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Item Open Access An observational study showed that explaining randomization using gambling-related metaphors and computer-agency descriptions impeded randomized clinical trial recruitment.(Elsevier BV, 2018-07) Jepson, Marcus; Elliott, Daisy; Conefrey, Carmel; Wade, Julia; Rooshenas, Leila; Wilson, Caroline; Beard, David; Blazeby, Jane M; Birtle, Alison; Halliday, Alison; Stein, Rob; Donovan, Jenny L; CSAW study group; Chemorad study group; POUT study group; ACST-2 study group; OPTIMA prelim study group; Elliott, Daisy [0000-0001-8143-9549]; Wilson, Caroline [0000-0002-1678-7974]OBJECTIVES: To explore how the concept of randomization is described by clinicians and understood by patients in randomized controlled trials (RCTs) and how it contributes to patient understanding and recruitment. STUDY DESIGN AND SETTING: Qualitative analysis of 73 audio recordings of recruitment consultations from five, multicenter, UK-based RCTs with identified or anticipated recruitment difficulties. RESULTS: One in 10 appointments did not include any mention of randomization. Most included a description of the method or process of allocation. Descriptions often made reference to gambling-related metaphors or similes, or referred to allocation by a computer. Where reference was made to a computer, some patients assumed that they would receive the treatment that was "best for them". Descriptions of the rationale for randomization were rarely present and often only came about as a consequence of patients questioning the reason for a random allocation. CONCLUSIONS: The methods and processes of randomization were usually described by recruiters, but often without clarity, which could lead to patient misunderstanding. The rationale for randomization was rarely mentioned. Recruiters should avoid problematic gambling metaphors and illusions of agency in their explanations and instead focus on clearer descriptions of the rationale and method of randomization to ensure patients are better informed about randomization and RCT participation.Item Open Access Published version Peer-reviewed Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling.(Elsevier BV, 2018-06-21) Periasamy, Jayaprakash; Kurdekar, Vadiraj; Jasti, Subbarao; Nijaguna, Mamatha B; Boggaram, Sanjana; Hurakadli, Manjunath A; Raina, Dhruv; Kurup, Lokavya Meenakshi; Chintha, Chetan; Manjunath, Kavyashree; Goyal, Aneesh; Sadasivam, Gayathri; Bharatham, Kavitha; Padigaru, Muralidhara; Potluri, Vijay; Venkitaraman, Ashok R; Raina, Dhruv [0000-0003-4140-3925]; Manjunath, Kavyashree [0000-0002-1838-5362]Intracellular signals triggered by DNA breakage flow through proteins containing BRCT (BRCA1 C-terminal) domains. This family, comprising 23 conserved phosphopeptide-binding modules in man, is inaccessible to small-molecule chemical inhibitors. Here, we develop Bractoppin, a drug-like inhibitor of phosphopeptide recognition by the human BRCA1 tandem (t)BRCT domain, which selectively inhibits substrate binding with nanomolar potency in vitro. Structure-activity exploration suggests that Bractoppin engages BRCA1 tBRCT residues recognizing pSer in the consensus motif, pSer-Pro-Thr-Phe, plus an abutting hydrophobic pocket that is distinct in structurally related BRCT domains, conferring selectivity. In cells, Bractoppin inhibits substrate recognition detected by Förster resonance energy transfer, and diminishes BRCA1 recruitment to DNA breaks, in turn suppressing damage-induced G2 arrest and assembly of the recombinase, RAD51. But damage-induced MDC1 recruitment, single-stranded DNA (ssDNA) generation, and TOPBP1 recruitment remain unaffected. Thus, an inhibitor of phosphopeptide recognition selectively interrupts BRCA1 tBRCT-dependent signals evoked by DNA damage.Item Open Access Accepted version Peer-reviewed A First-in-Human Study of the New Oral Selective Estrogen Receptor Degrader AZD9496 for ER+/HER2- Advanced Breast Cancer.(American Association for Cancer Research, 2018-02-13) Hamilton, Erika P; Patel, Manish R; Armstrong, Anne C; Baird, Richard D; Jhaveri, Komal; Hoch, Matthias; Klinowska, Teresa; Lindemann, Justin PO; Morgan, Shethah R; Schiavon, Gaia; Weir, Hazel M; Im, Seock-Ah; Baird, Richard [0000-0001-7071-6483]Purpose: AZD9496 is an oral nonsteroidal, small-molecule inhibitor of estrogen receptor alpha (ERα) and a potent and selective antagonist and degrader of ERα. This first-in-human phase I study determined the safety and tolerability of ascending doses of oral AZD9496 in women with estrogen receptor (ER)+/HER2- advanced breast cancer, characterized its pharmacokinetic (PK) profile, and made preliminary assessment of antitumor activity.Experimental design: Forty-five patients received AZD9496 [20 mg once daily (QD) to 600 mg twice daily (BID)] in a dose-escalation, dose-expansion "rolling 6" design. Safety, tolerability, and PK activity in each cohort were reviewed before escalating to the next dose. PK was determined by mass spectrometry. Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Objective tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.Results: Most common causally related AEs were diarrhea (35.6%), fatigue (31.1%), and nausea (22.2%), and seven patients had grade ≥3 AEs. Three patients experienced a dose-limiting toxicity: one each at 150 mg BID (abnormal hepatic function), 400 mg BID (diarrhea and elevated liver function tests), and 600 mg BID (diarrhea), and all were reversible. The maximum tolerated dose was not reached. Partial response was confirmed in one patient, who also had decreased tumor marker Ca15.3. Four patients had stable disease at 12 months' follow-up.Conclusions: AZD9496 is well tolerated with an acceptable safety profile, showing evidence of prolonged disease stabilization in heavily pretreated patients with ER+/HER2- advanced breast cancer. Clin Cancer Res; 1-9. ©2018 AACR.Item Open Access Accepted version Peer-reviewed The Landscape of Somatic Genetic Alterations in Breast Cancers From ATM Germline Mutation Carriers.(OUP, 2018-02-28) Weigelt, Britta; Bi, Rui; Kumar, Rahul; Blecua, Pedro; Mandelker, Diana L; Geyer, Felipe C; Pareja, Fresia; James, Paul A; kConFab Investigators; Couch, Fergus J; Eccles, Diana M; Blows, Fiona; Pharoah, Paul; Li, Anqi; Selenica, Pier; Lim, Raymond S; Jayakumaran, Gowtham; Waddell, Nic; Shen, Ronglai; Norton, Larry; Wen, Hannah Y; Powell, Simon N; Riaz, Nadeem; Robson, Mark E; Reis-Filho, Jorge S; Chenevix-Trench, Georgia; Pharoah, Paul [0000-0001-8494-732X]Pathogenic germline variants in ataxia-telangiectasia mutated (ATM), a gene that plays a role in DNA damage response and cell cycle checkpoints, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic characteristics and landscape of somatic genetic alterations in 24 BCs from ATM germline mutation carriers by whole-exome and targeted sequencing. ATM-associated BCs were consistently hormone receptor positive and largely displayed minimal immune infiltrate. Although 79.2% of these tumors exhibited loss of heterozygosity of the ATM wild-type allele, none displayed high activity of mutational signature 3 associated with defective homologous recombination DNA (HRD) repair. No TP53 mutations were found in the ATM-associated BCs. Analysis of an independent data set confirmed that germline ATM variants and TP53 somatic mutations are mutually exclusive. Our findings indicate that ATM-associated BCs often harbor bi-allelic inactivation of ATM, are phenotypically distinct from BRCA1/2-associated BCs, lack HRD-related mutational signatures, and that TP53 and ATM genetic alterations are likely epistatic.Item Open Access Published version Peer-reviewed Stable centrosomal roots disentangle to allow interphase centriole independence.(Public Library of Science (PLoS), 2018-04) Mahen, Robert; Mahen, Robert [0000-0002-4748-3690]The centrosome is a non-membrane-bound cellular compartment consisting of 2 centrioles surrounded by a protein coat termed the pericentriolar material (PCM). Centrioles generally remain physically associated together (a phenomenon called centrosome cohesion), yet how this occurs in the absence of a bounding lipid membrane is unclear. One model posits that pericentriolar fibres formed from rootletin protein directly link centrioles, yet little is known about the structure, biophysical properties, or assembly kinetics of such fibres. Here, I combine live-cell imaging of endogenously tagged rootletin with cell fusion and find previously unrecognised plasticity in centrosome cohesion. Rootletin forms large, diffusionally stable bifurcating fibres, which amass slowly on mature centrioles over many hours from anaphase. Nascent centrioles (procentrioles), in contrast, do not form roots and must be licensed to do so through polo-like kinase 1 (PLK1) activity. Transient separation of roots accompanies centriolar repositioning during the interphase, suggesting that centrioles organize as independent units, each containing discrete roots. Indeed, forced induction of duplicate centriole pairs allows independent reshuffling of individual centrioles between the pairs. Therefore collectively, these findings suggest that progressively nucleated polymers mediate the dynamic association of centrioles as either 1 or 2 interphase centrosomes, with implications for the understanding of how non-membrane-bound organelles self-organise.Item Open Access Published version Peer-reviewed Cost-effectiveness and Benefit-to-Harm Ratio of Risk-Stratified Screening for Breast Cancer: A Life-Table Model.(American Medical Association (AMA), 2018-11-01) Pashayan, Nora; Morris, Steve; Gilbert, Fiona J; Pharoah, Paul DP; Morris, Stephen [0000-0002-5828-3563]; Gilbert, Fiona [0000-0002-0124-9962]; Pharoah, Paul [0000-0001-8494-732X]IMPORTANCE: The age-based or "one-size-fits-all" breast screening approach does not take into account the individual variation in risk. Mammography screening reduces death from breast cancer at the cost of overdiagnosis. Identifying risk-stratified screening strategies with a more favorable ratio of overdiagnoses to breast cancer deaths prevented would improve the quality of life of women and save resources. OBJECTIVE: To assess the benefit-to-harm ratio and the cost-effectiveness of risk-stratified breast screening programs compared with a standard age-based screening program and no screening. DESIGN, SETTING, AND POPULATION: A life-table model was created of a hypothetical cohort of 364 500 women in the United Kingdom, aged 50 years, with follow-up to age 85 years, using (1) findings of the Independent UK Panel on Breast Cancer Screening and (2) risk distribution based on polygenic risk profile. The analysis was undertaken from the National Health Service perspective. INTERVENTIONS: The modeled interventions were (1) no screening, (2) age-based screening (mammography screening every 3 years from age 50 to 69 years), and (3) risk-stratified screening (a proportion of women aged 50 years with a risk score greater than a threshold risk were offered screening every 3 years until age 69 years) considering each percentile of the risk distribution. All analyses took place between July 2016 and September 2017. MAIN OUTCOMES AND MEASURES: Overdiagnoses, breast cancer deaths averted, quality-adjusted life-years (QALYs) gained, costs in British pounds, and net monetary benefit (NMB). Probabilistic sensitivity analyses were used to assess uncertainty around parameter estimates. Future costs and benefits were discounted at 3.5% per year. RESULTS: The risk-stratified analysis of this life-table model included a hypothetical cohort of 364 500 women followed up from age 50 to 85 years. As the risk threshold was lowered, the incremental cost of the program increased linearly, compared with no screening, with no additional QALYs gained below 35th percentile risk threshold. Of the 3 screening scenarios, the risk-stratified scenario with risk threshold at the 70th percentile had the highest NMB, at a willingness to pay of £20 000 (US $26 800) per QALY gained, with a 72% probability of being cost-effective. Compared with age-based screening, risk-stratified screening at the 32nd percentile vs 70th percentile risk threshold would cost £20 066 (US $26 888) vs £537 985 (US $720 900) less, would have 26.7% vs 71.4% fewer overdiagnoses, and would avert 2.9% vs 9.6% fewer breast cancer deaths, respectively. CONCLUSIONS AND RELEVANCE: Not offering breast cancer screening to women at lower risk could improve the cost-effectiveness of the screening program, reduce overdiagnosis, and maintain the benefits of screening.Item Open Access Accepted version Peer-reviewed Alternatives to Traditional Per-Oral Endoscopy for Screening.(Elsevier, 2017-07-27) Offman, Judith; Fitzgerald, Rebecca C; Fitzgerald, Rebecca [0000-0002-3434-3568]Barrett's esophagus (BE) predisposes patients to esophageal adenocarcinoma. 3 to 6% of individuals with gastro-esophageal reflux disease are estimated to have BE but only 20 to 25% of BE patients are currently diagnosed. The current gold standard for diagnosis of BE is per-oral upper GI endoscopy. As this is not suitable for large-scale screening, a number of alternative methods are currently being investigated: transnasal and video capsule endoscopy, endomicroscopy, cell collection devices like the cytosponge and biomarkers. Some of these are promising, however, well powered studies carried out in relevant screening populations are needed.Item Open Access Published version Peer-reviewed Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial.(Elsevier BV, 2017-07) Cameron, David; Morden, James P; Canney, Peter; Velikova, Galina; Coleman, Robert; Bartlett, John; Agrawal, Rajiv; Banerji, Jane; Bertelli, Gianfilippo; Bloomfield, David; Brunt, A Murray; Earl, Helena; Ellis, Paul; Gaunt, Claire; Gillman, Alexa; Hearfield, Nicholas; Laing, Robert; Murray, Nicholas; Couper, Niki; Stein, Robert C; Verrill, Mark; Wardley, Andrew; Barrett-Lee, Peter; Bliss, Judith M; TACT2 Investigators; Earl, Helena [0000-0003-1549-8094]BACKGROUND: Adjuvant chemotherapy for early breast cancer has improved outcomes but causes toxicity. The UK TACT2 trial used a 2×2 factorial design to test two hypotheses: whether use of accelerated epirubicin would improve time to tumour recurrence (TTR); and whether use of oral capecitabine instead of cyclophosphamide would be non-inferior in terms of patients' outcomes and would improve toxicity, quality of life, or both. METHODS: In this multicentre, phase 3, randomised, controlled trial, we enrolled patients aged 18 years or older from 129 UK centres who had histologically confirmed node-positive or high-risk node-negative operable breast cancer, had undergone complete excision, and were due to receive adjuvant chemotherapy. Patients were randomly assigned to receive four cycles of 100 mg/m2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either classic cyclophosphamide, methotrexate, and fluorouracil (CMF; 600 mg/m2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1-14; 40 mg/m2 methotrexate intravenously on days 1 and 8; and 600 mg/m2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m2 capecitabine (1250 mg/m2 given twice daily on days 1-14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs one to three vs four or more), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). The primary endpoint was TTR, defined as time from randomisation to first invasive relapse or breast cancer death, with intention-to-treat analysis of standard versus accelerated epirubicin and per-protocol analysis of CMF versus capecitabine. This trial is registered with ISRCTN, number 68068041, and with ClinicalTrials.gov, number NCT00301925. FINDINGS: From Dec 16, 2005, to Dec 5, 2008, 4391 patients (4371 women and 20 men) were recruited. At a median follow-up of 85·6 months (IQR 80·6-95·9) no significant difference was seen in the proportions of patients free from TTR events between the accelerated and standard epirubicin groups (overall hazard ratio [HR] 0·94, 95% CI 0·81-1·09; stratified p=0·42). At 5 years, 85·9% (95% CI 84·3-87·3) of patients receiving standard epirubicin and 87·1% (85·6-88·4) of those receiving accelerated epirubicin were free from TTR events. 4358 patients were included in the per-protocol analysis, and no difference was seen in the proportions of patients free from TTR events between the CMF and capecitabine groups (HR 0·98, 95% CI 0·85-1.14; stratified p=0·00092 for non-inferiority). Compared with baseline, significantly more patients taking CMF than those taking capecitabine had clinically relevant worsening of quality of life at end of treatment (255 [58%] of 441 vs 235 [50%] of 475; p=0·011) and at 12 months (114 [34%] of 334 vs 89 [22%] of 401; p<0·001 at 12 months) and had worse quality of life over time (p<0·0001). Detailed toxicity and quality-of-life data were collected from 2115 (48%) of treated patients. The most common grade 3 or higher adverse events in cycles 1-4 were neutropenia (175 [16%]) and fatigue (56 [5%]) of the 1070 patients treated with standard epirubicin, and fatigue (63 [6%]) and infection (34 [3%]) of the 1045 patients treated with accelerated epirubicin. In cycles 5-8, the most common grade 3 or higher adverse events were neutropenia (321 [31%]) and fatigue (109 [11%]) in the patients treated with CMF, and hand-foot syndrome (129 [12%]) and diarrhoea (67 [6%]) in the 1044 patients treated with capcitabine. INTERPRETATION: We found no benefit from increasing the dose density of the anthracycline component of chemotherapy. However, capecitabine could be used in place of CMF without significant loss of efficacy and with improved quality of life. FUNDING: Cancer Research UK, Amgen, Pfizer, and Roche.Item Open Access Published version Peer-reviewed Revised British Society of Gastroenterology recommendation on the diagnosis and management of Barrett's oesophagus with low-grade dysplasia.(BMJ, 2018-02) di Pietro, Massimiliano; Fitzgerald, Rebecca C; BSG Barrett's guidelines working group; Di Pietro, Massimiliano [0000-0003-4866-7026]; Fitzgerald, Rebecca [0000-0002-3434-3568]The most recent guidelines for the management of Barrett's oesophagus published in 2014 recommended endoscopic surveillance for patient with histological evidence of low-grade dysplasia (LGD) on random biopsies.1 In the last 2 years, new evidence on the natural history of LGD in Barrett's oesophagus and on the safety and efficacy of endoscopic treatment in this subgroup of patients has been published.Item Open Access Published version Peer-reviewed Adjuvant trastuzumab duration trials in HER2 positive breast cancer - what results would be practice-changing? Persephone investigator questionnaire prior to primary endpoint results.(2018-04-05) Hiller, Louise; Dunn, Janet A; Loi, Shrushma; Vallier, Anne-Laure; Howe, Donna L; Cameron, David A; Miles, David; Wardley, Andrew M; Earl, Helena; Wardley, Andrew M [0000-0002-9639-0888]; Earl, Helena [0000-0003-1549-8094]Item Open Access Accepted version Peer-reviewed Mendelian randomisation study of age at menarche and age at menopause and the risk of colorectal cancer.(Springer Science and Business Media LLC, 2018-06) Neumeyer, Sonja; Banbury, Barbara L; Arndt, Volker; Berndt, Sonja I; Bezieau, Stephane; Bien, Stephanie A; Buchanan, Dan D; Butterbach, Katja; Caan, Bette J; Campbell, Peter T; Casey, Graham; Chan, Andrew T; Chanock, Stephen J; Dai, James Y; Gallinger, Steven; Giovannucci, Edward L; Giles, Graham G; Grady, William M; Hampe, Jochen; Hoffmeister, Michael; Hopper, John L; Hsu, Li; Jenkins, Mark A; Joshi, Amit; Larsson, Susanna C; Le Marchand, Loic; Lindblom, Annika; Moreno, Victor; Lemire, Mathieu; Li, Li; Lin, Yi; Offit, Kenneth; Newcomb, Polly A; Pharaoh, Paul D; Potter, John D; Qi, Lihong; Rennert, Gad; Schafmayer, Clemens; Schoen, Robert E; Slattery, Martha L; Song, Mingyang; Ulrich, Cornelia M; Win, Aung K; White, Emily; Wolk, Alicja; Woods, Michael O; Wu, Anna H; Gruber, Stephen B; Brenner, Hermann; Peters, Ulrike; Chang-Claude, Jenny; Pharoah, Paul [0000-0001-8494-732X]BACKGROUND: Substantial evidence supports an association between use of menopausal hormone therapy and decreased colorectal cancer (CRC) risk, indicating a role of exogenous sex hormones in CRC development. However, findings on endogenous oestrogen exposure and CRC are inconsistent. METHODS: We used a Mendelian randomisation approach to test for a causal effect of age at menarche and age at menopause as surrogates for endogenous oestrogen exposure on CRC risk. Weighted genetic risk scores based on 358 single-nucleotide polymorphisms associated with age at menarche and 51 single-nucleotide polymorphisms associated with age at menopause were used to estimate the association with CRC risk using logistic regression in 12,944 women diagnosed with CRC and 10,741 women without CRC from three consortia. Sensitivity analyses were conducted to address pleiotropy and possible confounding by body mass index. RESULTS: Genetic risk scores for age at menarche (odds ratio per year 0.98, 95% confidence interval: 0.95-1.02) and age at menopause (odds ratio 0.98, 95% confidence interval: 0.94-1.01) were not significantly associated with CRC risk. The sensitivity analyses yielded similar results. CONCLUSIONS: Our study does not support a causal relationship between genetic risk scores for age at menarche and age at menopause and CRC risk.Item Open Access Accepted version Peer-reviewed New Screening Techniques in Barrett's Esophagus: Great Ideas or Great Practice?(Elsevier, 2018-05-01) Spechler, Stuart J; Katzka, David A; Fitzgerald, Rebecca C; Fitzgerald, Rebecca [0000-0002-3434-3568]The cellular origins of a precancerous condition called Barrett's oesophagus have been unclear. Tracking and analysis of epithelial cells at the affected site could shed light on the problem.Item Open Access Accepted version Peer-reviewed Accuracy and Safety of the Cytosponge for Assessing Histologic Activity in Eosinophilic Esophagitis: A Two-Center Study.(Springer Nature, 2017-10) Katzka, David A; Smyrk, Thomas C; Alexander, Jeffrey A; Geno, Debra M; Beitia, RoseMary A; Chang, Audrey O; Shaheen, Nicholas J; Fitzgerald, Rebecca C; Dellon, Evan S; Fitzgerald, Rebecca [0000-0002-3434-3568]OBJECTIVES: Management of eosinophilic esophagitis (EoE) requires repeated endoscopic mucosal sampling to assess disease activity. A less invasive and expensive means of monitoring of EoE is required. The objective of this study was to assess the accuracy, safety, and tolerability of the cytosponge compared to endoscopy and biopsy for histologic assessment of EoE. METHODS: In this prospective two-center cross-sectional study, patients with known EoE underwent cytosponge sampling followed by endoscopy and biopsy. Sample adequacy and eosinophil counts (eos/HPF) were determined for both cytosponge and endoscopic samples. The cytosponge was assessed for diagnostic accuracy, safety, and patient preference as compared to endoscopy. RESULTS: Six patients (7%) failed to swallow the sponge. One hundred and five procedures were successfully performed in 80 patients (66% male, 100% white, 19% stricture). The cytosponge sample was adequate in 102 and the biopsy in 104; 101 procedures had adequate samples by both techniques. Fifty-seven biopsies were graded as active EoE with ≥15 eos/HPF as the gold standard. Eosinophil counts highly correlated between the biopsy and cytosponge (r=0.78, P<0.0001). Using a cutoff of ≤15 eos/HPF for inactive disease, the sensitivity and specificity of the cytosponge was 75% and 86%, respectively. Six patients had active EoE on cytosponge not found on biopsy. For biopsies with inactive EoE, the cytosponge identified 38/44. No complications occurred, and cytosponge endoscopic abrasion scores were low (0.34/4). Patients preferred cytosponge to endoscopy with higher rating scores (7.27 vs. 6.11, P=0.002). CONCLUSIONS: Compared to endoscopy with biopsy, cytosponge provided a minimally invasive, safe, well tolerated, and accurate method to assess EoE histologic activity. (ClinicalTrial.gov number NCT01585103).Item Open Access Identifying risk factors for L'Hermitte's sign after IMRT for head and neck cancer.(Korean Society for Therapeutic Radiology and Oncology, 2018-05-04) Laidley, Hannah M; Noble, David; Barnett, Gill C; Forman, Julia R; Bates, Amy M; Benson, Richard J; Jefferies, Sarah J; Jena, Rajesh; Burnet, Neil; Laidley, Hannah M [0000-0001-8440-9898]; Noble, David [0000-0001-6738-2152]; Jena, Rajesh [0000-0002-3803-5968]; Burnet, Neil [0000-0001-9692-706X]BACKGROUND L’Hermitte’s sign (LS) after chemoradiotherapy for head and neck cancer appears related to higher spinal cord doses. IMRT plans limit spinal cord dose, but the incidence of LS remains high. METHODS 117 patients treated with TomoTherapy™ between 2008 and 2015 prospectively completed a side-effect questionnaire (VoxTox Trial Registration: UK CRN ID 13716). Baseline patient and treatment data were collected. Radiotherapy plans were analysed; mean and maximum spinal cord dose and volumes receiving 10, 20, 30 and 40 Gy were recorded. Dose variation across the cord was examined. These data were included in a logistic regression model. RESULTS 42 patients (35.9%) reported LS symptoms. Concurrent weekly cisplatin did not increase LS risk (p = 0.70, OR = 1.23 {95%CI 0.51 – 2.34}). Of 13 diabetic participants (9 taking metformin), only 1 developed LS (p = 0.025, OR = 0.13 {95%CI 0.051 – 3.27}). A refined binary logistic regression model showed that patients receiving unilateral radiation (p = 0.019, OR = 2.06 {95%CI 0.15 – 0.84}) were more likely to develop LS. Higher V40Gy (p = 0.047, OR = 1.06 {95%CI 1.00 – 1.12}), and younger age (mean age 56.6 vs 59.7, p = 0.060, OR = 0.96 {95%CI 0.92 – 1.00}) were associated with elevated risk of LS, with borderline significance. CONCLUSIONS In this cohort, concomitant cisplatin did not increase risk, and LS incidence was lower in diabetic patients. Patient age and dose gradients across the spinal cord may be important factors.Item Open Access Cost-effectiveness and Benefit-to-Harm Ratio of Risk-Stratified Screening for Breast Cancer: A Life-Table Model(American Medical Association) Pashayan, Nora; Morris, Steve; Gilbert, Fiona; Pharoah, Paul; Gilbert, Fiona [0000-0002-0124-9962]; Pharoah, Paul [0000-0001-8494-732X]Importance The age-based or “one-size-fits-all” breast screening approach does not take into account the individual variation in risk. Mammography screening reduces death from breast cancer at the cost of overdiagnosis. Identifying risk-stratified screening strategies with a more favorable ratio of overdiagnoses to breast cancer deaths prevented would improve the quality of life of women and save resources. Objective To assess the benefit-to-harm ratio and the cost-effectiveness of risk-stratified breast screening programs compared with a standard age-based screening program and no screening. Design, Setting, and Population A life-table model was created of a hypothetical cohort of 364 500 women in the United Kingdom, aged 50 years, with follow-up to age 85 years, using (1) findings of the Independent UK Panel on Breast Cancer Screening and (2) risk distribution based on polygenic risk profile. The analysis was undertaken from the National Health Service perspective. Interventions The modeled interventions were (1) no screening, (2) age-based screening (mammography screening every 3 years from age 50 to 69 years), and (3) risk-stratified screening (a proportion of women aged 50 years with a risk score greater than a threshold risk were offered screening every 3 years until age 69 years) considering each percentile of the risk distribution. All analyses took place between July 2016 and September 2017. Main Outcomes and Measures Overdiagnoses, breast cancer deaths averted, quality-adjusted life-years (QALYs) gained, costs in British pounds, and net monetary benefit (NMB). Probabilistic sensitivity analyses were used to assess uncertainty around parameter estimates. Future costs and benefits were discounted at 3.5% per year. Results The risk-stratified analysis of this life-table model included a hypothetical cohort of 364 500 women followed up from age 50 to 85 years. As the risk threshold was lowered, the incremental cost of the program increased linearly, compared with no screening, with no additional QALYs gained below 35th percentile risk threshold. Of the 3 screening scenarios, the risk-stratified scenario with risk threshold at the 70th percentile had the highest NMB, at a willingness to pay of £20 000 (US $26 800) per QALY gained, with a 72% probability of being cost-effective. Compared with age-based screening, risk-stratified screening at the 32nd percentile vs 70th percentile risk threshold would cost £20 066 (US $26 888) vs £537 985 (US $720 900) less, would have 26.7% vs 71.4% fewer overdiagnoses, and would avert 2.9% vs 9.6% fewer breast cancer deaths, respectively. Conclusions and Relevance Not offering breast cancer screening to women at lower risk could improve the cost-effectiveness of the screening program, reduce overdiagnosis, and maintain the benefits of screening.Item Open Access Published version Peer-reviewed Effect of a Low-Intensity PSA-Based Screening Intervention on Prostate Cancer Mortality: The CAP Randomized Clinical Trial(American Medical Association, 2018-03-06) Martin, RM; Donovan, JL; Turner, EL; Metcalfe, C; Young, GJ; Walsh, EI; Lane, JA; Noble, S; Oliver, SE; Evans, S; Sterne, JAC; Holding, P; Ben-Shlomo, Y; Brindle, P; Williams, NJ; Hill, EM; Ng, SY; Toole, J; Tazewell, MK; Hughes, LJ; Davies, CF; Thorn, JC; Down, E; Smith, GD; Neal, DE; Hamdy, FC; Martin, R; Donovan, J; Neal, D; Hamdy, F; Turner, E; Metcalfe, C; Athene Lane, J; Sterne, J; Noble, S; Frankel, S; Bollina, P; Catto, J; Doble, A; Doherty, A; Gillatt, D; Gnanapragasam, V; Holding, P; Hughes, O; Kockelbergh, R; Kynaston, H; Paul, A; Paez, E; Rosario, DJ; Rowe, E; Gnanapragasam, Vincent [0000-0003-4722-4207]IMPORTANCE Prostate cancer screening remains controversial because potential mortality or quality-of-life benefits may be outweighed by harms from overdetection and overtreatment. OBJECTIVE To evaluate the effect of a single prostate-specific antigen (PSA) screening intervention and standardized diagnostic pathway on prostate cancer-specific mortality. DESIGN, SETTING, AND PARTICIPANTS The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) included 419 582 men aged 50 to 69 years and was conducted at 573 primary care practices across the United Kingdom. Randomization and recruitment of the practices occurred between 2001 and 2009; patient follow-up ended on March 31, 2016. INTERVENTION An invitation to attend a PSA testing clinic and receive a single PSA test vs standard (unscreened) practice. MAIN OUTCOMES AND MEASURES Primary outcome: prostate cancer-specific mortality at a median follow-up of 10 years. Prespecified secondary outcomes: diagnostic cancer stage and Gleason grade (range, 2-10; higher scores indicate a poorer prognosis) of prostate cancers identified, all-cause mortality, and an instrumental variable analysis estimating the causal effect of attending the PSA screening clinic. RESULTS Among 415 357 randomizedmen(mean [SD] age, 59.0[5.6] years), 189 386 in the intervention group and 219 439 in the control groupwere included in the analysis (n = 408 825; 98%). In the intervention group, 75 707 (40%)attended the PSAtesting clinic and 67 313 (36%) underwent PSAtesting. Of 64 436 with a valid PSAtest result, 6857 (11%) had a PSA level between 3 ng/mLand 19.9 ng/mL, ofwhom5850 (85%) had a prostate biopsy. After a median follow-up of 10 years, 549 (0.30 per 1000 person-years) died of prostate cancer in the intervention group vs 647 (0.31 per 1000 person-years) in the control group (rate difference, -0.013 per 1000 person-years [95%CI, -0.047 to0.022]; rate ratio [RR] ,0.96 [95%CI,0.85 to 1.08]; P = .50). The number diagnosed with prostate cancerwas higher in the intervention group (n = 8054; 4.3%) than in the control group (n = 7853; 3.6%) (RR, 1.19 [95%CI, 1.14 to 1.25] ; P < .001). More prostate cancer tumors with a Gleason grade of 6 or lowerwere identified in the intervention group (n = 3263/189 386 [1.7%]) than in the control group (n = 2440/219 439 [1.1%] ) (difference per 1000 men, 6.11 [95%CI, 5.38 to 6.84]; P < .001). In the analysis of all-cause mortality, therewere 25 459 deaths in the intervention group vs 28 306 deaths in the control group (RR,0.99 [95%CI,0.94 to 1.03]; P = .49). In the instrumental variable analysis for prostate cancer mortality, the adherence-adjusted causal RRwas0.93 (95%CI,0.67 to 1.29; P = .66). CONCLUSIONS AND RELEVANCE Among practices randomized to a single PSA screening intervention vs standard practice without screening, there was no significant difference in prostate cancer mortality after a median follow-up of 10 years but the detection of low-risk prostate cancer cases increased. Although longer-term follow-up is under way, the findings do not support single PSA testing for population-based screening. TRIAL REGISTRATION ISRCTN Identifier: ISRCTN92187251.Item Open Access Accepted version Peer-reviewed A comparison of operative and margin outcomes from surgeon learning curves in robot assisted radical prostatectomy in a changing referral practice.(Royal College of Surgeons of England, 2018-03) Jaulim, A; Srinivasan, A; Hori, S; Kumar, N; Warren, AY; Shah, NC; Gnanapragasam, VJ; Warren, Anne [0000-0002-1170-7867]; Gnanapragasam, Vincent [0000-0003-4722-4207]Introduction The aim of this study was to explore the impact of increasing proportions of high risk referrals on surgical margin outcomes of a surgeon's learning curve in robotic prostatectomy. Methods All patients in this study underwent robot assisted radical prostatectomy (RARP) performed by three different consultant urological surgeons. Data collected included preoperative clinical stage, Gleason score and prostate specific antigen levels, which were used to risk stratify patients according to National Institute for Health and Care Excellence criteria. Oncological clearance was assessed by overall and stage specific positive margin status. Comparisons were made between each surgeon for the first and second 50 consecutive cases. Results For the three surgeons, there was a progressive increase in the proportion of high risk cases referred accompanied by a corresponding decline in low risk disease (p<0.001). Postoperative pathology also showed an upward trend in pT3 cases across the three eras. There was no statistical difference in overall positive margin rates between the surgeons. The overall rates were 12%, 20% and 23% for the first 50 cases, and 32%, 36% and 21% for the second 50 cases for the three surgeons respectively. Conclusions Our series demonstrates an upward trend in the risk profile of men referred for robotic prostatectomy over a nine-year period. Despite this, there was minimal impact on pathological and surgical outcomes among our surgeons, who were at the initial stages of their RARP learning curve. Our results suggest that there is no requirement for an active case selection bias against patients with high risk disease for surgeons newly embarking on their RARP learning experience.Item Open Access Published version Peer-reviewed Single-molecule localization microscopy reveals molecular transactions during RAD51 filament assembly at cellular DNA damage sites.(Oxford University Press (OUP), 2018-03-16) Haas, Kalina T; Lee, MiYoung; Esposito, Alessandro; Venkitaraman, Ashok R; Esposito, Alessandro [0000-0002-5051-091X]RAD51 recombinase assembles on single-stranded (ss)DNA substrates exposed by DNA end-resection to initiate homologous recombination (HR), a process fundamental to genome integrity. RAD51 assembly has been characterized using purified proteins, but its ultrastructural topography in the cell nucleus is unexplored. Here, we combine cell genetics with single-molecule localization microscopy and a palette of bespoke analytical tools, to visualize molecular transactions during RAD51 assembly in the cellular milieu at resolutions approaching 30-40 nm. In several human cell types, RAD51 focalizes in clusters that progressively extend into long filaments, which abut-but do not overlap-with globular bundles of replication protein A (RPA). Extended filaments alter topographically over time, suggestive of succeeding steps in HR. In cells depleted of the tumor suppressor protein BRCA2, or overexpressing its RAD51-binding BRC repeats, RAD51 fails to assemble at damage sites, although RPA accumulates unhindered. By contrast, in cells lacking a BRCA2 carboxyl (C)-terminal region targeted by cancer-causing mutations, damage-induced RAD51 assemblies initiate but do not extend into filaments. We suggest a model wherein RAD51 assembly proceeds concurrently with end-resection at adjacent sites, via an initiation step dependent on the BRC repeats, followed by filament extension through the C-terminal region of BRCA2.Item Open Access Published version Peer-reviewed BRCA2 Regulates Transcription Elongation by RNA Polymerase II to Prevent R-Loop Accumulation.(Elsevier, 2018-01-23) Shivji, MKK; Renaudin, X; Williams, CH; Venkitaraman, AR; Renaudin, Xavier [0000-0002-2970-6010]The controlled release of RNA polymerase II (RNAPII) from promoter-proximal pausing (PPP) sites is critical for transcription elongation in metazoans. We show that the human tumor suppressor BRCA2 interacts with RNAPII to regulate PPP release, thereby preventing unscheduled RNA-DNA hybrids (R-loops) implicated in genomic instability and carcinogenesis. BRCA2 inactivation by depletion or cancer-causing mutations instigates RNAPII accumulation and R-loop accrual at PPP sites in actively transcribed genes, accompanied by γH2AX formation marking DNA breakage, which is reduced by ERCC4 endonuclease depletion. BRCA2 inactivation decreases RNAPII-associated factor 1 (PAF1) recruitment (which normally promotes RNAPII release) and diminishes H2B Lys120 ubiquitination, impeding nascent RNA synthesis. PAF1 depletion phenocopies, while its overexpression ameliorates, R-loop accumulation after BRCA2 inactivation. Thus, an unrecognized role for BRCA2 in the transition from promoter-proximal pausing to productive elongation via augmented PAF1 recruitment to RNAPII is subverted by disease-causing mutations, provoking R-loop-mediated DNA breakage in BRCA2-deficient cells.Item Open Access Accepted version Peer-reviewed Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.(Elsevier BV, 2017-11) Machiela, Mitchell J; Hofmann, Jonathan N; Carreras-Torres, Robert; Brown, Kevin M; Johansson, Mattias; Wang, Zhaoming; Foll, Matthieu; Li, Peng; Rothman, Nathaniel; Savage, Sharon A; Gaborieau, Valerie; McKay, James D; Ye, Yuanqing; Henrion, Marc; Bruinsma, Fiona; Jordan, Susan; Severi, Gianluca; Hveem, Kristian; Vatten, Lars J; Fletcher, Tony; Koppova, Kvetoslava; Larsson, Susanna C; Wolk, Alicja; Banks, Rosamonde E; Selby, Peter J; Easton, Douglas F; Pharoah, Paul; Andreotti, Gabriella; Freeman, Laura E Beane; Koutros, Stella; Albanes, Demetrius; Mannisto, Satu; Weinstein, Stephanie; Clark, Peter E; Edwards, Todd E; Lipworth, Loren; Gapstur, Susan M; Stevens, Victoria L; Carol, Hallie; Freedman, Matthew L; Pomerantz, Mark M; Cho, Eunyoung; Kraft, Peter; Preston, Mark A; Wilson, Kathryn M; Gaziano, J Michael; Sesso, Howard S; Black, Amanda; Freedman, Neal D; Huang, Wen-Yi; Anema, John G; Kahnoski, Richard J; Lane, Brian R; Noyes, Sabrina L; Petillo, David; Colli, Leandro M; Sampson, Joshua N; Besse, Celine; Blanche, Helene; Boland, Anne; Burdette, Laurie; Prokhortchouk, Egor; Skryabin, Konstantin G; Yeager, Meredith; Mijuskovic, Mirjana; Ognjanovic, Miodrag; Foretova, Lenka; Holcatova, Ivana; Janout, Vladimir; Mates, Dana; Mukeriya, Anush; Rascu, Stefan; Zaridze, David; Bencko, Vladimir; Cybulski, Cezary; Fabianova, Eleonora; Jinga, Viorel; Lissowska, Jolanta; Lubinski, Jan; Navratilova, Marie; Rudnai, Peter; Szeszenia-Dabrowska, Neonila; Benhamou, Simone; Cancel-Tassin, Geraldine; Cussenot, Olivier; Bueno-de-Mesquita, H Bas; Canzian, Federico; Duell, Eric J; Ljungberg, Börje; Sitaram, Raviprakash T; Peters, Ulrike; White, Emily; Anderson, Garnet L; Johnson, Lisa; Luo, Juhua; Buring, Julie; Lee, I-Min; Chow, Wong-Ho; Moore, Lee E; Wood, Christopher; Eisen, Timothy; Larkin, James; Choueiri, Toni K; Lathrop, G Mark; Teh, Bin Tean; Deleuze, Jean-Francois; Wu, Xifeng; Houlston, Richard S; Brennan, Paul; Chanock, Stephen J; Scelo, Ghislaine; Purdue, Mark P; Easton, Douglas [0000-0003-2444-3247]; Pharoah, Paul [0000-0001-8494-732X]; Eisen, Tim [0000-0001-9663-4873]BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13). CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk. PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.