Holger J. Schünemann, MD, PhD, MSc; Donata Lerda, PhD; Cecily Quinn, MD; Markus Follmann, MD, MPH, MSc; Pablo Alonso-Coello, MD, PhD; Paolo Giorgi Rossi, PhD; Annette Lebeau, MD; Lennarth Nyström, PhD; Mireille Broeders, PhD; Lydia Ioannidou-Mouzaka, MD; Stephen W. Duffy, BSc, MSc, CStat; Bettina Borisch, MD; Patricia Fitzpatrick, MD; Solveig Hofvind, PhD; Xavier Castells, MD, PhD; Livia Giordano, MD; Carlos Canelo-Aybar, MD, MSc; Sue Warman, MEd; Robert Mansel, MD; Francesco Sardanelli, MD; Elena Parmelli, PhD; Axel Gräwingholt, MD; Zuleika Saz-Parkinson, PhD; for the European Commission Initiative on Breast Cancer (ECIBC) Contributor Group *
Acknowledgment: The authors thank Jesús López Alcalde who coordinated the JRC methods for the ECIBC guidelines between 2013 and 2016, Chris de Wolf, Roberto D'Amico, and Peter Rabe for their contributions to the ECIBC guidelines as previous Joint Research Centre colleagues or retired GDG members.
Financial Support: By the European Commission.
Disclosures: Members of the GDG do not receive financial compensation for their work but are reimbursed by the European Commission for travel-related expenses for the meetings organized by the Joint Research Centre. Dr. Schünemann reports that the European Commission had chosen to use GRADE as one of the core methods for its guidelines before involving Dr. Schünemann. He was invited to participate in the guideline development as a methodologist and was elected by the ECIBC GDG as its cochair. He is also cochair of the GRADE working group and has codeveloped its methodology and tools, was commissioned by the National Academy of Sciences to write the background reports for the Institute of Medicine standards for trustworthy guideline development with coauthors, has conducted Cochrane reviews (currently is director of Cochrane Canada), and is a member of the Board of Trustees of the Guidelines International Network. He has not received direct financial payments for ECIBC work but has received travel support and is under contract from the European Commission for a project relating to other guideline methods. Dr. Quinn is the chair of the European Working Group for Breast Screening Pathology (EWGBSP). Various companies have provided some sponsorship to the EWGBSP for group meetings. Dr. Alonso-Coello reports that his institution received payments from the European Commission to develop the systematic reviews informing the recommendations. He coordinated the systematic review team informing the guidelines. He is a member of the GRADE guidance group of the GRADE working group and a member of the board of the Guidelines International Network. He has contributed to the development of some of the methodology and tools. Dr. Giorgi Rossi reports that he published opinions about the superiority of public, organized, population-based screening programs instead of opportunistic and private screening, according to the European Commission recommendations 2003/878/EC. He is on the steering committee of MyPeBS (My Personal Breast Screening), a European multicentric trial to compare the effectiveness of personalized screening programs and standard protocols, and of the RETomo and MAITA trials, comparing digital mammography and DBT in breast cancer screening. Dr. Lebeau reports grants and reimbursement for travel-related expenses related to consultancy from Roche Pharma and Novartis Oncology, and grants from BioNTech Diagnostics, outside the submitted work. Dr. Lebeau reports that she is chair of the Breast Pathology Working Group of the German S3 Guidelines for the Early Detection, Diagnosis, Treatment and Follow-up of Breast Cancer; a member of the Scientific Advisory Council for the Cooperation Alliance Mammography (Kooperationsgemeinschaft Mammographie GBR), Germany; a member of the certification commission “breast cancer centres” as a representative of the German Society of Pathology and the Federal Association of German Pathologists; and a board member of the German Society of Pathology. Dr. Hofvind reports permanent employment as a researcher at the Cancer Registry of Norway, independent of her job as administrative leader of BreastScreen Norway. Dr. Canelo-Aybar reports that his institution received payments from the European Commission to develop the systematic reviews informing the recommendations. He is a member of the GRADE Working Group. Dr. Sardanelli is responsible for the department of radiology performing mammographic screening at the IRCCS Policlinico San Donato, Milan, Italy. He is a member of the executive board of the European Society of Breast Imaging and codirector of the Breast MRI training course run by this society; director of the European Network for Assessment of Imaging in Medicine, joint initiative of the European Institute for Biomedical Imaging Research; editor-in-chief of European Radiology Experimental; and a recipient of research grants from Bracco, Bayer, and General Electric. Dr. Sardanelli is not a member of the GDG but did participate in formulating the recommendations. Dr. Parmelli is employed by the European Commission. Dr. Gräwingholt is head of the mammography screening center Paderborn, consultant radiologist for screening programs in Switzerland, and consultant radiologist for Hellenic School of Senology. Dr. Saz-Parkinson is employed by the European Commission, coordinating the ECIBC's GDG. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum= M19-2125.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Catharine B. Stack, PhD, MS, Deputy Editor, Statistics, reports that she has stock holdings in Pfizer, Johnson & Johnson, and Colgate-Palmolive. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Corresponding Author: Holger J. Schünemann, MD, PhD, MSc, McMaster University Health Sciences Centre, Room 2C16, 1280 Main Street West, Hamilton, Ontario L8N 4K1, Canada (e-mail, firstname.lastname@example.org); and Zuleika Saz-Parkinson, PhD, European Commission, Joint Research Centre, Via Enrico Fermi 2749, TP 127, Ispra VA, 21027, Italy (e-mail, email@example.com).
Current Author Addresses: Dr. Schünemann: Michael G. DeGroote Cochrane Canada Centre and McMaster GRADE Centre, McMaster University 1280 Main Street West, Hamilton, Ontario L8N 4K1, Canada.
Drs. Lerda, Parmelli, and Saz-Parkinson: European Commission, Joint Research Centre, Via Enrico Fermi 2749, Ispra VA, 21027, Italy.
Dr. Quinn: St. Vincent's University Hospital, 96 Merrion Road, Elm Park, Dublin, D04 T6F4, Ireland.
Dr. Follmann: German Cancer Society, Kuno-fischer-straße 8, Berlin, 14057, Germany.
Drs. Alonso-Coello and Canelo-Aybar: Iberoamerican Cochrane Center, Biomedical Research Institute (IIB Sant Pau-CIBERESP), Sant Antoni Maria Claret 167, Barcelona, 8025, Spain.
Dr. Giorgi Rossi: Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Via Amendola 2, Reggio Emilia, 42122, Italy.
Dr. Lebeau: University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg, 20246, Germany.
Dr. Nyström: Umeå University, 90 187 Umeå, Sweden.
Dr. Broeders: Radboud University Medical Centre, Geert Grooteplein 21, Nijmegen, 6525 EZ, the Netherlands.
Dr. Ioannidou-Mouzaka: Leto Gynecological-Surgical and Obstetrical Clinic, 18, Avenue Kifissias, 11526 Athens, Greece.
Mr. Duffy: Centre for Cancer Prevention, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom.
Dr. Borisch: Institute of Global Health, University of Geneva, Chemin des Mines 9, Geneva, 1202, Switzerland.
Dr. Fitzpatrick: National Screening Service, Kings Inns House, 200 Parnell Street, Dublin, D01 A3Y8, Ireland.
Dr. Hofvind: Cancer Registry of Norway, Ullernchausseen 64, 0379 Oslo, Norway.
Dr. Castells: IMIM (Hospital del Mar Medical Research Institute), Carrer del Dr. Aiguader, 88, Barcelona, 8003, Spain.
Dr. Giordano: CPO Piedmont-AOU Città della Salute e della Scienza, via Cavour 31, Turin, 10131, Italy.
Mrs. Warman: Havyatt Lodge, Havyatt Road, Langford, North Somerset, BS40 5DD, United Kingdom.
Dr. Mansel: Cardiff University, The Gables, Monmouth, NP25 3PA, United Kingdom.
Dr. Sardanelli: Università degli Studi di Milano, Via Morandi 30, San Donato Milanese, Milan, 20097, Italy.
Dr. Gräwingholt: Radiologie am Theater, Neuer Platz 4, Paderborn, NRW, 33098, Germany.
Author Contributions: Conception and design: H.J. Schünemann, D. Lerda, Z. Saz-Parkinson.
Analysis and interpretation of the data: H.J. Schünemann, C. Quinn, M. Follmann, P. Alonso-Coello, P. Giorgi Rossi, A. Lebeau, M. Broeders, S.W. Duffy, P. Fitzpatrick, S. Hofvind, C. Canelo-Aybar, S. Warman, E. Parmelli, A. Gräwingholt, Z. Saz-Parkinson.
Drafting of the article: H.J. Schünemann, Z. Saz-Parkinson.
Critical revision for important intellectual content: H.J. Schünemann, C. Quinn, M. Follmann, P. Alonso-Coello, P. Giorgi Rossi, A. Lebeau, L. Nyström, M. Broeders, L. Ioannidou-Mouzaka, B. Borisch, X. Castells, C. Canelo-Aybar, S. Warman, R. Mansel, F. Sardanelli, E. Parmelli, A. Gräwingholt, L. Giordano, Z. Saz-Parkinson.
Final approval of the article: H.J. Schünemann, D. Lerda, C. Quinn, M. Follmann, P. Alonso-Coello, P. Giorgi Rossi, A. Lebeau, L. Nyström, M. Broeders, L. Ioannidou-Mouzaka, S.W. Duffy, B. Borisch, P. Fitzpatrick, S. Hofvind, X. Castells, L. Giordano, C. Canelo-Aybar, S. Warman, R. Mansel, F. Sardanelli, E. Parmelli, A. Gräwingholt, Z. Saz-Parkinson.
Provision of study materials or patients: H.J. Schünemann, D. Lerda, P. Alonso-Coello, Z. Saz-Parkinson.
Statistical expertise: H.J. Schünemann, P. Giorgi Rossi, L. Nyström, S.W. Duffy, C. Canelo-Aybar.
Administrative, technical, or logistic support: H.J. Schünemann, P. Alonso-Coello, B. Borisch, D. Lerda, E. Parmelli, Z. Saz-Parkinson.
Collection and assembly of data: H.J. Schünemann, P. Alonso-Coello, A. Lebeau, P. Fitzpatrick, C. Canelo-Aybar, S. Warman, Z. Saz-Parkinson.
The European Commission Initiative for Breast Cancer Screening and Diagnosis guidelines (European Breast Guidelines) are coordinated by the European Commission's Joint Research Centre. The target audience for the guidelines includes women, health professionals, and policymakers.
An international guideline panel of 28 multidisciplinary members, including patients, developed questions and corresponding recommendations that were informed by systematic reviews of the evidence conducted between March 2016 and December 2018. GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision frameworks were used to structure the process and minimize the influence of competing interests by enhancing transparency. Questions and recommendations, expressed as strong or conditional, focused on outcomes that matter to women and provided a rating of the certainty of evidence.
This synopsis of the European Breast Guidelines provides recommendations regarding organized screening programs for women aged 40 to 75 years who are at average risk. The recommendations address digital mammography screening and the addition of hand-held ultrasonography, automated breast ultrasonography, or magnetic resonance imaging compared with mammography alone. The recommendations also discuss the frequency of screening and inform decision making for women at average risk who are recalled for suspicious lesions or who have high breast density.
Table 1. Multiple-Intervention Comparison of Desirable and Undesirable Consequences of Annual, Biennial, and Triennial Mammography Screening for Women Aged 45 to 49, 50 to 69, and 70 to 74 Years
Table 2. Recommendations for Breast Cancer Screening for Average-Risk Women*
Richard M Fleming, PhD, MD, JD
November 26, 2019
Conflict of Interest:
Acknowledgment: FMTVDM is issued to first author.
FMTVDM - It’s time to quit screening and start diagnosing Breast Cancer.
FMTVDM - It’s time to quit screening and start diagnosing Breast Cancer.For decades we have been running screening tests looking for cancer, allowing physicians to make an educated guess as to whether we think you do or don’t have cancer. If we think the patient might have cancer, then we run more tests to find out. Alternatively, if we think the patient probably doesn’t have cancer, we wait –so too does the patient and their family. The entire concept of using screening tests is archaic and anything but comfortable if you’re the patient. The acceptance of screening tests is primarily based on the use of qualitative tests – tests that we look at, or blood tests. Is there something on the stool guaiac? Is it blood, iron, too much pepto bismol? Is the PSA elevated? Is it prostate cancer, prostatitis, BPH, too much exercise? In keeping with these Breast Cancer Screening Guidelines – the question becomes, just what is that questionable area on the mammogram – is it calcium, dense tissue, inflammation, cancer or nothing?The process of developing cancer is not an overnight, yes - no phenomena; although that is how we’ve been treating it . Cancer is the result of the interaction between the genetics of a cell – which is unique for each individual – and the cellular environment. That cellular environment is similarly unique and is the result of the air you breathe, the food you eat, the oxidative stress your body is experiencing at the moment, is there infection, et cetera . Rather than using a qualitative screening approach, with the associated problems with sensitivity (we missed your disease) and specificity (we told you there was a problem when there wasn’t), and the resulting personal, psychological, physical, financial, family, work costs – if we’re really interested in informed decision making, we should be focusing less on screening and more on actually measuring what’s happening in the body. To do that requires quantitative measurement -now made possible using FMTVDM .FMTVDM measures changes in tissue metabolism and the resulting regional blood flow differences (RBFDs) that are associated with the development of both cancer and coronary artery disease . By measuring what’s actually happening at the tissue level, we can tell someone where on the health-spectrum he or she actually is [1,2]. Consequently, we can also measure whether their treatment is working – thereby saving time, money and lives – thus providing true patient-specific, patient-guided treatment. By actually measuring what’s happening in each individual, we can do better than a screening guess – we can make a truly informed diagnostic decision and so can the patient.Acknowledgment: FMTVDM is issued to first author.References:1. Fleming RM, Fleming MR, Chaudhuri TK, McKusick A. Cancer: Our Body’s Global Warming Warning. Biomed Research. Open Acc J Oncol Med 2019;3(1):238-239. DOI: 10.32474/OAJOM.2019.03.000154 2. Fleming RM, Fleming MR. The Importance of Thinking about and Quantifying Disease like Cancer and Heart Disease on a “Health-Spectrum” Continuum. J Compr Cancer Rep 2019;3(1):1-3 (Article ID 100011). 3. The Fleming Method for Tissue and Vascular Differentiation and Metabolism (FMTVDM) using same state single or sequential quantification comparisons. Patent Number 9566037. Issued 02/14/2017. 4. Fleming RM, Fleming MR, Chaudhuri TK. The Similarities in Coronary Artery Disease and Cancer. Acta Scientific Med Sci. 2019;Special Issue 1:03-04. DOI:10.31080/ASMS.2019.S01.0002.
Hans-Olov Adami,MD, PhD, Philippe Autier, MD, PhD
Karolinska Institute, Harvard School of Public Health, University of Strathclyde,
December 19, 2019
TO THE EDITOR
In an era when almost half a century of intense research on mammography screening has made the balance between potential benefit and overwhelmingly documented harm so uncertain that the whole approach deserves reconsideration (1), the European Commission Initiative for Breast Screening and Diagnosis publishes updated guidelines that are indeed concerning (2). Although characterized as “rigorous” by the authors, their approach is based on such selective uncritical review of partly obsolete evidence that these guidelines, if implemented, may cause considerable harm and drain straightened health care resources.
Contrary to a recent exhaustive review of mammography screening commissioned by the European Academy of Cancer Sciences (3) the European Commission Initiative guidelines: 1) rely almost exclusively on randomized trials, chiefly initiated three to five decades ago; 2) ignore the profound methodological limitations revealed in some of these trials (3); 3) do not embrace that primary treatment of breast cancer has undergone substantial, almost revolutionary, improvement after women were enrolled into the randomized mammography screening trials; 4) do not cite the numerous assessments based on population-based cancer registries which failed to document significant reductions in the incidence of advanced-stage breast cancers (including stage 4 metastatic cancers), after more than twenty to thirty years of mammography screening in the United States of America, Australia, Denmark, the Netherlands, and Norway (3). Similarly, no significant breast cancer mortality reduction attributable to population-based screening was found in Norway (4) nor in Denmark or the Netherlands (3); 5) are largely dismissive about the fact that substantial overdiagnosis of invasive cancer – in addition to the unknown benefit of detecting ductal carcinoma in situ – is now a widely accepted consequence of mammography screening (3) and; 6) the increased rate of mastectomy among screened is repeatedly dismissed as due to lead time without mentioning overdiagnosis as a much more plausible explanation.
Because women’s preference would certainly change if they were fully informed about all these uncertainties and harms, the European Initiative guidelines are misleading. Why did the panel go so wrong in their judgement? Intellectual or professional conflict of interest may provide one explanation. In a time when guideline developers continue to receive critique for vested interests, the European Initiative recommendations will only fuel the fire. What we need now more than ever is evidence from well-designed studies that accommodate the benefit of modern, optimized primary treatment of breast cancer (5).
1. Adami HO, Kalager M, Valdimarsdottir U, et al. Time to abandon early detection cancer screening. Eur J Clin Invest. 2019;49:e13062.
2. Schünemann HJ, Lerda D, Quinn C, et al. European Commission Initiative on Breast Cancer (ECIBC) Contributor Group. Breast Cancer Screening and Diagnosis: A Synopsis of the European Breast Guidelines. Ann Intern Med. 2019;171(4):273-280.
3. Autier P, Boniol M. Mammography screening: A major issue in medicine. Eur J Cancer. 2018;90:34-62.
4. Kalager M, Zelen M, Langmark F, et al. Effect of screening mammography on breast-cancer mortality in Norway. N Engl J Med. 2010;363:1203-10.
5. Kalager M, Bretthauer M. Improving cancer screening programs. 0.1126/Science.aay3156. In press.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA (HOA); University of Strathclyde Institute of Global Public Health at iPRI, International Prevention Research Institute (iPRI), Lyon, France (PA).
Hans-Olov Adami, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, P.O.B 281, SE-171 65 Stockholm, Sweden.
Karsten J. Jørgensen, Asger S. Paludan-Müller
Nordic Cochrane Centre
January 8, 2020
European Guidelines on breast screening: recommendation for women aged 50 to 69 years.
A great strength of GRADE is that it makes transparent the necessarily subjective judgements made by guideline panels. This allows for discussion of each step in the process from evidence to recommendation.The original Evidence Profiles for the European Guidelines indicate that the certainty of the estimate of the most serious harm of breast screening, overdiagnosis, was downgraded to “moderate” because of the age of the trials (indirectness) . This is reasonable due to increased test sensitivity over time. However, the certainty of the cause-specific mortality reduction was not downgraded for indirectness and was considered “high” . This allowed a strong recommendation for this age group. Improvements in treatment since the trials have resulted in large reductions in breast cancer mortality. Since 1989, reductions across Europe were larger in women below the common age limit for screening of 50 years (-37%) compared to screened women (-21%) . Improved treatment was therefore likely most important.The certainty of the benefit estimate was also not downgraded due to risk of bias  although many trials had problems, i.e. with the randomization process, and despite good agreement between assessments in the European guidelines and the Cochrane review . However, a high risk of bias trial trial estimated a 38% reduction while a low risk trial estimated no benefit, with non-overlapping confidence intervals . The summarized estimated benefit for ages >50 years for the low risk of bias trials was a not statistically significant 7% reduction compared to a statistically significant 30% reduction for the high-risk trials . This difference was statistically significant (P=0.02) . This leaves two options: base recommendations on all trials, rating down to low certainty due to indirectness and risk of bias. Or use the low risk of bias trials. GRADE recommends using the low risk of bias trials, avoiding to rate down for risk of bias . The panel’s conclusion that there is high certainly of benefit  simply disregard two critically important problems. Beyond these issues, the estimate of overdiagnosis is not available in absolute numbers anywhere, even in the Evidence Profiles , a core feature of GRADE. This precludes a useful comparison of benefits and harms. There are clear requirements for high-quality evidence from randomized trials to recommend screening . Breast screening does not fulfil these requirements and the strong recommendation of breast screening for women aged 50 to 69 years  is therefore unjustified.References:1. Joint Research Centre, European Commission Initiative on Breast Cancer (ECIBC): European guidelines on breast cancer screening and diagnosis. European Union 2019. Available at: https://healthcare-quality.jrc.ec.europa.eu/sites/default/files/Guidelines/EtDs/ECIBC_GLs_EtD_screening_50-69.pdf2. Autier P, Boniol M, La Vecchia C, et al. Disparities in breast cancer mortality trends between 30 European countries: retrospective trend analysis of WHO mortality database. BMJ 2010;341:c3620.3. Gøtzsche PC, Jørgensen KJ. Screening for breast cancer with mammography. Cochrane Database of Systematic reviews 2013, issue 6. Art. No.:CD001877. 4. Iorio A, Spencer FA, Falavigna M, et al. Use of GRADE for assessment of evidence about prognosis: rating confidence in estimates of event rates in broad categories of patients. BMJ 2015;350:h870.5. UK National Screening Committee. Criteria for appraising the viability, effectiveness and appropriateness of a screening programme. 2015. Available at: https://www.gov.uk/government/publications/evidence-review-criteria-national-screening-programmes/criteria-for-appraising-the-viability-effectiveness-and-appropriateness-of-a-screening-programme
Schünemann HJ, Lerda D, Quinn C, et al, for the European Commission Initiative on Breast Cancer (ECIBC) Contributor Group. Breast Cancer Screening and Diagnosis: A Synopsis of the European Breast Guidelines. Ann Intern Med. 2020;172:46–56. [Epub ahead of print 26 November 2019]. doi: https://doi.org/10.7326/M19-2125
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Published: Ann Intern Med. 2020;172(1):46-56.
Published at www.annals.org on 26 November 2019
Breast Cancer, Cancer Screening/Prevention, Guidelines, Hematology/Oncology, Prevention/Screening.
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