Tim Rattay

Finding the Genetic Determinants of Adverse Reactions to Radiotherapy

Individual variation in radiosensitivity is thought to be at least partly determined by genetic factors. The remaining difference between individuals is caused by comorbidities, variation in treatment, body habitus and stochastic factors. Evidence for the heritability of radiosensitivity comes from rare genetic disorders and from cell-based studies. To what extent common and rare genetic variants might explain the genetic component of radiosensitivity has not been fully elucidated. If the genetic variants accounting for this heritability were to be determined, they could be incorporated into any future predictive statistical model of adverse reactions to radiotherapy. With the evolution of DNA sequencing and bioinformatics, radiogenomics has emerged as a new research field with the aim of finding the genetic determinants of adverse reactions to radiotherapy. Similar to the investigation of other complex genetic disease traits, early studies in radiogenomics involved candidate gene association studies--many plagued by false associations caused by low sample sizes and problematic experimental design. More recently, some promising genetic associations (e.g. with tumour necrosis factor) have emerged from large multi-institutional cohorts with built-in replication. At the same time, several small- to medium-sized genome-wide association studies (GWAS) have been or are about to be published. These studies will probably lead to an increasing number of genetic polymorphisms that may predict adverse reactions to radiotherapy. The future of the field is to create large patient cohorts for multiple cancer types, to validate the genetic loci and build reliable predictive models. For example, the REQUITE project involves multiple groups in Europe and North America. For further discovery studies, larger GWAS will be necessary to include rare sequence variants through next generation sequencing. Ultimately, radiogenomics seeks to predict which cancer patients will show radiosensitivity or radioresistance, so oncologists and surgeons can alter treatment accordingly to lower adverse reactions or increase the efficacy of radiotherapy.

The TeaM (Therapeutic Mammaplasty) study: Protocol for a prospective multi-centre cohort study to evaluate the practice and outcomes of therapeutic mammaplasty

Highlights • Multicentre prospective study involving breast and plastic surgical units across the UK.• Will produce valuable data regarding the practice and outcomes of therapeutic mammaplasty.• Will inform decision-making and lead to future definitive study.• Will strengthen the collaborative network to facilitate the delivery of future projects.• Will increase awareness of the techniques among trainees such that participation is educational.

Morgagni hernia--an uncommon cause of gastric outlet obstruction.

A 79-year-old man was admitted with a 3 day history of profuse vomiting. Plain chest x-ray on admission showed an elevated right hemidiaphragm. The abdominal film was within normal limits. A nasogastric tube was inserted and the patient was rehydrated. Subsequent CT of chest and abdomen demonstrated an anterior diaphragmatic hernia with the antrum, body and pylorus of stomach, along with the transverse colon in the chest (figures 1–3). The …

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.

Current practice and short-term outcomes of therapeutic mammaplasty in the international TeaM multicentre prospective cohort study: Short-term outcomes of therapeutic mammaplasty in the TeaM study

Therapeutic mammaplasty, which combines breast reduction and mastopexy techniques with tumour excision, may extend the boundaries of breast‐conserving surgery and improve outcomes for patients, but current practice is unknown and high‐quality outcome data are lacking. This prospective multicentre cohort study aimed to explore the practice and short‐term outcomes of the technique.

The Patient Perspective on Radiogenomics Testing for Breast Radiation Toxicity

Aims In the field of radiogenomics, several potential predictive genetic markers have been identified that are associated with individual susceptibility to radiation toxicity. Predictive models of radiation toxicity incorporating radiogenomics and other biomarkers are being developed as part of the ongoing multicentre REQUITE trial. The purpose of this study was to explore patient attitudes towards future predictive radiogenomics testing for breast radiation toxicity. Patients and methods Twenty-one semi-structured interviews were conducted with breast cancer patients taking part in the REQUITE study at one centre. We used inductive thematic analysis to generate common themes. Results We identified three emerging themes describing attitudes and feelings towards a predictive radiogenomics test for breast radiation toxicity: theme 1 – willingness to undergo a test (subthemes – information, trusted expert); theme 2 – implications of a test (subthemes – preparation and planning, anxiety without recourse); theme 3 – impact on treatment decision-making (subthemes – prioritising cancer cure, preserving breast integrity, patient preferences). Conclusions Results from the present study indicate that patients support and have confidence in the validity of a radiogenomics test for breast radiation toxicity, but they would prefer the result be provided to healthcare professionals. Except in cases of significant chronic symptoms and pain or significant end-organ damage, participants in this study rarely felt that advance knowledge of their personal risk of breast radiation toxicity would influence their treatment decision-making. These findings provide a number of insights that will allow us to anticipate how patients are likely to engage with predictive radiogenomics testing in the future.

Abstract P6-09-51: 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 international 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 years9 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. Citation Format: Rattay T, Johnson K, Azria D, Chang-Claude J, Davidson S, Dunning A, de Ruyscher D, Guiterrez-Enriquez S, Lambin P, Rancati T, Rosenstein B, Seibold P, Symonds RP, Thierens H, Valdagni R, Vega A, Webb A, Wenz F, West C, Talbot C. 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 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-51.

Abstract P1-14-15: Recent experience of neoadjuvant chemotherapy according to breast cancer subtype: experience from a large United Kindgom teaching hospital

INTRODUCTION: The most recent United Kingdom (NICE, 2009) guidelines recommend neoadjuvant chemotherapy as the most appropriate initial treatment for locally advanced breast cancer followed by mastectomy. Neoadjuvant chemotherapy should also be offered to patients with early breast cancer who are considering breast conserving surgery that is not advisable at presentation. However, the evidence base is still gathering. This study reviews the recent experience of neoadjuvant chemotherapy in a large United Kingdom breast unit according to breast cancer subtype. METHODS: Retrospective chart review of patients who received neoadjuvant chemotherapy for breast cancer at University Hospitals of Leicester between January 2008 and March 2011. Patients were identified from the unit database. Breast cancers were typed according to immunehistochemical marker profile: luminal A (ER or PR positive, HER2 negative), luminal B (ER or PR positive, HER2 positive), triple negative (ER and PR negative, HER2 negative), and HER2 positive (ER and PR negative, HER2 positive). RESULTS: Of 2,489 new patients with breast cancer seen during the study period, 153 patients received neoadjuvant chemotherapy. 20 patients had lobular-type cancers, and the remaining 133 patients had ductal- or mixed-type histology. 101 patients had locally advanced disease and 52 patients presented as early breast cancer. 24 of all patients (15 %) achieved complete pathological response. 18 patients (12 %) never proceeded to surgery, eight of whom died during the study period. In total to date, 23 patients (15 %) have died including one death due to complications from chemotherapy. Of 120 patients initially scheduled for mastectomy, the tumor was downsized in 26 patients (22 %) so that they were able to undergo breast conserving surgery (BCS), with margins involved in six patients. The outcome of neoadjuvant chemotherapy according to breast cancer subtype is presented (Tables 1 and 2). CONCLUSIONS: In our experience, patients receive neoadjuvant chemotherapy for breast cancer for a variety of indications. Compared to our standard population of breast cancer patients, early mortality remains relatively high, particlularly in the hormone receptor negative subtypes. BCS conversion rates were similar across breast cancer subtypes, but BCS was less likely to be successful in the Luminal A group. Luminal A cancers were also significantly less likely to achieve pCR after neoadjuvant chemotherapy. Breast cancer subtype should be taken into account when scheduling patients for neoadjuvant chemotherapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-15.