created that showed it is possible to collect this kind of information in a standardised way across countries. In the future, our database and linked biobank will be a resource for research and validation of clinical predictors and models of radiation sensitivity. REQUITE will also enable a better understanding of how many people suffer with radiotherapy toxicity

    Comparison of supine or prone crawl photon or proton breast and regional lymph node radiation therapy including the internal mammary chain

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    Abstract We report on a dosimetrical study comparing supine (S) and prone-crawl (P) position for radiotherapy of whole breast (WB) and loco-regional lymph node regions, including the internal mammary chain (LN_IM). Six left sided breast cancer patients were CT-simulated in S and P positions and four patients only in P position. Treatment plans were made using non-coplanar volumetric modulated arc photon therapy (VMAT) or pencil beam scanning intensity modulated proton therapy (IMPT). Dose prescription was 15*2.67 Gy(GyRBE). The average mean heart doses for S or P VMAT were 5.6 or 4.3 Gy, respectively (p = 0.16) and 1.02 or 1.08 GyRBE, respectively for IMPT (p = 0.8; p < 0.001 for IMPT versus VMAT). The average mean lung doses for S or P VMAT were 5.91 or 2.90 Gy, respectively (p = 0.002) and 1.56 or 1.09 GyRBE, respectively for IMPT (p = 0.016). In high-risk patients, average (range) thirty-year mortality rates from radiotherapy-related cardiac injury and lung cancer were estimated at 6.8(5.4–9.4)% or 3.8(2.8–5.1)% for S or P VMAT (p < 0.001), respectively, and 1.6(1.1–2.0)% or 1.2(0.8–1.6)% for S or P IMPT (p = 0.25), respectively. Radiation-related mortality risk could outweigh the ~8% disease-specific survival benefit of WB + LN_IM radiotherapy for S VMAT but not P VMAT. IMPT carries the lowest radiation-related mortality risks

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

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    BACKGROUND 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 &lt; 5 × 10 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 ), breast oedema grade = 2 with rs12657177 (p = 1.12 × 10 ), rs75912034 (p = 1.12 × 10 ), rs145328458 (p = 1.06 × 10 ) and rs61966612 (p = 1.23 × 10 ), induration grade = 2 with rs77311050 (p = 2.54 × 10 ) and rs34063419 (p = 1.21 × 10 ), and arm lymphoedema grade = 1 with rs643644 (p = 3.54 × 10 ). 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

    Development of a method for generating SNP interaction-aware polygenic risk scores for radiotherapy toxicity

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    Aim: To identify the effect of single nucleotide polymorphism (SNP) interactions on the risk of toxicity following radiotherapy (RT) for prostate cancer (PCa) and propose a new method for polygenic risk score incorporating SNP-SNP interactions (PRSi). Materials and methods: Analysis included the REQUITE PCa cohort that received external beam RT and was followed for 2 years. Late toxicity endpoints were: rectal bleeding, urinary frequency, haematuria, nocturia, decreased urinary stream. Among 43 literature-identified SNPs, the 30% most strongly associated with each toxicity were tested. SNP-SNP combinations (named SNP-allele sets) seen in >= 10% of the cohort were condensed into risk (RS) and protection (PS) scores, respectively indicating increased or decreased toxicity risk. Performance of RS and PS was evaluated by logistic regression. RS and PS were then combined into a single PRSi evaluated by area under the receiver operating characteristic curve (AUC). Results: Among 1,387 analysed patients, toxicity rates were 11.7% (rectal bleeding), 4.0% (urinary frequency), 5.5% (haematuria), 7.8% (nocturia) and 17.1% (decreased urinary stream). RS and PS combined 8 to 15 different SNP-allele sets, depending on the toxicity endpoint. Distributions of PRSi differed significantly in patients with/without toxicity with AUCs ranging from 0.61 to 0.78. PRSi was better than the classical summed PRS, particularly for the urinary frequency, haematuria and decreased urinary stream endpoints. Conclusions: Our method incorporates SNP-SNP interactions when calculating PRS for radiotherapy toxicity. Our approach is better than classical summation in discriminating patients with toxicity and should enable incorporating genetic information to improve normal tissue complication probability models. (C) 2021 The Authors. Published by Elsevier B.V
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