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BackgroundTargeting MRI remission in rheumatoid arthritis (RA) patients in clinical remission may improve long term clinical, functional and MRI outcomes.ObjectivesTo investigate whether a 2-year treat-to-target (T2T) strategy, based on structured MRI assessments targeting absence of osteitis combined with clinical remission, compared with a conventional clinical T2T strategy targeting clinical remission only, improves disease activity, physical function and suppresses MRI-inflammation over 5 years in RA patients.MethodsThe IMAGINE-more trial was designed as an extension protocol to the 2-year IMAGINE-RA randomised controlled trial (RCT). IMAGINE-RA included 200 RA patients, in clinical remission (DAS28-CRPand no swollen joints), who received conventional synthetic disease-modifying antirheumatic drugs (csDMARD) and investigated whether an MRI T2T strategy targeting absence of osteitis in combination with clinical remission (DAS28-CRP≤3.2 and no swollen joints) could increase remission rates and prevent erosive progression compared with a conventional T2T strategy targeting clinical remission only. If target was not met, treatment was escalated according to a predefined treatment algorithm starting with increment in csDMARDs and then adding biologics. At the end of the study, participants were invited to participate in the IMAGINE-more follow-up study. Patients were managed in routine outpatient clinic and had three IMAGINE-more visits including clinical examination (year 3, 4 and 5) and contrast-enhanced MRI of the dominant wrist and 2nd-5th metacarpophalangeal joints (year 3 and 5). The primary clinical endpoint was the proportion of patients achieving DAS28-CRP remission (DAS28-CRPResultsFifty-nine patients in the MRI T2T arm and 72 patients in conventional T2T arm consented to participate. Of these, 47 patients (80%) in the MRI T2T group and 54 patients (75%) in the conventional T2T group reached the primary clinical endpoint (p=0.161) (Table 1 and Figure 1). No statistically significant differences between treatment strategies in key secondary outcomes were seen.Table 1.Primary and key secondary outcomes at 5 yearsMRI T2TConventional T2TDifference between groupsP valueN=59N=72Primary endpointDAS28-CRP remission (DAS28-CRP47 (80%)54 (75%)2.00 (0.76 to 5.28)0.161Key secondary endpointsDAS28-CRP1.79 (0.08)1.94 (0.08)-0.15 (-0.38 to 0.07)0.176Change from baseline in MRI osteitis (RAMRIS)-0.17 (0.58)0.18 (0.54)-0.35 (-1.96 to 1.25)0.663Change from baseline in HAQ-0.02 (0.03)0.05 (0.03)-0.07 (-0.15 to 0.01)0.080Group estimates are presented as No. (%) for dichotomous data and least squares means (SE) for continuous data. For the primary endpoint, adjusted odds ratio and 95%CI between groups were calculated from a logistic regression model including a fixed factor for treatment arm, and an adjustment for propensity score as a covariate. For endpoints with continuous data, least squares mean differences between groups were calculated based on repeated-measures mixed linear models adjusted for baseline values and propensity scores.ConclusionA 2-year MRI T2T strategy targeting absence of MRI osteitis combined with clinical remission as compared to a conventional clinical T2T strategy in RA patients had no effect on the long-term probability of achieving DAS28-CRP remission. These findnings do not support the use of an MRI-guided strategy for treating patients with RA.References[1]Møller-Bisgaard S et al: JAMA 2019, 321(5):461-472.Disclosure of InterestsSigne Møller-Bisgaard Grant/research support from: AbbVie, Kim Hørslev-Petersen: None declared, Daniel Glinatsi: None declared, Bo Ejbjerg: None declared, Merete L. Hetland: None declared, Jakob Møllenbach Møller: None declared, Robin Christensen: None declared, Sabrina Mai Nielsen: None declared, Mikael Boesen: None declared, Kristian Stengaard-Pedersen: None declared, Ole Madsen: None declared, Bente Jensen: None declared, Jan Alexander Villadsen: None declared, Ellen Margrethe Hauge: None declared, Oliver Hendricks: None declared, Hanne Merete Lindegaard: None declared, Niels Steen Krogh: None declared, Anne Grethe Jurik: None declared, Henrik Thomsen: None declared, Mikkel Østergaard Speakers bureau: Abbvie, BMS, Celgene, Eli-Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Orion, Pfizer, Roche and UCB, Consultant of: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi and UCB, Grant/research support from: Abbvie, Amgen, BMS, Merck, Celgene and Novartis.

Background: There is a strong association between gout and obesity. Lowering urate is the cornerstone of gout management [1] and urate levels correlate strongly with central obesity. Previous studies suggest that weight loss has a positive effect on serum urate, however, the studies are sparse and small [2].Objectives: To assess the impact of an initial low-calorie diet-induced weight loss and subsequent randomisation to the body weight-lowering drug liraglutide (a glucagon-like peptide 1 receptor agonist) or placebo on serum urate levels.Methods: In the LOSE-IT trial (NCT02905864), a randomised, double-blinded, placebo-controlled, parallel group, single-centre trial [3], 156 obese individuals with knee osteoarthritis, but without gout, were offered an initial 8-week intensive diet intervention (week -8 to 0) on Cambridge Weight Plan (800-1000 kcal/day) followed by a weight loss maintenance period in which participants were randomised to either liraglutide 3 mg/day or placebo for 52 weeks. We conducted a secondary analysis of blood samples collected at week -8, 0 and 52. The primary outcome measure was change in serum urate. We used paired t-test for the change from week -8 to 0, and for change from week 0 to 52 we used an ANCOVA model adjusted for stratification factors (sex, age category and obesity class), and the level of the outcome at baseline. Data were analysed as observed (i.e. no imputation of missing data).Results: 156 individuals were randomised and 155 had blood samples taken at baseline. In the initial intensive diet intervention period (week -8 to 0) they lost a mean of 12.5 kg (9513.1 to -11.9, n 156). In the following 52 weeks, the liraglutide group lost an additional 4.1 kg (SE 1.2, n 71) whereas the control group was almost unchanged with a weight loss of 0.2 kg (SE 1.2, n 66). Looking at the main outcome of serum urate levels change, the initial intensive diet resulted in a mean decrease of 0.21 mg/dL (95.35 to 0.07, n 155) for the entire cohort. In the following year (week 0 to 52) the liraglutide group exhibited a further mean decrease in serum urate of 0.48 mg/dL (SE 0.11, n 69), whereas the placebo group exhibited a slight decrease in mean serum urate of 0.07 mg/dL (SE 0.12, n 65) resulting in a significant between-group difference of -0.40 mg/dL (950.69 to -0.12, n 134) textendash see Figure 1. Four participants in each group experienced serious adverse events; no deaths were observed.Conclusion: This secondary analysis of the LOSE-IT trial suggests that liraglutide provides a potential novel serum urate lowering drug mechanism in obese patient populations, with potential implication for gout treatment.References: [1]Richette P et al. 2016. Ann Rheum Dis 2017;76:29textendash42.[2]Nielsen SM et al. Ann Rheum Dis 2017 76(11):1870-1882.[3]Gudbergsen H et al. BMJ 2019. 71textendash2.Disclosure of Interests: Kristian Zobbe: None declared, Sabrina Mai Nielsen: None declared, Robin Christensen: None declared, Anders Overgaard: None declared, henrik gudbergsen Speakers bureau: Pfizer 2016, Marius Henriksen: None declared, Henning Bliddal Grant/research support from: received research grant fra NOVO Nordic, Consultant of: consultant fee fra NOVO Nordic, Lene Dreyer: None declared, Lisa Stamp: None declared, Filip Krag Knop Shareholder of: Minority shareholder in Antag Therapeutics Aps, Grant/research support from: AstraZeneca, Gubra, Novo Nordisk, Sanofi and Zealand Pharma, Consultant of: Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, MSD/Merck, Mundipharma, Novo Nordisk, Sanofi and Zealand Pharma., Speakers bureau: AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, MedImmune, MSD/Merck, Mundipharma, Norgine, Novo Nordisk, Sanofi and Zealand Pharma., Lars Erik Kristensen Consultant of: UCB Pharma (Advisory Board), Sannofi (Advisory Board), Abbvie (Advisory Board), Biogen (Advisory Board), Speakers bureau: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Forward Pharma, Janssen Pharmaceuticals, MSD, Novartis, Pfizer, and UCB Pharma

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management. We thank Sue Healey for her contribution to CIMBA, in particular, for taking on the task of mutation classification with Olga Sinilnikova. BCFR Australia: We acknowledge Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis. BCFR Ontario: We thank members and participants in the Ontario Familial Breast Cancer Registry for their contributions to the study. BFBOCC-LT (Baltic Familial Breast Ovarian Cancer Consortium Lithuanian section): We acknowledge Vilius Rudaitis and Laimonas Griˇskeviˇcius. CBCS (Copenhagen Breast Cancer Study, Rigshospitalet): We thank Bent Ejlertsen Ejlertsen and Anne-Marie Gerdes for the recruitment and genetic counseling of participants. CNIO (Spanish National Cancer Centre): We thank Alicia Barroso, Rosario Alonso, and Guillermo Pita for their assistance. COH-CCGCRN (City of Hope Clinical Cancer Genomics Community Research Network): Patients were recruited for study from the City of Hope Clinical Cancer Genomics Community Research Network. CONSIT TEAM:We acknowledge Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy; Brunella Pilato of the Istituto Nazionale Tumori “Giovanni Paolo II”, Bari, Italy; and the personnel of the Cogentech Cancer Genetic Test Laboratory, Milan, Italy. FCCC (Fox Chase Cancer Center):We thank Jo EllenWeaver and Betsy Bove, MD, for their technical support. GEMO (GeneticModifiers of cancer risk in BRCA1/2 mutation carriers):We pay a tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet, initiated and coordinated GEMO until she died on June 30, 2014, and we thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unit´e Mixte de G´en´etique Constitutionnelle des Cancers Fr´equents, Hospices Civils de Lyon–Centre L´eon B´erard, Equipe G´en´etique du cancer du sein, Centre de Rechercheen Canc´erologie de Lyon: Olga Sinilnikova (deceased), Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, M´elanie L´eone, Nadia Boutry-Kryza, Alain Calender, Sophie Giraud; and Service de G´en´etique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Etienne Rouleau, Lisa Golmard, Agn`es Collet, Virginie Moncoutier, Muriel Belotti, Antoine de Pauw, Camille Elan, Catherine Nogues, Emmanuelle Fourme, Anne-Marie Birot; Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Olivier Caron, Marine Guillaud- Bataille; Centre Jean Perrin, Clermont–Ferrand: Yves-Jean Bignon, Nancy Uhrhammer; Centre L´eon B´erard, Lyon: Christine Lasset, Val´erie Bonadona, Sandrine Handallou; Centre François Baclesse, Caen: Agn`es Hardouin, Pascaline Berthet, Dominique Vaur, Laurent Castera; Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, François Eisinger; CHUArnaud-de-Villeneuve,Montpellier: Isabelle Coupier, Pascal Pujol; Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Jo¨elle Fournier, Françoise R´evillion, Philippe Vennin (deceased), Claude Adenis; Centre Paul Strauss, Strasbourg: Dani`ele Muller, Jean-Pierre Fricker; Institut Bergoni´e, Bordeaux: Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy; Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel; CHU Grenoble: Dominique Leroux, H´el`ene Dreyfus, Christine Rebischung, Magalie Peysselon; CHU Dijon: Fanny Coron, Laurence Faivre; CHU St-Etienne: Fabienne Prieur, Marine Lebrun, Caroline Kientz; HˆotelDieu Centre Hospitalier, Chamb´ery: Sandra Fert Ferrer; Centre Antoine Lacassagne, Nice: Marc Fr´enay; CHU Limoges: Laurence V´enat-Bouvet; CHU Nantes: Capucine Delnatte; CHU Bretonneau, Tours: Isabelle Mortemousque; Groupe Hospitalier Piti´e-Salp´etri`ere, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier, MathildeWarcoin; CHU Vandoeuvre-les- Nancy: Johanna Sokolowska, Myriam Bronner; CHU Besançon: Marie-Agn`es Collonge-Rame, Alexandre Damette; Creighton University, Omaha, NE: Henry T. Lynch, Carrie L. Snyder. G-FAST (Ghent University Hospital): B.P. is a senior clinical investigator of FWO. We acknowledge the technical support of Ilse Coeneen Brecht Crombez. HCSC (Hospital Clinico San Carlos): We acknowledge Alicia Tosar and Paula Diaque for their technical assistance. HEBCS (Helsinki Breast Cancer Study):We thank Taru A. Muranen, Carl Blomqvist, MD, Kirsimari Aaltonen, MD, Irja Erkkil¨a, RN, and Virpi Palola, RN, for their help with the HEBCS data and samples. Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON): HEBON consists of the following collaborating centers: Coordinating center: Netherlands Cancer Institute, Amsterdam: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N.S. Russell, J.L. de Lange, R. Wijnands; Erasmus Medical Center: J.M. Coll´ee, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center: C.J. van Asperen, J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University NijmegenMedical Center: C.M. Kets, A.R.Mensenkamp; UniversityMedical Center Utrecht: M.G.E.M. Ausems, R.B. van der Luijt, C.C. van der Pol; Amsterdam Medical Center: C.M. Aalfs, T.A.M. van Os; Vrije Universiteit Medical Center: J.J.P. Gille, Q.Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht: E.B. G´omez-Garcia, M.J. Blok; University Medical Center Groningen: J.C. Oosterwijk, A.H. van der Hout, M.J.Mourits, G.H. de Bock; The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J. Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek. HEBON thanks the registration teams of IKNL and PALGA for part of the data collection. HUNBOCS (Molecular Genetic Studies of Breast- and Ovarian Cancer in Hungary):We thank the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Aniko Bozsik, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study. HVH (University Hospital Vall d’Hebron): We thank the Cellex Foundation for providing research facilities and equipment. ICO (Institut Catal`a d’Oncologia): We thank the ICO Hereditary Cancer Program team led by Gabriel Capella, MD. INHERIT (INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility):We thank Martine Dumont, MD, Martine Tranchant and St´ephane Dubois for QC, sample management and skillful assistance. J.S. is Chair holder of the Canada Research Chair in Oncogenetics. J.S. and P.S. were part of the QC and Genotyping coordinating group of iCOGS and Oncoarray (BCAC and CIMBA). IPOBCS (Portuguese Oncology Institute-Porto jco.org © 2017 by American Society of Clinical Oncology Polygenic Risk Scores in Male BRCA1 and BRCA2 Mutation Carriers Downloaded from ascopubs.org by CNIO-FUND on September 27, 2019 from 193.147.150.201 Copyright © 2019 American Society of Clinical Oncology. All rights reserved. Breast Cancer Study): We thank Catarina Santos, MD, for her skillful contribution to the study. kConFab (Kathleen Cuningham Consortium for Research into Familial Breast Cancer): We thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study for their contributions to this resource, and the many families who contribute to kConFab.Memorial Sloan Kettering Cancer Center:We acknowledge Lauren Jacobs, MD. OCGN (Ontario Cancer Genetics Network): We thank members and participants in the Ontario Cancer Genetics Network for their contributions to the study. OSUCCG (The Ohio State University Comprehensive Cancer Center): Kevin Sweet, Caroline Craven, Julia Cooper, Leigha Senter, and Michelle O’Conor were instrumental in accrual of study participants, ascertainment of medical records, and database management. SEABASS (South East Asian Breast Cancer Association Study): We thank Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan, and all the research nurses, research assistants, and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection, and sample preparation. In addition, we thank Philip Iau, Sng Jen-Hwei, and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study, respectively. SWE-BRCA (Swedish Breast Cancer Study): Swedish scientists participating as SWE-BRCA collaborators are: from Lund University and University Hospital: A° ke Borg, H°akan Olsson, Helena Jernstr¨om, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna O¨ fverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna vonWachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala; from Ume°a University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellstr¨om Pigg, Richard Rosenquist; from Link¨oping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren. University of Chicago: O.I.O. is an ACS Clinical Research Professor. We thank Cecilia Zvocec, Qun Niu, physicians, genetic counsellors, research nurses, and staff of the Cancer Risk Clinic for their contributions to this resource, and the many families who contribute to our program. VFCTG (Victorian Familial Cancer Trials Group):We acknowledge Geoffrey Lindeman, Marion Harris, Martin Delatycki of the Victorian Familial Cancer Trials Group.We thank Sarah Sawyer and Rebecca Driessen for assembling these data and Ella Thompson for performing all DNA amplification. © 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Sí

PURPOSE Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing—initial testing of priority genes followed by expanded testing—was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.