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The origin and hazardous potential of human mpox is obscured by a lack of genomic data between the 2018, when exportations from Nigeria were recorded, and 2022 when the global outbreak started. Here, 18 genomes from patients across southern Nigeria in 2019/20 reveal multiple lineages of Monkeypox virus have achieved sustained human-to-human transmission, co-existing in humans for several years and accumulating mutations consistent with APOBEC3 activity suggesting the virus in humans is now segregated from its natural reservoir. Remarkably, three genomes have disruptions in the A46R gene, which contributes to innate immune modulation. The data demonstrates that the A.2 lineage, multiply exported to North America since 2021 independently of the global outbreak, has persisted in Nigeria for more than two years prior to its latest exportation.One-Sentence SummaryMpox is now a human diseae evolving in humans with multiple variants taking separate paths towards adaptation, some analogous to those ofVariola

Background No consensus exists regarding adequacy of margins after mastectomy. To determine if pathological margin proximity is associated with local (LR) or distant recurrence after mastectomy for early invasive breast cancer or ductal carcinoma in situ. Methods A systematic review of literature published from 1980 to 2019 and meta-analysis was conducted. Unpublished data were sought from authors (PROSPERO (CRD42019127541)). Thirty-four studies comprising 34,833 breast cancer patients were included in the quantitative synthesis. Eligible studies reported on patients undergoing curative mastectomy for cancer allowing estimation of outcomes in relation to margin status/width. The association between pathological margin status and local (LR) and distant recurrence was considered using random effects modelling. PRISMA guidelines were followed. Results Positive margins were associated with increased LR on multivariable analyses (HR, 2·64, (95%CI 2·01–3·46)) and LR was higher regardless of the distance of tumour from the margin defined as positive. After skin-sparing mastectomy, positive margins were associated with increased LR (HR 3·40, (95%CI 1·9–6·2)). In the 4 studies reporting distant recurrence, patients with involved margins had a higher risk (HR 1·53, (95%CI 1·03–2·25)). Conclusions Failure to achieve clear margins after mastectomy may increase the risks of local and distant recurrence. Adequate margin clearance should be recommended to minimize recurrence after mastectomy in National and International Guidelines.

PURPOSE Checkpoint kinase 2 ( CHEK2) is frequently included in multigene panels. We describe the associated outcomes among carriers of CHEK2 pathogenic variants in young patients with symptomatic breast cancer. PATIENTS AND METHODS Participants (N = 2,344) in the Prospective Outcomes in Sporadic Versus Hereditary Breast Cancer study had a diagnosis of primary invasive breast cancer at age ≤ 40 years. Summary statistics were used to compare tumor characteristics among CHEK2+ carriers with those who were CHEK2−. Kaplan-Meier curves were used to demonstrate overall survival (OS) and distant disease-free survival. RESULTS Overall, 53 of the 2,344 participants (2.3%) had a pathogenic CHEK2 variant. CHEK2+-associated tumors were significantly more likely to be grade 2, estrogen receptor and progesterone receptor–positive compared with CHEK2− tumors (grade 2, n = 28 of 52 [53.8%] v n = 803 of 2,229 [36.0%]; P = .029). CHEK2-associated tumors were significantly more likely to have nodal involvement (N1, n = 37 of 53 [69.8%] v 1,169 of 2,253 [51.9%]; P = .0098) and demonstrated a trend toward multifocality. A higher proportion of participants with CHEK2+ variants with invasive breast cancer were obese than were those with CHEK2− variant (28.3% v 18.8%; P = .039). Univariate and multivariable analyses revealed that OS and distant disease-free survival were significantly worse in CHEK2+ versus CHEK2− carriers (OS hazard ratio, 1.58; 95% CI, 1.01 to 2.48; P = .043). CONCLUSION This work highlights the adverse prognosis associated with breast cancer in carriers of CHEK2 pathogenic variants. It also identifies a potential association among obesity, family history, and breast cancer risk in young CHEK2 gene carriers.

OBJECTIVE: Troublesome hot flushes and night sweats (HFNS) are experienced by many women after treatment for breast cancer, impacting significantly on sleep and quality of life. Cognitive behavioural therapy (CBT) is known to be effective for the alleviation of HFNS. However, it is not known if it can effectively be delivered by specialist nurses. We investigated whether group CBT, delivered by breast care nurses (BCNs), can reduce the impact of HFNS.METHODS: We recruited women with primary breast cancer following primary treatment with seven or more HFNS/week (including 4/10 or above on the HFNS problem rating scale), from six UK hospitals to an open, randomised, phase 3 effectiveness trial. Participants were randomised to Group CBT or usual care (UC). The primary endpoint was HFNS problem rating at 26 weeks after randomisation. Secondary outcomes included sleep, depression, anxiety and quality of life.RESULTS: Between 2017 and 2018, 130 participants were recruited (CBT:63, control:67). We found a 46% (6.9-3.7) reduction in the mean HFNS problem rating score from randomisation to 26 weeks in the CBT arm and a 15% (6.5-5.5) reduction in the UC arm (adjusted mean difference -1.96, CI -3.68 to -0.23, P = .039). Secondary outcomes, including frequency of HFNS, sleep, anxiety and depression all improved significantly.CONCLUSION: Our results suggest that specialist nurses can be trained to deliver CBT effectively to alleviate troublesome menopausal hot flushes in women following breast cancer in the NHS setting.

Background It is not clear how the pathology, presentation and outcome for patients who present with de novo metastatic breast cancer (dnMBC) compare with those who later develop distant metastases. DnMBC is uncommon in younger patients. We describe these differences within a cohort of young patients in the United Kingdom. Methods Women aged 40 years or younger with a first invasive breast cancer were recruited to the prospective POSH national cohort study. Baseline clinicopathological data were collected, with annual follow-up. Overall survival (OS) and post-distant relapse-free survival (PDRS) were assessed using Kaplan–Meier curves. Results In total, 862 patients were diagnosed with metastatic disease. DnMBC prevalence was 2.6% (76/2977). Of those with initially localised disease, 27.1% (786/2901) subsequently developed a distant recurrence. Median follow-up was 11.00 years (95% CI 10.79–11.59). Patients who developed metastatic disease within 12 months had worse OS than dnMBC patients (HR 2.64; 1.84–3.77). For PDRS, dnMBC was better than all groups, including those who relapsed after 5 years. Of dnMBC patients, 1.3% had a gBRCA1, and 11.8% a gBRCA2 mutation. Conclusions Young women with dnMBC have better PDRS than those who develop relapsed metastatic breast cancer. A gBRCA2 mutation was overrepresented in dnMBC.

Although survival rates for pediatric acute lymphoblastic leukemia are now excellent, this is at the expense of prolonged chemotherapy regimens. We report the long-term immune effects in children treated according to the UK Medical Research Council UKALL 2003 protocol. Peripheral blood lymphocyte subsets and immunoglobulin levels were studied in 116 participants, at six time points, during and for 18-month following treatment, with 30-39 patients analyzed at each time point. Total lymphocytes were reduced during maintenance chemotherapy and remained low 18 months following treatment completion. CD4 T cells remained significantly reduced 18 months after treatment, but CD8 cells and natural killer cells recovered to normal values. The fall in naïve B-cell numbers during maintenance was most marked, but numbers recovered rapidly after cessation of treatment. Memory B cells, particularly nonclass-switched memory B cells, remained below normal levels 18 months following treatment. All immunoglobulin subclasses were reduced during treatment compared to normal values, with IgM levels most affected. This study demonstrates that immune reconstitution differs between lymphocyte compartments. Although total B-cell numbers recover rapidly, disruption of memory/naïve balance persists and T-cell compartment persist at 18 months. This highlights the impact of modern chemotherapy regimens on immunity, and thus, infectious susceptibility and response to immunization.

Background: The interim analysis of the multicentre New EPOC trial in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival. Methods: New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0–2 were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m 2 administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m 2 administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m 2 repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m 2 administered intravenously over 2 h and oral capecitabine 1000 mg/m 2 twice daily on days 1–14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m 2 intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m 2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m 2 followed by a weekly infusion of 250 mg/m 2 with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367. Findings: Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (IQR 58·0–77·5). Median progression-free survival was 22·2 months (95% CI 18·3–26·8) in the chemotherapy alone group and 15·5 months (13·8–19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 0·87–1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5–71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02–2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3–4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), oral mucositis (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]). Interpretation: Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting. Funding: Cancer Research UK.

To identify genetic variants associated with breast cancer prognosis we conduct a meta-analysis of overall survival (OS) and disease-free survival (DFS) in 6042 patients from four cohorts. In young women, breast cancer is characterized by a higher incidence of adverse pathological features, unique gene expression profiles and worse survival, which may relate to germline variation. To explore this hypothesis, we also perform survival analysis in 2315 patients aged ≤ 40 years at diagnosis. Here, we identify two SNPs associated with early-onset DFS, rs715212 (P meta = 3.54 × 10−5) and rs10963755 (P meta = 3.91 × 10−4) in ADAMTSL1. The effect of these SNPs is independent of classical prognostic factors and there is no heterogeneity between cohorts. Most importantly, the association with rs715212 is noteworthy (FPRP, Genetic variance can influence breast cancer prognosis. Here, the authors conduct a meta-analysis to explore genetic variance linked to breast cancer in young women, identifying a prognostic association with germline variation of ADAMTSL1.

Background Fractional flow reserve measurement based on computed tomography (FFRCT) is a novel, well validated, non-invasive method for determining the presence and extent of coronary artery disease (CAD) combined with a physiological assessment of vessel-specific ischemia in patients with chest pain. Previous studies indicate that FFRCT reduces the uptake of invasive angiography that shows no significant CAD, without compromising patient safety. The clinical effectiveness and economic impact of using FFRCT instead of other tests in the initial evaluation of patients with stable chest pain has not been tested in a randomized trial. Methods The FORECAST trial will randomise 1400 patients with stable chest pain to receive either FFRCT or routine clinical assessment as directed by the National Institute for Health and Care Excellence (NICE) CG95 guideline for Chest Pain of Recent Onset. The primary endpoint will be resource utilisation over the subsequent nine months, including non-invasive cardiac investigations, invasive coronary angiography, coronary revascularization, hospitalization for cardiac events, and the use of cardiac medications. Key pre-specified secondary endpoints will be major adverse cardiac events, angina severity, quality of life, patient satisfaction, time to definitive management plan, time to completion of initial evaluation, number of hospital attendances, and working days lost in patients who are in employment. Conclusion The FORECAST randomized trial will assess the clinical and economic outcomes of using FFRCT as the primary test to evaluate patients presenting with stable chest pain.

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P −6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 −8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 −7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 −7 , HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

Objectives The aim was to investigate if offering symptomatic therapy (Uva-ursi or ibuprofen) alongside a delayed prescription would relieve symptoms and reduce the consumption of antibiotics for adult women presenting with acute uncomplicated urinary tract infection (UTI). Methods A 2 × 2 factorial placebo controlled randomized trial in primary care. The participants were 382 women aged 18–70 years with symptoms of dysuria, urgency, or frequency of urination and suspected by a clinician to have a lower UTI. The interventions were Uva-ursi extract and/or ibuprofen advice. All women were provided with a delayed or ‘back-up' prescription for antibiotics. Missing data were imputed using multiple imputation methods (ISRCTN registry: ISRCTN43397016). Results An ITT analysis of mean score for frequency symptoms assessed on Days 2–4 found no evidence of a difference between Uva-ursi vs. placebo –0.06 (95% CI –0.33 to 0.21; p 0.661), nor ibuprofen vs. no ibuprofen advice –0.01 (95% CI –0.27 to 0.26; p 0.951). There was no evidence of a reduction in antibiotic consumption with Uva-ursi (39.9% vs. placebo 47.4%; logistic regression odds ratio (OR) 0.59 (95% CI 0.22–1.58; p 0.293) but there was a significant reduction for ibuprofen advice (34.9% vs. no advice 51.0%; OR 0.27 (95% CI 0.10 to 0.72; p 0.009). There were no safety concerns and no episodes of upper tract infection were recorded. Conclusions We found no evidence of an effect of either intervention on the severity of frequency symptoms. There is evidence that advice to take ibuprofen will reduce antibiotic consumption without increasing complications. For every seven women given this advice, one less will use antibiotics.

Objectives: inflammatory Breast cancer (IBC) is a rare but aggressive form of breast cancer. Its incidence and behaviour in the UK is poorly characterised. We collected retrospective data from hospitals in the UK and Ireland to describe the presentation, pathology, treatment and clinical course of IBC in the UK. Materials and Methods: patients with IBC diagnosed between 1997 -2014 at fourteen UK and Irish hospitals were identified from local breast unit databases. Patient characteristics, tumour pathology and stage, and details of surgical, systemic and radiotherapy treatment and follow-up data were collected from electronic patient records and medical notes.Results: this retrospective review identified 445 patients with IBC accounting for 0.4-1.8% of invasive breast cancer cases. Median follow-up was 4.2 years. 53.2% of tumours were grade 3, 56.2% were oestrogen receptor positive, 31.3% were HER2 positive and 25.1% were triple negative. 20.7% of patients had distant metastases at presentation. Despite trimodality treatment in 86.4%, 40.1% of stage III patients developed distant metastases. Five-year overall survival (OS) was 61.0% for stage III and 21.4% for stage IV patients.Conclusions: this is the largest series of UK IBC patients reported to date. It indicates a lower incidence than in American series, but confirms that IBC has a high risk of recurrence with poor survival despite contemporary multi- modality therapy. A national strategy is required to facilitate translational research into this aggressive disease.Key words: Inflammatory breast cancer, Breast, Cancer, Large cohort

Background Women who have been treated for breast cancer may identify vasomotor symptoms, such as hot flushes and night sweats (HFNS), as a serious problem. HFNS are unpleasant to experience and can have a significant impact on daily life, potentially leading to reduced adherence to life saving adjuvant hormonal therapy. It is known that Cognitive Behavioural Therapy (CBT) is effective for the alleviation of hot flushes in both well women and women who have had breast cancer. Most women with breast cancer will see a breast care nurse and there is evidence that nurses can be trained to deliver psychological treatments to a satisfactory level, whilst also maintaining treatment fidelity. The research team will assess whether breast care nurses can effectively deliver a CBT intervention to alleviate hot flushes in women with breast cancer. Methods This study is a multi-centre phase III individually randomised controlled trial of group CBT versus usual care to reduce the impact of hot flushes in women with breast cancer. 120–160 women with primary breast cancer experiencing seven or more problematic HFNS a week will be randomised to receive either treatment as usual (TAU) or participation in the group CBT intervention plus TAU (CBT Group). A process evaluation using May’s Normalisation Process Theory will be conducted, as well as practical and organisational issues relating to the implementation of the intervention. Fidelity of implementation of the intervention will be conducted by expert assessment. The cost effectiveness of the intervention will also be assessed. Discussion There is a need for studies that enable effective interventions to be implemented in practice. There is good evidence that CBT is helpful for women with breast cancer who experience HFNS, yet it is not widely available. It is not yet known whether the intervention can be effectively delivered by breast care nurses or implemented in practice. This study will provide information on both whether the intervention can effectively help women with hot flushes and whether and how it can be translated into routine clinical practice. Trial registration ISRCTN 12824632. Registered 25–01-2017. Electronic supplementary material The online version of this article (10.1186/s12905-018-0550-z) contains supplementary material, which is available to authorized users.

Background: To investigate if offering symptomatic therapy alongside a delayed prescription would relieve symptoms and reduce the consumption of antibiotics for adult women presenting with acute uncomplicated urinary tract infection (UTI). Methods: A 2x2 factorial placebo controlled randomised trial in primary care. Participants 382 women aged 18-70 with symptoms of dysuria, urgency or frequency of urination and suspected by a GP or nurse practitioner to have a lower UTI. Interventions: Uva-ursi extract: containing 20% arbutin with a total daily dose of 3600 mg. Ibuprofen advice: A daily dose of 1200 mg was recommended or prescribed on request. All women were provided with a delayed or 'back-up' prescription for antibiotics. Findings: An ITT analysis of mean score for frequency symptoms found no evidence of a difference between Uva-ursi vs. placebo -0·06 (95% CI -0·33 to 0·21) p=0·661, nor ibuprofen vs. no ibuprofen advice -0·01 (95% CI -0·27 to 0·26) p=0·951. There was no evidence of a significant reduction in antibiotic consumption with Uva-ursi (39·9% vs. placebo 47·4%; logistic regression odds ratio (OR) 0·59 (95% CI 0·22 to 1·58) p=0·293) but a significant reduction for ibuprofen advice (ibuprofen advice 34·9% vs. no advice 51·0%; OR 0·27 (95% CI 0·10 to 0·72) p=0·009). There were no safety concerns and no episodes of upper tract infection were recorded. Interpretation: We found no evidence of an effect of either intervention on the severity of frequency symptom. However a substantial proportion of women willing to consider delaying antibiotics for UTI will not use the antibiotics, and there is evidence that advice to take ibuprofen will result in a significant reduction in antibiotic use without increasing the risks of complications. For every six women given this advice one less will use antibiotics. The clinical trial was coordinated by the Southampton Clinical Trials Unit, a UKCRC registered, NIHR support funded Clinical Trials Unit. The trial was sponsored by the University of Southampton and funded by the NIHR School of Primary Care. The trial had received favourable ethical approval and registered with the UK MHRA. Clinical Trial Number: Trial Registration Number: ISRCTN registry: ISRCTN43397016. Registered on 11 February 2015. Funding Statement: This project is funded by the National Institute for Health Research (NIHR) School of Primary Care, project number 170. The project is sponsored by the University of Southampton. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR School of Primary Care. Declaration of Interests: All authors have completed the ICMJE uniform disclosure form online at icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work. Ethics Approval Statement: In compliance with the Helsinki declaration, the ATAFUTI trial has been granted ethical approval by the South Central – Hampshire Research Ethics Committee (REC, 14/SC/1143), and UK Medicines and Health Care Products Regulatory Agency (MHRA) (reference16730/0215/001-0001). Informed written consent was obtained from all participants.

BACKGROUND: Obese breast cancer patients have a poorer prognosis than non-obese patients. We examined data from a large prospective cohort study to explore the associations of obesity with tumour pathology, treatment and outcome in young British breast cancer patients receiving modern oncological treatments. PATIENTS AND METHODS: A total of 2956 patients aged ≤40 at breast cancer diagnosis were recruited from 126 UK hospitals from 2001 to 2007. Height and weight were measured at registration. Tumour pathology and treatment details were collected. Follow-up data were collected at 6, 12 months, and annually. RESULTS: A total of 2843 eligible patients (96.2%) had a body mass index (BMI) recorded: 1526 (53.7%) were under/healthy-weight (U/H, BMI

Objective: To compare the efficacy and cost of specialised individually-delivered parent training (PT) for preschool children with attention-deficit/ hyperactivity disorder (ADHD) against generic group-based PT and treatment as usual (TAU). Design: Multi-centre, three-arm parallel group randomised controlled trial. Research Setting: National Health Service Trusts. Participants: Preschool children (33-54 months) fulfilling ADHD research diagnostic criteria. Interventions: New Forest Parenting Programme (NFPP) – 12 week individual, home-delivered ADHD PT programme; Incredible Years (IY) – 12 week group-based, PT programme initially designed for children with behaviour problems. Main outcome measures: Primary outcome - Parent ratings of child’s ADHD symptoms (Swanson, Nolan & Pelham Questionnaire - SNAP-IV). Secondary outcomes - teacher ratings (SNAP-IV) and direct observations of ADHD symptoms and parent/teacher ratings of conduct problems. NFPP, IY and TAU outcomes were measured at baseline (T1) and post-treatment (T2). NFPP and IY outcomes only were measured 6 months post treatment (T3). Researchers, but not therapists or parents, were blind to treatment allocation. Analysis employed mixed effect regression models (multiple imputation). Intervention and other costs were estimated using standardized approaches. Results: NFPP and IY did not differ on parent-rated SNAP-IV, ADHD combined symptoms (mean difference -0.009 95%CI [-0.191, 0.173], p=0.921) or any other measure. Small, non-significant, benefits of NFPP over TAU were seen for parent-rated SNAP-IV, ADHD combined symptoms (-0.189 95%CI [-0.380, 0.003], p=0.053). NFPP significantly reduced parent-rated conduct-problems compared to TAU across scales (p-values.05). The cost per family of providing NFPP in the trial was significantly lower than IY (£1,591 versus £2,103). \ud Conclusions: Although, there were no differences between NFPP and IY with regards clinical effectiveness, individually-delivered NFPP cost less. However, this difference may be reduced when implemented in routine clinical practice. Clinical decisions should take into account parental preferences between delivery approaches. \ud Funding: National Institute of Health Research. \ud Trial Registration: Trial name: COPPI Trial; ISRCTN39288126.

Background Women with acute uncomplicated urine infection are usually treated with antibiotics. One trial has demonstrated that delayed antibiotic treatment offered without symptom relief results in a modest reduction in antibiotic use. There is some evidence that ibuprofen provides symptom relief and reduces antibiotic use. Uva-ursi, a herbal product, has a traditional use for urinary infection symptom relief. We set out to test: in adult women with suspected UTI who accept the delayed prescription strategy: Do NSAIDs or uva-ursi (a herbal product) provide relief from urinary symptoms and reduce antibiotic use. Methods/design Adult women with suspected urinary tract infection presenting to primary care will be randomised using a factorial trial design in which patients will be randomised to one of two interventions as below:Group 1 – Uva-ursi + advice to take ibuprofenGroup 2 – Placebo + advice to take ibuprofenGroup 3 – Uva-ursi + no advice to take ibuprofenGroup 4 – Placebo + no advice to take ibuprofen Patients and physicians will be blinded to the randomised group for the herb. The main outcome is symptom severity at days 2–4 recorded in a validated, self-report diary used in previous studies. Secondary outcomes include antibiotic use and symptom duration. In total the trial will require 328 patients in order to achieve at least 90% power for the primary endpoint and 80% for the secondary endpoint. In accordance with CONSORT guidelines all comparative analyses will be conducted on an intention-to-treat basis using SPSS or similar package. Discussion The outcomes from this trial have the potential to modify the current approach to the management of acute urinary symptoms with less dependence on the use of antibiotics. Trial registration ISRCTN registry, ID: ISRCTN43397016. Registered on 11 February 2015. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2145-7) contains supplementary material, which is available to authorized users.

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P

Background: Multifocal (MF) breast cancers are more common in pre and perimenopausal women and in estrogen receptor (ER) positive disease. Young onset breast cancer and a positive family history of breast/ovarian cancer are characteristic of BRCA1 and BRCA2 carriers, but tumour receptor status and other pathological features may also be helpful in identifying BRCA gene carriers, particularly where family history is negative or unknown. Multifocal cancer may either be clonal in origin or unrelated multiple primaries (multicentric) and in a patient with a strong genetic predisposition the latter might be expected due to a field change effect. There are few data on whether multifocality is a predictor of an underlying BRCA 1 or BRCA2 mutation. A mutation frequency of 18% (combined BRCA1 and 2) in 61 multifocal cancers has been previously reported. We sought evidence of an association between multifocality and BRCA carrier status in young women both with and without a relevant cancer family history. Methods: POSH, the UK population based cohort study recruited breast cancer patients aged ≤40 at diagnosis. Family history data were collected by patient questionnaire (positive family history defined as any number of first or second degree relatives diagnosed with breast or ovarian cancer). Genetic testing occurred either as part of clinical breast cancer management or the research study. Results: MF cancer was present in 797 of 2956 patients (27.0%) of the whole POSH cohort, more frequent in ER positive (34.9%) than ER negative (19.9%) cancers (p Type of BRCA mutation with distribution of breast cancer by ER status Localised n = 150Multifocal n = 47Missing n = 17Total n = 214BRCA1110 (73.3%)17 (36.2%)9136 (63.6%)ER pos23 (20.9%)6 (35.3%)029 (21.3%)ER neg87 (79.1%)11 (64.7%)9107 (78.7%)BRCA240 (26.7%)30 (68.8%)878 (36.4%)ER pos33 (82.5%)27 (90.0%)666 (84.6%)ER neg7 (17.5%)3 (10.0%)212 (15.4%) Conclusions: Multifocal disease is associated with an increased probability of BRCA2 mutations in our data and may be an indicator of BRCA2 genetic status. The ratio of multifocal to unifocal disease in BRCA1, BRCA2 carriers and non BRCA1/2 cases was highest in BRCA2 cases for both ER positive and ER negative tumours. With the caveat of small numbers and incomplete testing of the cohort, there is some evidence pointing to BRCA2 causing a field effect rather than just as a function of predominantly ER positive cancers, and this characteristic may be useful in an algorithm to predict BRCA2 status incorporating further adjustment for other potential confounders. We plan to conduct further genetic testing across the whole cohort to refine the algorithm and to confirm the observed multifocal/BRCA2 association. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-12-01.

BACKGROUND: Breast cancer at a young age is associated with poor prognosis. The Prospective Study of Outcomes in Sporadic and Hereditary Breast Cancer (POSH) was designed to investigate factors affecting prognosis in this patient group. METHODS: Between 2000 and 2008, 2956 patients aged 40 years or younger were recruited to a UK multicenter prospective observational cohort study (POSH). Details of tumor pathology, disease stage, treatment received, and outcome were recorded. Overall survival (OS) and distant disease-free interval (DDFI) were assessed using Kaplan-Meier curves. All statistical tests were two-sided. RESULTS: Median age of patients was 36 years. Median tumor diameter was 22 mm, and 50% of patients had positive lymph nodes; 59% of tumors were grade 3, 33.7% were estrogen receptor (ER) negative, and 24% were human epidermal growth factor receptor 2 (HER2) positive. Five-year OS was higher for patients with ER-positive than ER-negative tumors (85.0%, 95% confidence interval [CI] = 83.2% to 86.7% vs 75.7%, 95% CI = 72.8% to 78.4%; P < .001), but by eight years, survival was almost equal. The eight-year OS of patients with ER-positive tumors was similar to that of patients with ER-negative tumors in both HER2-positive and HER2-negative subgroups. The flexible parametric survival model for OS shows that the risk of death increases steadily over time for patients with ER-positive tumors in contrast to patients with ER-negative tumors, where risk of death peaked at two years. CONCLUSIONS: These results confirm the increased frequency of ER-negative tumors and early relapse in young patients and also demonstrate the equally poor longer-term outlook of young patients who have ER-positive tumors with HER2-negative or -positive disease.

Background PREDICT is a breast cancer prognostic and treatment benefit model implemented online. The overall fit of the model has been good in multiple independent case series, but PREDICT has been shown to underestimate breast cancer specific mortality in women diagnosed under the age of 40. Another limitation is the use of discrete categories for tumour size and node status resulting in ‘step’ changes in risk estimates on moving between categories. We have refitted the PREDICT prognostic model using the original cohort of cases from East Anglia with updated survival time in order to take into account age at diagnosis and to smooth out the survival function for tumour size and node status. Methods Multivariable Cox regression models were used to fit separate models for ER negative and ER positive disease. Continuous variables were fitted using fractional polynomials and a smoothed baseline hazard was obtained by regressing the baseline cumulative hazard for each patients against time using fractional polynomials. The fit of the prognostic models were then tested in three independent data sets that had also been used to validate the original version of PREDICT. Results In the model fitting data, after adjusting for other prognostic variables, there is an increase in risk of breast cancer specific mortality in younger and older patients with ER positive disease, with a substantial increase in risk for women diagnosed before the age of 35. In ER negative disease the risk increases slightly with age. The association between breast cancer specific mortality and both tumour size and number of positive nodes was non-linear with a more marked increase in risk with increasing size and increasing number of nodes in ER positive disease. The overall calibration and discrimination of the new version of PREDICT (v2) was good and comparable to that of the previous version in both model development and validation data sets. However, the calibration of v2 improved over v1 in patients diagnosed under the age of 40. Conclusions The PREDICT v2 is an improved prognostication and treatment benefit model compared with v1. The online version should continue to aid clinical decision making in women with early breast cancer. Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0852-3) contains supplementary material, which is available to authorized users.

BACKGROUND: Black ethnic groups have a higher breast cancer mortality than Whites. American studies have identified variations in tumour biology and unequal health-care access as causative factors. We compared tumour pathology, treatment and outcomes in three ethnic groups in young breast cancer patients treated in the United Kingdom. METHODS: Women aged ≤ 40 years at breast cancer diagnosis were recruited to the POSH national cohort study (MREC: 00/06/69). Personal characteristics, tumour pathology and treatment data were collected at diagnosis. Follow-up data were collected annually. Overall survival (OS) and distant relapse-free survival (DRFS) were assessed using Kaplan-Meier curves, and multivariate analyses were performed using Cox regression. RESULTS: Ethnicity data were available for 2915 patients including 2690 (91.0%) Whites, 118 (4.0%) Blacks and 87 (2.9%) Asians. Median tumour diameter at presentation was greater in Blacks than Whites (26.0 mm vs 22.0 mm, P=0.0103), and multifocal tumours were more frequent in both Blacks (43.4%) and Asians (37.0%) than Whites (28.9%). ER/PR/HER2-negative tumours were significantly more frequent in Blacks (26.1%) than Whites (18.6%, P=0.043). Use of chemotherapy was similarly high in all ethnic groups (89% B vs 88.6% W vs 89.7% A). A 5-year DRFS was significantly lower in Blacks than Asians (62.8% B vs 77.0% A, P=0.0473) or Whites (62.8 B% vs 77.0% W, P=0.0053) and a 5-year OS for Black patients, 71.1% (95% CI: 61.0-79.1%), was significantly lower than that of Whites (82.4%, 95% CI: 80.8-83.9%, W vs B: P=0.0160). In multivariate analysis, Black ethnicity had an effect on DRFS in oestrogen receptor (ER)-positive patients that is independent of body mass index, tumour size, grade or nodal status, HR: 1.60 (95% CI: 1.03-2.47, P=0.035). CONCLUSION: Despite equal access to health care, young Black women in the United Kingdom have a significantly poorer outcome than White patients. Black ethnicity is an independent risk factor for reduced DRFS particularly in ER-positive patients.

BackgroundThe addition of cetuximab to perioperative chemotherapy for operable colorectal liver metastases resulted in a shorter progression free survival. Details of disease progression are described to further inform the primary study outcome.MethodsA total of 257 KRAS wild-type patients were randomised to chemotherapy alone or chemotherapy with cetuximab. Data regarding sites and treatment of progressive disease were obtained for the 109 (chemotherapy n=48, chemotherapy and cetuximab n=61) patients with progressive disease at the cut-off date for analysis of November 2012. ResultsThe liver was the most frequent site of progression (chemotherapy 67% (32/48); chemotherapy and cetuximab 66% (40/61)). A higher proportion of patients in the cetuximab group had multi-site/other sites of progressive disease (chemotherapy 8%, 4/48; chemotherapy and cetuximab 23%, 14/61 p=0.04). Further treatment for progressive disease is known for 84 patients of whom 69 received further chemotherapy, most frequently irinotecan based. Twenty two patients, 11 in each arm, received cetuximab as a further line agent. ConclusionBoth the distribution of progressive disease and further treatment are as expected for such a cohort. The pattern of disease progression seen is consistent with failure of systemic micrometastatic disease control rather than failure of local disease control following liver surgery.

BackgroundIn the UK almost 7000 people are diagnosed with leukaemia each year, but despite continuing advances in diagnosis and treatment with new drugs, such as the tyrosine kinase inhibitors, the majority of these patients will eventually die from their disease. Until quite recently, the only treatment to offer the possibility of long-term disease-free survival was allogeneic stem cell transplantation. However, this carries a substantial risk of mortality and is available to only a minority of patients.ObjectivesThe aim of the study was to test the hypothesis that molecular and clinical responses, induced by T lymphocytes (T cells), can be predicted by increases in the number of CD8+ (cluster of differentiation 8-positive) T cells specific for the vaccine-encoded T-cell epitopes. This project also aimed to build on the established programme of deoxyribonucleic acid (DNA) fusion-gene vaccination delivered by intramuscular injection, exploiting a unique experience with electroporation, to induce durable immune responses with the aim of controlling disease by precision attack of the tumour by CD8+ T cells.MethodA non-randomised, open-label, single-dose-level Phase II clinical trial in two patient groups [chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML)] on stable doses of imatinib. Human leucocyte antigen A2-positive (HLA A2+) patients were vaccinated with two DNA vaccines: (1) p.DOM–WT1-37 (epitope sequence: VLDFAPPGA); and (2) p.DOM–WT1-126 (epitope sequence: RMFPNAPYL). The HLA A2-negative patients formed an unvaccinated control group. The sample size for the HLA A2+ group was originally determined following Simon’s optimal Phase II trial design (Simon R. Optimal two-stage designs for phase II clinical trials.Control Clin Trials1989;10:1–10). This was changed to A’Hern’s single-stage design during the course of the trial (A’Hern RP. Sample size tables for single-stage phase II designs.Stat Med2001;20:859–66), which was endorsed by the trial’s independent oversight committees.ResultsThe study included 12 patients with CML who were vaccinated and nine patients with CML who were unvaccinated as the control group. Both the vaccines and the electroporation were safe, with no new or unexpected toxicities. The evaluation adverse events of special interest (heart, bone marrow, renal) did not reveal safety concerns. TwoBCR–ABL(breakpoint cluster region–Abelson murine leukaemia viral oncogene homolog 1) responses were observed, both of which were defined as a major response, with one in each group. Two Wilms’ tumour antigen 1 (WT1) molecular responses were observed in the vaccinated group and one was observed in the control group. At an immunological level, the vaccine performed as expected.ConclusionsThe study met its primary decision-making target with one major molecular response inBCR–ABLtranscript levels. Overall, the data showed, in this clinical setting, the immunogenicity and safety of the vaccine.LimitationsThe study did not complete recruitment and there were multiple hurdles that contributed to this failure. This is disappointing given the robust induction immune responses againstWT1T-cell responses in 7 out of 10 evaluable patients.Future workEvaluation of the p.DOM–WT1 vaccines in AML remains attractive clinically, but it is unlikely to be feasible at this time. Combination of the DNA vaccine approach with strategies to expand T-cell responses with immunomodulatory antibodies is in development.Funding detailsThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership, and Bloodwise.

DLBL subtypes identified by patterns of gene expression correspond to germinal center (GCB) or activated (ABC) B‐cells like. The latter demonstrate dysregulation of the NF‐KB pathway. Outcomes of treatment with R‐CHOP are inferior for ABC DLBL in retrospective series. This study investigated whether adding bortezomib (B), a putative NF‐KB inhibitor, can reverse this phenotype.

Background Germline mutations in BRCA1/2 account for ∼3% of breast cancer cases but >10% of young patients who present with triple negative (TN) breast cancer. Young age at diagnosis is also associated with an increased risk of recurrence and inferior survival compared to older patients. Numerous publications describe an increased incidence of adverse biological features in tumours from young breast cancer patients; however it is unclear whether these fully explain the poor outcome. The effect of carrying a BRCA1/2 mutation on the prognosis of breast cancer remains controversial with retrospective studies reporting better, similar and worse outcomes for mutation carriers compared to patients with sporadic tumours. BRCA carriers could feasibly have enhanced or reduced sensitivity to certain chemotherapeutics; however retrospective studies are problematic due to missing data and biased ascertainment. POSH is multicentre prospective observational cohort study designed to investigate factors which affect prognosis in young breast cancer patients (Copson et al, JNCI, 2013). Here we report the pathology, treatment and outcome of patients with TN tumours as a preliminary analysis to determine the impact of a germline BRCA1 mutation on survival. The whole cohort analysis including BRCA1 and BRCA2 is in progress. Methods 2956 patients aged ≤40 at breast cancer diagnosis were recruited from 127 UK oncology centres between 2000 and 2008. Patient characteristics, family history, risk factors, tumour pathology and treatment information, and blood DNA were collected at recruitment. Follow-up data were collected at 6 and 12 months, then annually. Summary statistics were used to describe patients by BRCA1 status. Kaplan-Meier estimates were used to describe univariate survival data. Results BRCA1 status is currently available for 542 patients with TN tumours. Pathogenic BRCA1 mutations were identified in 122 patients (BRCA1+); 420 had no BRCA1 mutation (BRCA1-). BRCA1+ were younger than BRCA1- (median age 34 vs 36 years, p Median follow-up was 7.3 years. Overall survival of patients with stage 1-3 disease treated with anthracycline +/- taxane neoadjuvant chemotherapy (n=538; 151 deaths) was better for BRCA1+ vs BRCA1- (79.1% vs 73.6% at 5-yrs; HR[95%CI]=0.84[0.57,1.25],p=0.388). Distant disease-free survival (DDFS) was also higher for BRCA1+ (5-yr DDFS 76.1% vs 71.5%; HR[CI]=0.92[0.63,1.35], p=0.682). Moreover, survival after first distant relapse was better for BRCA1+ patients (41.9% vs 36.8% at 1-yr; HR[CI]=0.78[0.51,1.18], p=0.233). Conclusions Our prospective data show better survival in young BRCA1+ patients with early TN breast cancer treated with anthracycline/-taxane chemotherapy than BRCA1- patients. However, the difference between the groups was not significant in this partial sample. Results for the whole cohort will be available by the time of the meeting. Citation Format: Eccles DM, Copson ER, Maishman T, Tapper W, Cutress R, Gerty S, Stanton L, Altman DG, Durcan L, Simmonds P, Decker B, Allen J, Luccarini C, Easton D, Dunning A, POSH Steering Group and Collaborators. Does BRCA status affect outcome in young breast cancer patients? Results from the prospective study of outcomes in sporadic and hereditary breast cancer (POSH) [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 S2-03.

Background DLBCL is the most common non-Hodgkin lymphoma (NHL) comprising one third of all adult NHL cases, accounting for an annual incidence in the UK of approximately 5,000 patients. R-CHOP has been accepted as the international standard first-line regimen, with cure rates of around 60-70%. There is a need to further improve efficacy of first line treatment. Chronic and tonic B-cell receptor (BCR) signaling has been identified as a feature of DLBCL. Preclinical models of this lymphoma have demonstrated cytotoxicity through interruption of BCR-signaling. Inhibition of Bruton's tyrosine kinase (BTK), downstream of the BCR has proven active clinical trials in DLBCL, particularly in the activated B-cell subtype. The second generation BTK inhibitor, acalabrutinib, has demonstrated improved target specificity and bioavailability, with potential for better efficacy and tolerability compared to earlier agents. It is appealing to combine this targeted agent with R-CHOP in untreated de novo DLBCL to understand its safety profile and efficacy. Method Patients must be 16 years or older, treatment naive with histologically confirmed DLBCL. All will receive 6 cycles of R-CHOP chemotherapy on a standard 21-day schedule, with the addition of acalabrutinib in cycles 2-6, to allow determination of the subtype by whole transcriptome gene expression profiling during cycle 1. This will be followed by a continuation phase of acalabrutinib only, for 2 cycles of 28 days. The primary objective of the phase I is to establish a recommended phase II dose of acalabrutinib in combination with R-CHOP. The primary objective of the phase II is to assess activity of the combination (by overall response rate) and determine additional safety information. Secondary endpoints include duration of response, PFS and OS and their relation to the cell of origin subtype, and BTK receptor occupancy in peripheral blood mononuclear cells and tumor measured by a drug analogue enzyme-linked immunosorbent assay. The effect of acalabrutinib on antibody-directed cellular cytotoxicity mediated by rituximab will be measured in vitro during treatment. The trial is coordinated by the Cancer Research UK Southampton Clinical Trials Unit. It will recruit up to 24 patients during phase I in a modified classical 6+6 design, and 15 patients during phase II. This is an investigator initiated study that has been granted free access to investigational medicinal product, trial Management and translational study support through a grant from Acerta Pharma B.V. (IST-LY-801) and has endorsement from Cancer Research UK (CRUKDE/16/006). Trial registration: ISRCTN11965217 Progress Phase I of the study opened in April 2017 and has recruited 6 eligible patients to the first cohort at a dose of 100mg acalabrutinib once daily, with a further 4 patients recruited to the second cohort at a dose of 100mg twice daily. Citation Format: Peter W M Johnson, Joshua Caddy, Tom Cumin, Bridgen Merton, Tom Maishman, Angelic Galanopoulou, Gareth Griffiths, Andrew Davies. ACCEPT: A phase Ib/II combination of acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for patients with diffuse large B-cell lymphoma (DLBCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT162.

TPS8586Background: Mesothelioma, an incurable, apoptosis-resistant cancer, represents a growing health burden but remains under-researched, with limited treatment options. Despite a significant num...

Breast cancer is the most common cancer women in the UK, with approximately 50,000 new cases each year. PREDICT (http://www.predict.nhs.uk) is an online prognostic tool developed to help determine the best available treatment and long-term outcome for early breast cancer. This study was conducted to establish how well PREDICT performs in estimating survival in a large cohort of younger women (aged ≤40 years) recruited to the POSH study.

Familial studies were among the first to indicate that breast cancer prognosis has a heritable component. Subsequently many variants associated with prognosis have been identified using a range of techniques including genome-wide association studies (GWAs). Despite these advances, much of the heritability remains unexplained. In young women, breast cancer is characterised by a higher incidence of adverse pathological features, unique tumour gene expression profiles and worse survival. In addition, the association of risk with conventional epidemiological exposures is less clear in women with early onset. We hypothesise that some of these difference between early and late onset could be influenced by germline variation. To identify additional variants that influence breast cancer prognosis we conducted a two stage meta-analysis of four GWAs consisting of 6,042 patients from the UK (POSH), Finland (HEBCS), Germany (SUCCESS-A) and Australia (ABCFS). Cox-regression analyses were used to investigate overall survival (OS, n=1,101 events) and disease-free survival (DFS, n=1,316 events) with correction for oestrogen status (ER). These survival analyses were repeated in a subset of patients with early onset (aged ≤40 at diagnosis, n=2,315 patients, OS n=604 events, DFS n=716 events). Meta-analysis identified two intronic SNPs in ADAMTSL1 that were associated exclusively with early onset DFS, rs715212 (Pmeta=3.54x10-5) and rs10963755 (Pmeta=3.91x10-4) without heterogeneity between cohorts. Multivariable Cox-regression demonstrated that the effect of these SNPs were independent of the classical prognostic factors. Most importantly, rs715212 reached genome-wide significance (Pmultivariate=5.37x10-8) in the multivariate model. ADAMTSL1 encodes a glycoprotein that forms part of the extracellular matrix (ECM) and may function in cell-cell or cell-matrix interactions or may regulate other ADAMTS proteases. Previous studies have shown that ADAMTSL1 is hypermethylated in ER positive breast cancer tumours. Using GTEx to perform eQTL analysis, we found that rs715212 is associated with the expression of several biologically relevant genes AREG (P=0.035), TNF (P=0.015), FASLG (P=0.0031) and EGF (P=0.0018) in breast mammary tissue. Interestingly, separate studies have shown that AREG is overexpressed in ER-positive breast tumours from pre-menopausal women versus post-menopausal women. Furthermore, AREG is differentially expressed between parous and non-parous mammary glands and is persistently downregulated by parity, which suggests it may contribute to the susceptibility of the nulliparous gland to breast cancer. We conclude that rs715212 is associated with an increased risk of disease progression in patients with early onset and speculate that this could be due to an interaction with the expression of AREG. Note: This abstract was not presented at the meeting. Citation Format: Latha Kadalayil, Sofia Khan, Heli Nevanlinna, Peter A. Fasching, Fergus J. Couch, John Hopper, Jianjun Liu, Tom Maishman, Lorraine Durcan, Carl Bloomqvist, Andy Collins, Dianna Eccles, William Tapper. A meta-analysis of genome-wide association studies identifies novel loci that influence breast cancer prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1322. doi:10.1158/1538-7445.AM2017-1322

Aim To evaluate the surgical and clinical factors affecting local recurrence and other outcomes in young breast cancer patients using the POSH study. Background POSH (MREC:00/06/69) is a prospective cohort study of 3024 women aged 18-40 with breast cancer. Randomized controlled trials suggest equivalent survival between mastectomy and breast conserving surgery (BCS); however, very few young patients were included in these analyses. Emerging data also suggests a possible survival advantage for mastectomy in gene mutation carriers, and young age may be a predictor of higher rates of local recurrence. Methods Summary statistics were used to describe the cohort by surgical type (mastectomy or BCS). Study endpoints were in-breast ipsilateral local-recurrence interval, distant disease-free interval and overall survival. Cumulative hazard and Kaplan-Meier plots were used to describe survival data. Univariable and multivariable analyses were carried out using Cox proportional hazards models and flexible parametric survival (FPS) models (for any models with time-varying covariates). Results Of 2882 patients analysed, 1464 underwent mastectomy, 1395 BCS; and 23 had lymph node surgery only. Patients undergoing mastectomy had significantly larger tumours and higher proportions of positive Family History, positive estrogen receptor (ER+), progesterone receptor (PR+) and/or human epidermal growth factor 2 (HER2+) tumours. Local events only accounted for 15% of recurrences. Local recurrence varied over time by surgical type; local recurrence rate was similar at 18 months but higher for BCS compared to mastectomy at 5- and 10-years (18-months: 1.0% vs 1.0%, FPS-HR[95%CI]=1.43[0.89,2.32], p=0.348; 5-years: 5.3% vs 2.6%, FPS-HR[CI]=3.39[2.03,5.66], p Conclusions In the short term, there is no difference in local recurrence between BCS and mastectomy in young women. Longer term, local recurrence is higher in BCS, but there is no difference in survival between surgical groups after adjusting for known prognostic factors. Surgical extent appears to be less important for distant relapse or death from breast cancer than completeness of excision or, where appropriate, chest-wall radiotherapy. Acknowledgements Data collection/analysis funded by CRUK (grants:A7572,A11699,C1275/A15956). Sponsored by UHS NHS Foundation Trust. Citation Format: Maishman T, Cutress RI, Hernandez A, Gerty S, Copson ER, Durcan L, Eccles DM. Local recurrence in young women with invasive breast cancer; the prospective study of outcomes in sporadic and hereditary breast cancer (POSH) [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 PD6-02.

Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment Study (COGS) initiative. We carry out replication using Asian COGS samples (n=522, 53 events) and the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study (n=315, 108 events). Rs4458204_A near CCL20 (2q36.3) is found to be associated with breast cancer-specific death at a genome-wide significant level (n=2,641, 440 events, combined allelic hazard ratio (HR)=1.81 (1.49–2.19); P for trend=1.90 × 10−9). Such survival-associated variants can represent ideal targets for tailored therapeutics, and may also enhance our current prognostic prediction capabilities., Studies have shown that breast cancer prognosis is hereditary. Here the authors show that a genetic variant in CCL20, a chemokine ligand involved in immune response, is significantly associated with breast cancer survival and may therefore represent an important therapeutic or prognostic target.

Introduction: DLBCL subtypes may be classified by gene expression corresponding to germinal centre (GCB) or activated peripheral blood (ABC) B-cells. Treatment outcomes with R-CHOP therapy were inferior for ABCs in retrospective series, and this study investigated whether adding bortezomib could reverse the adverse prognosis. The trial used gene expression profiling (GEP) to stratify cases, with adaptive design to analyse the outcome by subtypes at predefined timepoints. Methods: Newly diagnosed patients with DLBCL underwent staging and commenced standard R-CHOP. During cycle 1, formalin-fixed paraffin-embedded (FFPE) tissue was used to extract messenger RNA for GEP using the Illumina DASL array platform. Cases were allocated to GCB, ABC or Unclassifiable (Unc) type before starting cycle 2, using an established algorithm based upon 20 genes. Patients with successful GEP were randomised 1:1 to receive R-CHOP +/- bortezomib 1.6 mg/m2 s/c on days 1+8 in cycles 2-6. The study was powered to detect a difference in progression-free survival (PFS) of 10% with bortezomib, with a 2-sided significance, 5% and 90% power. The adaptive design allowed for closure of randomization for GCB cases if 1-year PFS was Results: Between 6/2011 and 5/2015 1132 patients were enrolled from 109 sites, with 1078 samples analysed. Of these, 157 (15%) biopsies had inadequate material for GEP, but the remaining 921 were classified as 246 (27%) ABC, 476 (52%) GCB and 199 (22%) Unc. Successful classification was possible from both surgical and needle core biopsies. Median laboratory turnaround time was 12 working days and all results were available prior to the scheduled administration of cycle 2. Characteristics of the patients of different subtypes are shown in the table. Following both interim analyses the DMEC recommended continued recruitment of patients with a GCB phenotype. Table. ABC GCB Unc Age (years): median 67 63 63 Age (years) : range 23 to 86 20 to 82 20 to 85 % performance status 0-1 88 88 90 % at least one extranodal site 53 54 62 % bone marrow involved 15 14 23 % LDH>ULN 69 76 79 % IPI score 0/1 29 27 26 % IPI score 2/3 57 55 55 % IPI score 4/5 15 19 19 % B symptoms 46 43 49 % Bulk>10cm 17 26 21 Conclusions: This study has demonstrated the feasibility of GEP at diagnosis to subsequently guide therapy in a large multicentre trial. Although patients with ABC type lymphoma were in general slightly older, they did not appear to have other adverse prognostic features at diagnosis vs GCB. All patients will have completed therapy by the time of the meeting, allowing the initial response and toxicity data to be available for presentation. Disclosures Davies: GIlead: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; CTI: Honoraria; Takeda: Honoraria, Research Funding; Bayer: Research Funding; GSK: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Pfizer: Honoraria; Celgene: Honoraria, Research Funding. Off Label Use: The addition of bortezomib to R-CHOP chemotherapy in diffuse large B-cell lymphoma. Pocock:Janssen: Honoraria. Jack:Jannsen: Research Funding. Johnson:Takeda: Honoraria; Pfizer: Honoraria; Janssen: Research Funding.