Heidi D. Nelson, MD, MPH; Kari Tyne, MD; Arpana Naik, MD; Christina Bougatsos, BS; Benjamin K. Chan, MS; Linda Humphrey, MD, MPH
This systematic review is an update of evidence since the 2002 U.S. Preventive Services Task Force recommendation on breast cancer screening.
To determine the effectiveness of mammography screening in decreasing breast cancer mortality among average-risk women aged 40 to 49 years and 70 years or older, the effectiveness of clinical breast examination and breast self-examination, and the harms of screening.
Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the fourth quarter of 2008), MEDLINE (January 2001 to December 2008), reference lists, and Web of Science searches for published studies and Breast Cancer Surveillance Consortium for screening mammography data.
Randomized, controlled trials with breast cancer mortality outcomes for screening effectiveness, and studies of various designs and multiple data sources for harms.
Relevant data were abstracted, and study quality was rated by using established criteria.
Mammography screening reduces breast cancer mortality by 15% for women aged 39 to 49 years (relative risk, 0.85 [95% credible interval, 0.75 to 0.96]; 8 trials). Data are lacking for women aged 70 years or older. Radiation exposure from mammography is low. Patient adverse experiences are common and transient and do not affect screening practices. Estimates of overdiagnosis vary from 1% to 10%. Younger women have more false-positive mammography results and additional imaging but fewer biopsies than older women. Trials of clinical breast examination are ongoing; trials for breast self-examination showed no reductions in mortality but increases in benign biopsy results.
Studies of older women, digital mammography, and magnetic resonance imaging are lacking.
Mammography screening reduces breast cancer mortality for women aged 39 to 69 years; data are insufficient for older women. False-positive mammography results and additional imaging are common. No benefit has been shown for clinical breast examination or breast self-examination.
Agency for Healthcare Research and Quality.
BSE = breast self-examination; CBE = clinical breast examination; MRI = magnetic resonance imaging.
* Includes radiation exposure, pain, psychological responses, false-positive and false-negative test results, and overdiagnosis.
BSE = breast self-examination; CBE = clinical breast examination; SR = systematic review; USPSTF = U.S. Preventive Services Task Force.
* Cochrane databases include the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews.
† Other sources include reference lists and studies suggested by experts.
‡ Some articles are included for more than 1 key question.
Appendix Table 1.
CNBSS-1 = Canadian National Breast Screening Study-1; CrI = credible interval; HIP = Health Insurance Plan of Greater New York.
* Swedish Two-County trial.
Appendix Table 2.
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Annals of Internal Medicine
November 20, 2009
The Editors' Response
"In response to media reports that imply otherwise, Annals of Internal Medicine did not schedule the publication of the US Preventive Services Task Force recommendations about breast cancer screening to coincide with a particular date or event. The background papers (which underwent several rounds of revision over about 5 months based on independentpeer review comments and Annals' statistical editor's comments) and the recommendation statement were all in final, accepted form by September 10, 2009. Annals scheduled them to appear in the next available print issue, which was the November 17th issue. Our routine print production process takes about 2 months from final acceptance to print." The Editors
Karsten J. Jorgensen
The Nordic Cochrane Centre
Overdiagnosis with breast screening was seriously underestimated
Nelson et al. calculate the reduction in breast cancer mortality based on the randomised trials (1), but for the most important harm, overdiagnosis, they present no calculations. They quote a mixture of observational studies and results from statistical models with unverifiable and doubtful assumptions. Only for the Malmo trial do they quote real data, but these data were obtained 15 years after the trial ended, when many additional cancers had occurred in both arms of the trial. When we corrected for this dilution, and for the fact that 24% of the women in the control group were also screened during the trial, we found 25% overdiagnosis (2), rather than the 10% reported by the authors.
It is indefensible that Nelson et al. base their estimate of overdiagnosis on flawed studies when there are data from about 600,000 randomised women, which we pooled in our Cochrane systematic review in 2009 (3), and before that in 2006 and 2001. We found 31% more lumpectomies and mastectomies. In July, we reported 52% overdiagnosis in a systematic review of publicly organised mammography screening programmes, without using assumptions or statistical modelling (4). It is also curious that Nelson et al. do not quote our Cochrane review, as they searched the Cochrane Library.
Nelson et al. reported that most studies found between 1% and 10% overdiagnosis. However, systematic reviewing is not a consensus conference, it is a scientific discipline, and Nelson et al. overlook that the small estimates of overdiagnosis are based on poor science, mostly produced by researchers with vested interests in screening. If one opens one's eyes, unaided by any statistical tricks, one cannot escape seeing a huge amount of overdiagnosis, e.g. in the UK (4,5).
The U.S. Preventive Services Task Force now recommends against breast screening in women aged 40-49 years, but it may be the case for all age groups that the harms outweigh the benefits. An effect of 15% and an overdiagnosis of 30% mean that for every 2000 women invited for screening throughout 10 years, one will have her life prolonged and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily (3). Furthermore, in USA about 1000 women will have experienced a false positive diagnosis (3). The psychological strain until one knows whether or not it was cancer can be severe. The harms caused by overdiagnosis are life-long.
1. Nelson HD, Tyne K, Naik A, Bougatsos C, Chan BK, Humphrey L. Screening for Breast Cancer: An Update for the U.S. Preventive Services Task Force. Ann Intern Med 2009; 151: 727-37.
2. Gotzsche PC, Jorgensen KJ. Estimate of harm/benefit ratio of mammography screening was five times too optimistic. http://bmj.bmjjournals.com/cgi/eletters/332/7543/691, 2006.
3. Gotzsche PC, Nielsen M. Screening for breast cancer with mammography. Cochrane Database Syst Rev 2009;(4):CD001877.
4. Jorgensen KJ, Gotzsche PC. Overdiagnosis in publicly organised mammography screening programmes: systematic review of incidence trends. BMJ 2009; 339: b2587.
5. Jorgensen KJ, Gotzsche PC. It is time for a new paradigm for overdiagnosis with screening mammography. http://www.bmj.com/cgi/eletters/339/jul09_1/b2587 - 218754, 2009.
Johannes Van Netten
University of Victoria
December 8, 2009
Mammographic screening in pre and post menopausal women: what is the difference?
Regarding the recent controversy about screening mammography (1) an important aspect of tumor biology, namely the effect of wounding on cancer tissue growth, has been overlooked (2). The difference in compression forces used in mammographic screening between pre- and postmenopausal women may shed some light on this phenomenon.
Premenopausal women often have denser breasts than postmenopausal women due to the presence of more epithelial tissue embedded in dense stroma and less fatty tissue. More compressive force is needed in premenopausal women in order to obtain a useful image. Recommendations in a well-known radiology journal have been made that describe that breast tissue should be compressed to the point where it is Ã¢"Â˜sufficiently flattened, the skin taut, or the limits of the patientÃ¢"Â™s tolerance to pressure have been reachedÃ¢"Â™ (3). This statement is simply unbelievable, as it may well have formed a baseline for screening mammography for years following. As if this is not enough, women are often advised to take analgesics before painful mammograms, which masks pain so that even more pressure can be applied. The safety of such advice has not been established. In living biological systems pain is a universal warning sign of tissue damage that should not be ignored. Nobody would squeeze a dangerous skin infection for fear of spreading the disease. How can this be allowed in cancer diagnosis? Normal breast tissue is soft and spreads easily under pressure, carcinoma is hard and will bear the brunt of the compression. Younger women with denser breasts will be exposed to more compressive forces and more potential tissue damage than older women, particularly during diagnostic spot compression. We propose that the negative effect of mammographic compression on tumors has counteracted the anticipated benefit of 10 years of additional screening in younger women. Tissue damage caused by increased compression during mammography could also contribute to the observed difference in effectiveness of mammography and increased mortality rate in black versus white women (4). Since the average age for black women of breast cancer detection is 46 years of age and for white women it is 57, breast cancer is mainly a pre-menopausal disease for blacks and for whites it is mainly postmenopausal, resulting in more intense pressure in black women (4). It has been said before, Ã¢"ÂœA routine screening method that does not involve intense compression should be actively pursuedÃ¢"Â (5).
1. Nelson HD, Tyne K, Naik A, Bougatsos C, Chan BK, Humphtey L. Screening for Breast Cancer: An Update for the U.S. Preventative Screening Task Force. Ann Intern Med. 2009; 151(10): 727-737.
2. Stuelten CH, Barbul A, Busch ji, Sutton E, Katz R, Sato M, et al. Acute Wounds Accelerate Tumorigenesis by a T-Cell Dependent Mechanism. Cancer Res. 2008; 68(18): 7278-7282.
3. Russell DG, Ziewacz JT. Pressures in a simulated breast subject to compression forces comparable to those of mammography. Radiology 1995; 194: 383-387.
4. Retsky MW, Demicheli R, Gucas ID, Hrushesky WJM. Enhanced Surgery-Induced Angiogenesis among Premenopausal Women might partially explain Excess Breast Cancer Mortality of Blacks compared to Whites. Int J Surgery 2007; 5(5): 300-304.
5. Van Netten JP, Mogentale T, Ashwood-Smith MJ, Fletcher C, Coy P. Physical Trauma and Breast Cancer [Letter]. Lancet. 1994; 343: 978-779.
Nananda F Col
Center for Outcomes Research and Evaluation, Maine Medical Center
December 17, 2009
Rationing Health Care or Rational Health Care for Breast Cancer Screening?
The US Preventative Services Task Force's guidelines sensibly conclude that the decision about mammography should be an individual one, reflecting the patient's values regarding specific benefits and harms.(1) However, the Task Force did little to enable women to understand these risks and benefits and did not help women to make sound choices about screening. For women in their 40s, a 55% chance of a false alarm (2) to prevent one breast cancer death for every 1900 women screened was considered unacceptable. Curiously, they reached the opposite conclusion for women in their 50s, where "only" a 46% chance of a false alarm to prevent one breast cancer death for 1300 women screened is acceptable. The difference between 1 in 1300 and 1 in 1900 (0.053% vs. 0.077%) is so small that it is difficult to imagine a woman for whom it would matter, making this an odd policy distinction. This is a classic "close call" or "toss-up," and either choice should be acceptable.(3)
Other factors to consider are the psychological stress of treatment and the reassurance of having "done everything possible" by being screened. Women are entitled to know the chances that mammography will uncover a treatable cancer and the chances that screening will lead to useless, risky treatment. Reasonable women could make different choices, depending on how they feel about these risks and benefits. Rather than having numbers dictate their decision, women should decide how high a risk they want to take for how much potential benefit.
The public debate sadly veered to whether the Task Force served the interests of bureaucrats, eager to ration medical care, and insurance companies, eager to deny coverage. But history is repeating itself. A dozen years ago, an NIH consensus panel created similar guidelines and similarly suggested that women in their 40's 'decide for themselves' about screening.(4) Public reaction was similar: widespread concern that the recommendations were driven by health care costs, not science.(5) We should have learned that the motivation behind guidelines is easily misconstrued and that the public does not trust expert panels.
Patients cannot make informed medical decisions without adequate information that is clearly communicated. The difference between rationing health care and rational health care lies in who makes the decision. If policy makers or insurers limit the availability of tests, it feels like rationing. However, if informed patients choose to forego tests that are less effective, it becomes rational decision making.
1. Clinical Guidelines: Screening for Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med, November 17, 2009 151:716-26.
2. Christiansen CL, Wang F, Barton MB, Kreuter W, Elmore JG, Gelfand AE, Fletcher SW. Predicting the Cumulative Risk of False-Positive Mammograms. J Natl Cancer Inst 2000;92:1657-66.
3. Kassirer JP, Pauker SG. The "Toss Up". NEJM 1981;305:1467-69.
4. NIH Consensus statement. Breast Cancer Screening for Women Ages 40-49. NIH Consensus Statement. January 21-23, 1997;15:1-35.
5. Woloshin S, Schwartz L, Byram SJ, Sox HC, Fischhoff B, Welch GH. Women's understanding of the mammography screening debate. Arch Int Med 2000;160:1434-40.
Heidi D. Nelson
Oregon Health & Science University, Portland, Oregon
January 12, 2010
Authors' Response to Letters: Screening for Breast Cancer: An Update for the USPSTF
We agree with comments from Dr. Dickersin and colleagues that findings of our systematic review for the U.S. Preventive Services Task Force (1) and relevant Cochrane reviews (2, 3) provide corroborative evidence about benefits and harms of breast cancer screening. When we completed our final literature search in December 2008, the existing Cochrane review had not yet included the Age trial in its meta-analysis of mammography trials. This was added to the 2009 Cochrane meta-analysis with similar results as our estimate (2).
We also agree with points raised by Drs. DeFrank and Brewer regarding transience of effects of false-positive mammography results. In our paper, we state that results of studies are mixed, and "in several studies, women had persistent anxiety, despite eventual negative [biopsy] results, whereas some showed only transient anxiety." Certainly, the long- term adverse effects of false-positive mammography results can be important and we did not intend to minimize this problem.
Drs. Jorgensen and Gotzsche raise important issues about studies of overdiagnosis. We did not include the papers they cite because they were published after our review was completed. We also identified many problems with the available studies including inconsistent methods, use of different outcome measures, not reporting results by age, and lack of estimates specific to U.S. populations. As a result, we determined that studies were too heterogeneous to combine statistically and we described them qualitatively. Most agree that overdiagnosis is an important adverse effect of screening, but data to accurately estimate its magnitude and appropriately apply this information to patient decision-making in U.S. practice are not yet available.
2. Gotzsche PC, Nielsen M. Screening for breast cancer with mammography. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD001877. DOI: 10.1002/14651858.CD001877.pub3.
3. Kosters JP, Gotzsche PC. Regular self-examination or clinical examination for early detection of breast cancer. Cochrane Database of Systematic Reviews 2003, Issue 2. Art. No.: CD003373. DOI: 10.1002/14651858.CD003373.
Oregon Evidence-based Practice Center, Oregon Health & Science University
August 12, 2010
Screening for Breast Cancer: An Update for the U.S. Preventive Services Task Force
We agree with Dr. Saika and colleagues that adjusting for follow-up time when estimating the number needed to invite (NNI) to mammography screening to prevent one breast cancer death provides more comparable results across age groups. However, the purpose of our meta-analysis was primarily to determine the effectiveness of mammography screening in reducing breast cancer mortality among women in their 40s, not to determine differences between age groups (1). Number needed to invite estimates are a way of illustrating magnitudes of effect that may be more relevant to clinical applications than relative risks for some audiences. These estimates were calculated in the 2002 review (2) and we provided them in the updated review for consistency. Results indicate imprecise point estimates with overlapping confidence intervals that do not differentiate the three age groups in both the unadjusted NNI estimates and estimates adjusted for follow-up time provided by Dr. Saika and colleagues.
In general, NNI estimates would be expected to decrease with longer follow-up periods for any event that accumulates over time, and Dr. Saika and colleagues results are consistent with this. However, their results are also a consequence of dividing the NNI estimates by the follow-up period, thereby imposing an inverse relationship by definition, rather than allowing the data to reveal such a relationship. Their calculations also assume that the mortality rate is the same across all follow-up periods, which may not be accurate, and for 20 years after screening, a time period for which data are not yet available.
The U.S. Preventive Services Task Force (USPSTF) enlisted a more rigorous approach than using NNI estimates to evaluate ages to initiate and discontinue screening by commissioning statistical models from the Cancer Intervention and Surveillance Modeling Network (CISNET) (3). The USPSTF final recommendations (4) were based on their determination of the balance of benefits and harms of screening mammography for specific age groups from multiple data sources detailed in our evidence review (1) and the CISNET report (3). Our NNI estimates were only one piece of this puzzle.
Also, to clarify, we included the Canadian National Breast Screening Study-2 (5) in our analysis of women age 50-59 years, although the reference in our review was incorrectly cited as the Canadian National Breast Screening Study-1.
2. Humphrey LL, Helfand M, Chan BK, Woolf SH. Breast cancer screening: a summary of evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002;137:347-60.
3. Mandelblatt JS, Cronin KA, Bailey S, Berry DA, de Koning HJ, Draisma G, et al. Effects of mammography screening under different screening schedules: model estimates of potential benefits and harms. Ann Intern Med 2009;151:738-747.
4. U.S. Preventive Services Task Force. Screening for breast cancer: U.S. Preventive Services Task Force recommendations. Ann Intern Med 2009;151:716-726.
5. Miller AB, To T, Baines CJ, Wall C. Canadian National Breast Screening Study-2: 13-year results of a randomized trial in women aged 50- 59 years. J Natl Cancer Inst 2000; 92:1490-9. [PMID: 10995804]
Nelson HD, Tyne K, Naik A, Bougatsos C, Chan BK, Humphrey L. Screening for Breast Cancer: An Update for the U.S. Preventive Services Task Force. Ann Intern Med. 2009;151:727–737. doi: 10.7326/0003-4819-151-10-200911170-00009
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