. 2015 Nov;108(3).
doi: 10.1093/jnci/djv345.

Recognizing the Limitations of Cancer Overdiagnosis Studies: A First Step Towards Overcoming Them

Ruth Etzioni 1 Roman Gulati 2 
  • PMID: 26582245
  •     38 References
  •     9 citations


Numerous studies have attempted to quantify the number of breast cancers that would never have been diagnosed in the absence of screening. Unfortunately, results are highly variable across studies and there is considerable disagreement about both the frequency of overdiagnosis and the validity of different methodologic approaches. In this Commentary, we review limitations of the two major approaches used in existing studies. Studies that use excess incidence as a proxy for overdiagnosis require a valid estimate of incidence in the absence of screening and sufficient follow-up to ensure the excess excludes relevant (ie, nonoverdiagnosed) cancers detected early. The requirement of sufficient follow-up applies to both population studies and clinical trials, but only certain clinical trial designs have the potential to yield unbiased results. Studies that model disease natural history to infer overdiagnosis must, in addition, examine whether their models produce valid estimates in the presence of nonprogressive cases. In this setting, limited follow-up could lead to a lack of identifiability of the parameters needed to accurately infer overdiagnosis. In a polarized research community, the excess incidence and modeling approaches are generally viewed as competitors, but we argue that they are complementary, with models being more complex but having greater potential to inform about disease natural history and the outcomes of candidate screening policies. Rather than arguing why one approach should be preferred to another, investigators should focus on developing studies that generate reliable estimates of overdiagnosis. Recognizing that both approaches have limitations, which existing studies rarely overcome, is a first step towards reconciling methodologic perspectives and achieving consensus about the real magnitude of the overdiagnosis problem.

Counterpoint: Overdiagnosis in breast cancer screening.
Robert A Smith.
J Am Coll Radiol, 2014 May 06; 11(7). PMID: 24794765
Overdiagnosis in screening mammography in Denmark: population based cohort study.
Sisse Helle Njor, Anne Helene Olsen, +3 authors, Elsebeth Lynge.
BMJ, 2013 Feb 28; 346. PMID: 23444414    Free PMC article.
Lead-time models produce far too low estimates of overdiagnosis with mammographic screening.
Peter C Gøtzsche, Karsten Juhl Jørgensen, Per-Henrik Zahl.
J Am Coll Radiol, 2014 Oct 11; 11(11). PMID: 25301416
Overdiagnosis and overtreatment of breast cancer: estimates of overdiagnosis from two trials of mammographic screening for breast cancer.
Stephen W Duffy, Olorunsola Agbaje, +5 authors, Jane Warwick.
Breast Cancer Res, 2006 Feb 07; 7(6). PMID: 16457701    Free PMC article.
Estimates of overdiagnosis of invasive breast cancer associated with screening mammography.
Stephen Morrell, Alexandra Barratt, +3 authors, Bruce Armstrong.
Cancer Causes Control, 2009 Nov 07; 21(2). PMID: 19894130
Lead time and overdiagnosis.
Stuart G Baker, Philip C Prorok, Barnett S Kramer.
J Natl Cancer Inst, 2014 Nov 05; 106(12). PMID: 25362702
Overdiagnosis in breast cancer: design and methods of estimation in observational studies.
Donella Puliti, Guido Miccinesi, Eugenio Paci.
Prev Med, 2011 Jun 11; 53(3). PMID: 21658405
Race-specific impact of natural history, mammography screening, and adjuvant treatment on breast cancer mortality rates in the United States.
Nicolien T van Ravesteyn, Clyde B Schechter, +5 authors, Jeanne S Mandelblatt.
Cancer Epidemiol Biomarkers Prev, 2010 Dec 02; 20(1). PMID: 21119071    Free PMC article.
The Swedish Two-County Trial twenty years later. Updated mortality results and new insights from long-term follow-up.
L Tabár, B Vitak, +6 authors, R A Smith.
Radiol Clin North Am, 2000 Aug 16; 38(4). PMID: 10943268
Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial.
Anthony B Miller, Claus Wall, +3 authors, Steven A Narod.
BMJ, 2014 Feb 13; 348. PMID: 24519768    Free PMC article.
Highly Cited.
Prediction of adjuvant chemotherapy benefit in endocrine responsive, early breast cancer using multigene assays.
Kathy S Albain, Soonmyung Paik, Laura van't Veer.
Breast, 2009 Nov 17; 18 Suppl 3. PMID: 19914534
Influence of study features and methods on overdiagnosis estimates in breast and prostate cancer screening.
Ruth Etzioni, Roman Gulati, Leslie Mallinger, Jeanne Mandelblatt.
Ann Intern Med, 2013 Jun 05; 158(11). PMID: 23732716    Free PMC article.
Point: The New England Journal of Medicine article suggesting overdiagnosis from mammography screening is scientifically incorrect and should be withdrawn.
Daniel B Kopans.
J Am Coll Radiol, 2013 Apr 02; 10(5). PMID: 23542028
Overestimated lead times in cancer screening has led to substantial underestimation of overdiagnosis.
P-H Zahl, K J Jørgensen, P C Gøtzsche.
Br J Cancer, 2013 Aug 22; 109(7). PMID: 23963144    Free PMC article.
Interpreting overdiagnosis estimates in population-based mammography screening.
Rianne de Gelder, Eveline A M Heijnsdijk, +3 authors, Harry J de Koning.
Epidemiol Rev, 2011 Jun 29; 33. PMID: 21709144    Free PMC article.
Effects of study methods and biases on estimates of invasive breast cancer overdetection with mammography screening: a systematic review.
Corné Biesheuvel, Alexandra Barratt, +2 authors, Les Irwig.
Lancet Oncol, 2007 Dec 07; 8(12). PMID: 18054882
Systematic Review.
Oversimplifying overdiagnosis.
Ruth Etzioni, Roman Gulati.
J Gen Intern Med, 2014 May 17; 29(9). PMID: 24830739    Free PMC article.
Screening sensitivity and sojourn time from breast cancer early detection clinical trials: mammograms and physical examinations.
Y Shen, M Zelen.
J Clin Oncol, 2001 Aug 02; 19(15). PMID: 11481355
Rate of over-diagnosis of breast cancer 15 years after end of Malmö mammographic screening trial: follow-up study.
Sophia Zackrisson, Ingvar Andersson, +2 authors, Jens Peter Garne.
BMJ, 2006 Mar 07; 332(7543). PMID: 16517548    Free PMC article.
Overdiagnosis of invasive breast cancer due to mammography screening.
Per-Henrik Zahl.
Ann Intern Med, 2012 Aug 08; 157(3). PMID: 22868851
A reality check for overdiagnosis estimates associated with breast cancer screening.
Ruth Etzioni, Jing Xia, +2 authors, Roman Gulati.
J Natl Cancer Inst, 2014 Nov 05; 106(12). PMID: 25362701    Free PMC article.
Gene expression profiling: decoding breast cancer.
Femke de Snoo, Richard Bender, Annuska Glas, Emiel Rutgers.
Surg Oncol, 2009 Nov 03; 18(4). PMID: 19879448
Estimate of overdiagnosis of breast cancer due to mammography after adjustment for lead time. A service screening study in Italy.
Eugenio Paci, Guido Miccinesi, +13 authors, Manuel Zorzi.
Breast Cancer Res, 2006 Dec 07; 8(6). PMID: 17147789    Free PMC article.
Arguments against mammography screening continue to be based on faulty science.
Daniel B Kopans.
Oncologist, 2014 Feb 19; 19(2). PMID: 24536051    Free PMC article.
Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context.
Gerrit Draisma, Ruth Etzioni, +5 authors, Harry de Koning.
J Natl Cancer Inst, 2009 Mar 12; 101(6). PMID: 19276453    Free PMC article.
Highly Cited.
Effect of three decades of screening mammography on breast-cancer incidence.
Archie Bleyer, H Gilbert Welch.
N Engl J Med, 2012 Nov 23; 367(21). PMID: 23171096
Highly Cited.
Lead-time models should not be used to estimate overdiagnosis in cancer screening.
Per-Henrik Zahl, Karsten Juhl Jørgensen, Peter C Gøtzsche.
J Gen Intern Med, 2014 Mar 05; 29(9). PMID: 24590736    Free PMC article.
Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
Soonmyung Paik, Gong Tang, +11 authors, Norman Wolmark.
J Clin Oncol, 2006 May 25; 24(23). PMID: 16720680
Highly Cited.
Overdiagnosis in early detection programs.
Ori Davidov, Marvin Zelen.
Biostatistics, 2004 Oct 12; 5(4). PMID: 15475422
A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
Soonmyung Paik, Steven Shak, +12 authors, Norman Wolmark.
N Engl J Med, 2004 Dec 14; 351(27). PMID: 15591335
Highly Cited.
Overdiagnosis in publicly organised mammography screening programmes: systematic review of incidence trends.
Karsten Juhl Jørgensen, Peter C Gøtzsche.
BMJ, 2009 Jul 11; 339. PMID: 19589821    Free PMC article.
Highly Cited. Systematic Review.
Overdiagnosis from non-progressive cancer detected by screening mammography: stochastic simulation study with calibration to population based registry data.
Arnaud Seigneurin, Olivier François, +3 authors, Marc Colonna.
BMJ, 2011 Nov 25; 343. PMID: 22113564    Free PMC article.
Nonparametric estimation of asymptomatic duration from a randomized prospective cancer screening trial.
Yu Shen, Xuelin Huang.
Biometrics, 2006 Jan 13; 61(4). PMID: 16401272
Personalizing age of cancer screening cessation based on comorbid conditions: model estimates of harms and benefits.
Iris Lansdorp-Vogelaar, Roman Gulati, +14 authors, Jeanne S Mandelblatt.
Ann Intern Med, 2014 Jul 16; 161(2). PMID: 25023249    Free PMC article.
Long-term effects of mammography screening: updated overview of the Swedish randomised trials.
Lennarth Nyström, Ingvar Andersson, +3 authors, Lars Erik Rutqvist.
Lancet, 2002 Mar 29; 359(9310). PMID: 11918907
Highly Cited. Review.
Estimation and prediction for cancer screening models using deconvolution and smoothing.
P F Pinsky.
Biometrics, 2001 Jun 21; 57(2). PMID: 11414561
Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer.
Gerrit Draisma, Rob Boer, +4 authors, Harry J de Koning.
J Natl Cancer Inst, 2003 Jun 19; 95(12). PMID: 12813170
Highly Cited.
Overdiagnosis in breast cancer screening: the importance of length of observation period and lead time.
Stephen W Duffy, Dharmishta Parmar.
Breast Cancer Res, 2013 May 18; 15(3). PMID: 23680223    Free PMC article.
Conditions for Valid Empirical Estimates of Cancer Overdiagnosis in Randomized Trials and Population Studies.
Roman Gulati, Eric J Feuer, Ruth Etzioni.
Am J Epidemiol, 2016 Jul 01; 184(2). PMID: 27358266    Free PMC article.
Missteps in Current Estimates of Cancer Overdiagnosis.
Christoph I Lee, Ruth Etzioni.
Acad Radiol, 2016 Nov 30; 24(2). PMID: 27894707    Free PMC article.
Decision-Making Regarding Mammography Screening for Older Women.
Mara A Schonberg.
J Am Geriatr Soc, 2016 Dec 06; 64(12). PMID: 27917463    Free PMC article.
Cancer Screening in the Elderly: A Review of Breast, Colorectal, Lung, and Prostate Cancer Screening.
Ashwin A Kotwal, Mara A Schonberg.
Cancer J, 2017 Jul 22; 23(4). PMID: 28731949    Free PMC article.
Estimating the frequency of indolent breast cancer in screening trials.
Yu Shen, Wenli Dong, +2 authors, Ruth Etzioni.
Stat Methods Med Res, 2018 Feb 07; 28(4). PMID: 29402176    Free PMC article.
An exploration for quantification of overdiagnosis and its effect for breast cancer screening.
Lei Yang, Shengfeng Wang, Yubei Huang.
Chin J Cancer Res, 2020 Mar 21; 32(1). PMID: 32194302    Free PMC article.
Global Burden of Thyroid Cancer From 1990 to 2017.
YuJiao Deng, HongTao Li, +12 authors, ZhiJun Dai.
JAMA Netw Open, 2020 Jun 27; 3(6). PMID: 32589231    Free PMC article.
Personalized early detection and prevention of breast cancer: ENVISION consensus statement.
Nora Pashayan, Antonis C Antoniou, +31 authors, Martin Widschwendter.
Nat Rev Clin Oncol, 2020 Jun 20; 17(11). PMID: 32555420    Free PMC article.
Second opinion strategies in breast pathology: a decision analysis addressing over-treatment, under-treatment, and care costs.
Anna N A Tosteson, Qian Yang, +9 authors, Donald L Weaver.
Breast Cancer Res Treat, 2017 Sep 08; 167(1). PMID: 28879558    Free PMC article.