From kilovoltage to genetically predicted personalised radiotherapy: a quest to reduce breast radiotherapy side effects

Article sections:  The development of megavoltage-based breast conservation techniques   Radiotherapy is necessary in most cases after conservative surgery   Further technological change   Genetic variation and response to radiotherapy   Body clock genes and the scheduling of radiotherapy  </ul

Therapeutic Mammoplasty yields a high rate of successful primary excision and ultimate breast preservation - initial results from the UK TeaM study

Background: In recent years Therapeutic Mammaplasty (TM) has gained popularity as a technique to excise invasive and pre-invasive breast lesions. It has the dual aims of breast preservation and improved cosmesis. TM techniques often involve larger excision volumes than conventional wide local excision. However there is little existing data regarding positive margin rates and subsequent further surgery resulting in either successful breast preservation or completion mastectomy. Materials and Methods: Data was collected as part of the TeaM (Therapeutic Mammaplasty) study. This was a prospective multicentre audit looking at the practice and outcomes of TM and was based mainly in the UK. Patients undergoing TM between 1st September 2016 and 30th June 2017 were included. Demographic, pre-operative, operative, oncological and complication data were collected. Operative data included any subsequent operations needed to successfully achieve clear excision margins. The definition of a clear excision margin was determined locally. Results: 899 procedures were performed on 880 patients from 51 centres. Average excision volume was 126.5g (IQR 50-319g, Range 5-2522g). Average total lesion size was 24mm (IQR 16-38mm, Range 0-145mm). 756 (84.1%) patients achieved complete excision on the first attempt. At this point 134 (14.9%) patients with unsatisfactory margins were reported. For those undergoing a second procedure 79 (59%) underwent margin re-excision, 38 (28%) underwent completion mastectomy with or without reconstruction. 16 patients still did not attain clear margins after the second operation. For those undergoing a third procedure, 6 had a completion mastectomy with or without reconstruction and 6 women had a second attempt at re-excision. 5/6 undergoing a second re-excision achieved clear margins. 1/6 had a further positive margin but underwent a successful third re-excision. In total breast preservation was successfully achieved in 828 (92%) cases. Less than 5% ultimately underwent completion mastectomy. Conclusions: The vast majority of women undergoing TM successfully achieved breast preservation. This was usually achieved at the first or second attempt with only a few percent requiring a third or fourth procedure to obtain clear excision margins. Under 5% ultimately required completion mastectomy.</p

Immediate breast reconstruction and time to adjuvant therapy - Results from the iBRA-2 (immediate Breast Reconstruction and Adjuvant therapy) multi-centre prospective cohort study

IntroductionImmediate breast reconstruction (IBR) is routinely offered to improve quality of life for women with breast cancer requiring a mastectomy. There are concerns that more complex reconstructive surgery may delay the delivery of adjuvant treatments and compromise long-term oncological outcomes. Previous studies addressing this research question have yielded conflicting results. iBRA-2 is a national prospective multicentre cohort study with the aim of investigating the effect of IBR on the delivery of adjuvant therapy and long-term oncological outcomes.MethodsBreast and plastic surgery centres performing mastectomy with or without (+/−) IBR using any technique were invited to participate in the study through the UK trainee research collaborative network. Consecutive women undergoing mastectomy +/− IBR for breast cancer between 1st July 2016 and 31st December 2016 were recruited into the study. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy +/− IBR were compared to determine if IBR impacted on the time of delivery of adjuvant therapy.Results2,548 patients were recruited from 76 centres, of whom 1,016 (39.9%) underwent IBR. 675 (26.5%) patients received implant-based reconstruction; 105 (4.1%) pedicled-flaps, and 228 (8.9%) free-flap reconstructions. 932 patients (36.6%) experienced at least one complication. There were no significant differences in complication rates between procedure types (p = 0.12), but patients undergoing implant-based or free-flap reconstruction were significantly more likely to require re-admission (p ConclusionsIBR does not lead to clinically significant delays to delivery of adjuvant therapy. This study provides important information to guide patients and professionals making decisions regarding reconstructive surgery in the future.</p

Development and validation of a predictive risk model for acute skin toxicity in patients undergoing breast radiotherapy

BackgroundClinically significant side-effects from radiotherapy affect around a quarter of breast cancer patients and may have a considerable impact on breast cosmesis and quality of life. If patients at high risk of radiation toxicity could be identified at breast cancer diagnosis, this could be taken into account when discussing treatment options. The aim of this study was to develop a predictive model for acute skin toxicity in patients undergoing breast radiotherapy.MethodsUsing multivariate logistic regression and backwards elimination, the risk model for acute skin toxicity (moderately brisk reaction and/or ≥1 acute desquamation) was first developed in patient cohorts treated by breast-conserving surgery and whole breast radiotherapy in three European centres (Leicester, Heidelberg/Mannheim, Cambridge; total n=2,012) with a biologically effective dose (BED) range from 47.1 to 67.2 Gy. It was externally validated in breast cancer patients enrolled in the multi-centre REQUITE cohort study (n=2,062; BED range 44.6 to 75.4 Gy).ResultsThe final model with the variables age, BED, cup size or BMI, and presence/absence of diabetes, smoking, and hypertension proved to give best prediction of acute skin toxicity with a c-statistic (AUC) of 0.79 in the development and 0.75 in the validation cohort and was well calibrated (Hosmer-Lemeshow p=0.53). ConclusionsA predictive model for radiotoxicity has the potential to give clinicians important information when planning treatment to reduce side-effects and optimise quality of life. The addition of prognostic genetic markers investigated as part of the REQUITE study is likely to improve model performance. Similar models can be developed for other toxicity endpoints, such as breast fibrosis, and should also be validated for patients undergoing chest wall radiotherapy and breast reconstruction. </p

Genetic Variants Predict Optimal Timing of Radiotherapy to Reduce Side-effects in Breast Cancer Patients

AIMS: Radiotherapy is an important treatment for many types of cancer, but a minority of patients suffer long-term side-effects of treatment. Multiple lines of evidence suggest a role for circadian rhythm in the development of radiotherapy late side-effects. MATERIALS AND METHODS: We carried out a study to examine the effect of radiotherapy timing in two breast cancer patient cohorts. The retrospective LeND cohort comprised 535 patients scored for late effects using the Late Effects of Normal Tissue-Subjective Objective Management Analytical (LENT-SOMA) scale. Acute effects were assessed prospectively in 343 patients from the REQUITE study using the CTCAE v4 scales. Genotyping was carried out for candidate circadian rhythm variants. RESULTS: In the LeND cohort, patients who had radiotherapy in the morning had a significantly increased incidence of late toxicity in univariate (P = 0.03) and multivariate analysis (P = 0.01). Acute effects in the REQUITE group were also significantly increased in univariate analysis after morning treatment (P = 0.03) but not on multivariate analysis. Increased late effects in the LeND group receiving morning radiotherapy were associated with carriage of the PER3 variable number tandem repeat 4/4 genotype (P = 6 × 10-3) and the NOCT rs131116075 AA genotype (P = 5 × 10-3). CONCLUSION: Our results suggest that it may be possible to reduce toxicity associated with breast cancer radiotherapy by identifying gene variants that affect circadian rhythm and scheduling for appropriate morning or afternoon radiotherapy

The iBRA-2 (immediate breast reconstruction and adjuvant therapy audit) study: protocol for a prospective national multicentre cohort study to evaluate the impact of immediate breast reconstruction on the delivery of adjuvant therapy.

INTRODUCTION: Immediate breast reconstruction (IBR) is routinely offered to improve quality of life for women with breast cancer requiring a mastectomy, but there are concerns that more complex surgery may delay the delivery of adjuvant oncological treatments and compromise long-term oncological outcomes. High-quality evidence, however, is lacking. iBRA-2 is a national prospective multicentre cohort study that aims to investigate the effect of IBR on the delivery of adjuvant therapy. METHODS AND ANALYSIS: Breast and plastic surgery centres in the UK performing mastectomy with or without (±) IBR will be invited to participate in the study through the trainee research collaborative network. All women undergoing mastectomy ± IBR for breast cancer between 1 July and 31 December 2016 will be included. Patient demographics, operative, oncological and complication data will be collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR will be compared to determine the impact that IBR has on the time of delivery of adjuvant therapy. Prospective data on 3000 patients from ∼50 centres are anticipated. ETHICS AND DISSEMINATION: Research ethics approval is not required for this study. This has been confirmed using the online Health Research Authority decision tool. This novel study will explore whether IBR impacts the time to delivery of adjuvant therapy. The study will provide valuable information to help patients and surgeons make more informed decisions about their surgical options. Dissemination of the study protocol will be via the Mammary Fold Academic and Research Collaborative (MFAC) and the Reconstructive Surgery Trials Network (RSTN), the Association of Breast Surgery (ABS) and the British Association of Plastic, Reconstructive and Aesthetic Surgeons (BAPRAS). Participating units will have access to their own data and collective results will be presented at relevant surgical conferences and published in appropriate peer-reviewed journals

The REQUITE-AB study: Validating predictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve quality of life in breast cancer patients

Clinically significant side-effects from radiotherapy affect around a quarter of breast cancer patients and may impact considerably on outcomes from treatment. An increasing number of replicated genetic associations for radiotherapy toxicity are being reported[1],[2]. The EU-funded REQUITE consortium aims to validate genetic markers and clinical factors implicated in radiotoxicity. The purpose of the REQUITE-AB project is to develop an integrated set of predictors for acute radiotherapy side-effects in breast cancer patients to be used as a clinical decision-making tool.As part of the REQUITE prospective cohort study, 2,000 patients eligible for adjuvant breast radiotherapy will be recruited in nine centres across Europe and North America between April 2014 and August 2016, with centralised data management, biobanking and two years’ follow-up using a standardised data collection protocol. Patient characteristics and treatment details being captured also include dose-volume histograms and DICOM files. Genotyping will take place in fall 2016. Primary endpoints are acute skin toxicity (CTC-AE v4.0) and quality-of-life (QoL) on completion of radiotherapy and at 3 months from start of radiotherapy. Secondary endpoints are late side-effects including change in breast appearance.1,766 breast cancer patients have been recruited to date with standardized documentation of toxicity and QoL. Among patients who completed radiotherapy so far, 21.6% of patients developed grade 2 skin toxicity (brisk erythema) and 1.3% grade 3 (moist desquamation). The ability of patient, treatment and genetic variables to predict clinical outcomes and QoL will be examined. The REQUITE study includes the largest radiogenomics cohort of breast cancer patients to date recruited under a single standardised protocol. Findings of the REQUITE-AB project are likely to inform the development of interventional biomarker trials and personalise breast cancer care in the future. [1] Talbot et al, Br J Cancer, 2012; 107: 748-53.[2] Seibold et al, Int J Radiat Oncol Biol Phys, 2015; 92: 1084-92</div

Acute toxicity and quality of life in breast cancer patients treated by radiotherapy - results from the REQUITE multi-centre cohort study

BackgroundAlthough patient-reported outcomes (PROs) to assess health-related quality-of-life (QoL) are increasingly incorporated in radiotherapy trials, QoL in the acute period following treatment remains under-reported. This study assessed the relationship between QoL in the acute treatment phase, toxicity, patient and treatment variables in breast cancer patients.MethodsBreast cancer patients (n = 2,072) were recruited following breast-conserving surgery across eight centres in Europe and North America into a multicentre prospective cohort study (www.requite.eu). Treatment data, toxicity scored according to CTCAE v4.0, and PROs from EORTC-QLQ-C30 and –B23 were available for 1,750 patients at baseline and on completion of radiotherapy. Association of acute toxicity endpoints (dichotomised) and worsening QoL (≥ 10 point change from baseline) was investigated using multivariate logistic regression, adjusted for age, BMI, total radiotherapy dose, seroma, chemotherapy, tamoxifen, analgesic use, smoking and alcohol intake.ResultsBy the end of radiotherapy, 24.2 % of patient experienced ≥ grade 2 erythema, 31.6 % ≥ grade 1 oedema, and 9.5 % were affected by acute desquamation (skin loss). Global health status, fatigue, pain, and breast symptoms worsened significantly compared to baseline. Acute erythema and acute desquamation were significantly associated with worsening breast symptoms (OR 1.71, 95 % CI 1.41-2.06; and OR 1.77, 1.18-2.67), while acute erythema was also associated with worsening pain (1.24, 1.03-1.50). There was no significant association of any acute toxicity endpoint with worsening global health status.ConclusionsManagement of early toxicities that affect breast-specific symptoms and pain may improve QoL during radiotherapy. Overall QoL (global health status) during breast radiotherapy is likely to be influenced by a range of non-treatment factors.</p

The REQUITE project: integrating biomarkers and clinical predictors of radiotherapy side effects

The European Union funded REQUITE consortium aims to validate predictors of radiotherapy-related adverse reactions to develop clinically useful tools. Potential predictors include clinical and dose parameters, genetic markers, gene expression and the radiation-induced lymphocyte apoptosis (RILA)

Treatment time and circadian genotype interact to influence radiotherapy side-effects. A prospective European validation study using the REQUITE cohort

Background: Circadian rhythm impacts broad biological processes, including response to cancer treatment. Evidence conflicts on whether treatment time affects risk of radiotherapy side-effects, likely because of differing time analyses and target tissues. We previously showed interactive effects of time and genotypes of circadian genes on late toxicity after breast radiotherapy and aimed to validate those results in a multi-centre cohort. Methods: Clinical and genotype data from 1690 REQUITE breast cancer patients were used with erythema (acute; n=340) and breast atrophy (two years post-radiotherapy; n=514) as primary endpoints. Local datetimes per fraction were converted into solar times as predictors. Genetic chronotype markers were included in logistic regressions to identify primary endpoint predictors. Findings: Significant predictors for erythema included BMI, radiation dose and PER3 genotype (OR 1.27(95%CI 1.03-1.56); P < 0.03). Effect of treatment time effect on acute toxicity was inconclusive, with no interaction between time and genotype. For late toxicity (breast atrophy), predictors included BMI, radiation dose, surgery type, treatment time and SNPs in CLOCK (OR 0.62 (95%CI 0.4-0.9); P < 0.01), PER3 (OR 0.65 (95%CI 0.44-0.97); P < 0.04) and RASD1 (OR 0.56 (95%CI 0.35-0.89); P < 0.02). There was a statistically significant interaction between time and genotypes of circadian rhythm genes (CLOCK OR 1.13 (95%CI 1.03-1.23), P < 0.01; PER3 OR 1.1 (95%CI 1.01-1.2), P < 0.04; RASD1 OR 1.15 (95%CI 1.04-1.28), P < 0.008), with peak time for toxicity determined by genotype. Interpretation: Late atrophy can be mitigated by selecting optimal treatment time according to circadian genotypes (e.g. treat PER3 rs2087947C/C genotypes in mornings; T/T in afternoons). We predict triple-homozygous patients (14%) reduce chance of atrophy from 70% to 33% by treating in mornings as opposed to mid-afternoon. Future clinical trials could stratify patients treated at optimal times compared to those scheduled normally. Funding: EU-FP7