Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial
BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g366 (Published 11 February 2014) Cite this as: BMJ 2014;348:g366
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In this Rapid Response, we take the opportunity to respond both to recent comments on our study (1), as well as previous comments to which we have not already responded.
Ana Rosengurtt (RR 5 March 2014) is concerned about the radiation implicit in mammography. So were we when planning the study. However our computations suggested benefit would exceed any risk from radiation (2), and a subsequent study showed that women exposed to multiple fluoroscopies over the age of 35 had little increased risk of breast cancer (3). During the study, our reference physicist took care to ensure the mammography machines did not emit too much radiation, while maintaining adequate image quality (4). Nevertheless, we agree that unnecessary exposure to radiation should be avoided as far as possible.
Mohammad Tahir (RR 1 March 2014) suggests that screening mammography would offer “survival advantage” if DCIS cases had not been excluded from our analyses. That is not so. Any woman with a previously diagnosed DCIS who developed invasive breast cancer was included in our analyses from the date of diagnosis of the invasive cancer. Any deaths from such cancers were included in our analyses of mortality. There is good evidence that DCIS is not a breast cancer precursor but a marker of future risk of breast cancer. In no breast screening trial has it been demonstrated that detection and treatment of DCIS following screening results in a reduction in subsequent incidence of breast cancer. The results of the follow-up of cases of in situ cancer ascertained in the trial has just appeared on line in the International Journal of Cancer (5).
Mona P. Tan (RR 26 February 2014) is concerned that our study design required informed consent from all participants and that the women in the control arm were not blinded as to their allocation. Implicitly she raises the question as to whether the breast examinations and the teaching of breast self-examination to all women resulted in the null effect of mammography on breast cancer mortality. Application of the Miscan model to our data suggested the breast examinations might have resulted in a 20% reduction in breast cancer mortality (6). However, as the modellers used data from the Two-county trial, the absence of modern adjuvant therapy in that trial (7) may have led to an over-estimation of the effect of the breast examinations. Dr Tan is concerned that absence of mammography in screening could lead to litigation because of delay in diagnosis. Perhaps more critical is that over-diagnosis by mammography screening may lead to litigation for over-treatment and its consequences.
Elsebeth Lynge and Sisse Njor (RR February 2014) comment on small increases in numbers of screen-detected breast cancers in our succeeding reports on mortality in the trial. They are correct in that the increases from 1992 to 2000-2 resulted from delayed registration of cancers in some provincial cancer registries. The difference from 2000-2 to the present report arose from re-coding of histology to ensure that we only considered invasive breast cancers.
J. Tristram C Dammin (RR 19 February 2014) is concerned that we do not make any reference to breast size, shape or "lumpy, bumpy breast" as possible confounding issues that could have nullified our data. Although we did not specifically characterise women as to whether they had “lumpy” breasts, at the first screen referral by the examiners to review by the study surgeon in the centres for abnormalities detected on breast examination was almost identical in the two arms, 14.1% in the mammography arm and 14.6% in the control arm for women age 40-49 (8), and 11.0% and 11.2%, respectively, for women age 50-59 (9). Thus there was no excess in the mammography arm which would have been anticipated had women suspected of having breast cancer been shifted from the control to the mammography arm as postulated by Kopans (RR 12 February 2014). Dr Dammin also asks if our data can be extrapolated to all postmenopausal women. We believe so, there is no major shift in the behaviour of breast cancer at the age of 60, although incidence and competing causes of death (and therefore over-diagnosis) increase with increasing age.
Peter Sasieni (RR 17 February 2014) had asked whether there was a typographical error in Table 3 and that the number presented of fatal breast cancers incident “in year 5” should have been “in years 2-5”. Dr Sasieni is correct, we regret the error.
Martin Heilweil (RR 17 February 2014) comments “The study is silent on treatment for these discovered conditions”. We have no reason to believe treatment decisions were differential between the arms. However, we have data on the initial surgery applied and we performed a special study of treatment given for women age 40-49. Treatment quality was assessed by experienced oncologists blind as to allocation (10). There was no evidence that treatment was inferior in the mammography arm.
Judith Malmgren (RR 14 February 2014) pointed out that at no point in the RCT was there an arm without either initial clinical breast examination, training in self breast examination, or usual care. That is correct, such an arm was considered unethical at the time we initiated the study, in part because of the results of the HIP trial (11), and because the Canadian Cancer Society, a major sponsor of the trial, had adopted a policy of advocating breast self examination (BSE). Many consider there is no benefit from BSE, though there are good observational data from Finland (12) as well as from a nested case-control study within the CNBSS (13) that indicate a benefit. Dr Malmgren comments that a relatively small number of cancers, 32%, were found by mammography alone in the mammography arm of the study. That is true, but she has failed to include the cancers detected by both mammography and breast examination, which brings the total found by mammography to 69% of the screen-detected breast cancers among women age 40-49 (8) and 81% among women age 50-59 (9). Dr Malmgren also states that the mean tumour sizes found in the control arm are not as expected in a study with a nonintervention control arm. However, we suspect that the patient/physician detected (palpable) tumour mean size of 3 cm in her study was based upon a symptomatic group of women, not an asymptomatic group as enrolled in our trial. Her statement that fewer deaths from breast cancer were seen among the mammography detected tumors compared to the palpable tumors is true, but the figures she quotes should be corrected for the over-diagnosis resulting from mammography. She also comments “All breast cancer discovered in this RCT had a hefty breast cancer death rate of 20 to 33% presenting a situation in which it does not appear any of the breast cancer discovered was not going to present harm to the patient during her lifetime.” When the estimated number of over-diagnosed breast cancers is deducted from the denominator in the mammography arm, the proportion of women with screen-detected breast cancers who died from breast cancer during the 25-year follow-up becomes 32% in the mammography arm compared to 33% in the control.
Carmen Vidal and Montse Garcia (RR 14 February 2014) wondered why we did not stratify the analysis according to age groups. In fact we reported under the heading Breast Cancer Mortality: “For women aged 40-49 at assignment the hazard ratio for 25 year breast cancer specific mortality associated with mammography was 1.09 (95% confidence interval 0.80 to 1.49; P=0.58) and for women aged 50-59 at assignment was 1.02 (0.77 to 1.36; P=0.88).” (1) As the results were similar, we did retain this stratification throughout our report. Vidal and Garcia also suggested we should use a “population approach” to the estimation of over-diagnosis. We were interested in their table 1, but this does not give an adequate depiction of the extent of over-diagnosis in relation to screen-detected cancers. They ask why we chose the 15-year point to compute the extent of over-diagnosis, as did Lynge and Njor (RR 19 February 2014). Fifteen years was when the differential between the numbers of breast cancers ascertained in the two arms became stable, indicating that the effect of lead time in the mammography arm was past. Subsequently, towards the end of the period of follow-up, the numbers of breast cancers newly ascertained falls off in each arm, and the differential between the arms suffers from random fluctuation. Computing over-diagnosis at the end of the period of screening results in confounding by lead time. The proportion of screen-detected cancers over-diagnosed at 10 years is 21%, and at the end of follow-up 24%.
References
1. Miller AB, Wall C, Baines CJ, Sun P, To T, Narod SA. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial. BMJ 2014.348:g366 doi: 10.1136/bmj.g366.
2. Howe GR, Sherman GJ, Semincew RM, Miller AB. Estimated benefits and risks of screening for breast cancer. CMA Journal 1981; 124:399-403.
3. Miller AB, Howe GR, Sherman GJ et al Mortality from breast cancer after radiation during fluoroscopic examination in patients being treated for tuberculosis. New Engl. J. Med. 1989; 321:1285-89.
4. Yaffe M, Mawdsley GE, Nishikawa RM. Quality assurance in a national breast screening study. Proc Soc Photo-Optical Instrum Eng 1983; 419: 23-30.
5. To T, Wall C, Cornelia J. Baines CJ, Miller AB. Is carcinoma in situ a precursor lesion of invasive breast cancer? Int. J. Cancer 2014; 00: 00–00.
6. Rijnsburger AI, van Oortmarssen GJ, Boer R, Draisma G, To T, Miller AB, de Koning
HJ. Mammography benefit in the Canadian National Breast Screening Study-2:
a model evaluation. Int J Cancer 2004;110:756–62.
7. Tabar L, Chen H-HT, Duffy SW, Kruesmo UB. Primary and adjuvant therapy, prognostic factors and survival in 1053 breast cancers diagnosed in a trial of mammography screening. Jpn J Clin Oncol 1999;2129:608–16.
8. Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Screening Study: 1. Breast cancer detection and death rates among women aged 40 to 49 years. CMAJ 1992; 147:1459-76.
9. Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Screening Study: 2. Breast
cancer detection and death rates among women aged 50 to 59 years. CMAJ 1992; 147:1477-88.
10. Kerr M: A Case-Control Study of Treatment Adequacy and Mortality from Breast Cancer for Women of Age 40-49 Years at Entry into the National Breast Screening Study (master's thesis), U of Toronto, Toronto, 1991.
11. Shapiro S, Strax P, Venet L. Periodic breast cancer screening in reducing mortality from breast cancer. JAMA 1971;215:1777-85.
12. Gastrin G, Miller AB, To T, Aronson KJ, Wall C, Hakama M et al. Incidence and mortality from breast cancer in the Mama program for breast screening in Finland, 1973-1986. Cancer 1994; 73:2168-74.
13. Harvey BJ, Miller AB, Baines CJ, Corey PN. Effect of breast self-examination techniques on the risk of death from breast cancer. Can Med Assoc J 1997;157:1205-12.
Competing interests: No competing interests
Miller’s recent article on the results of the Canadian National Breast Screening Study [1] has been heavily criticized for errors in the randomisation employed, leading to more challenging patients being disproportionately assigned to the mammography arm of the trial [2, 3]. Miller has made the claim that randomisation was done appropriately [4]. However, it should be noted that Miller’s own mortality data [1] is supportive of the criticisms raised against his study [2, 3]. The hazard ratio comparing breast cancer mortality from women in the mammography arm to women in the control arm during the first round of screening was reported as 1.47 [1], implying that being assigned to the mammography arm was associated with substantially increased risk of dying of breast cancer (based on the results of the first round of screening only). This is a remarkable imbalance regarding the hazard associated with death from breast cancer between the mammography arm and the control arm and the most likely explanation is that the criticisms regarding the randomisation employed in this trial are valid [2, 3]. Women presenting to the trial with pre-existing concerns regarding their breast health were most likely regularly assigned to the mammography arm of the trial for this study’s results to demonstrate such a marked increase in the hazard of breast cancer mortality in the mammographic screening arm based exclusively on the first year of the trial.
It is not ideal to assess a disease screening technology based on the first round of screening (even in trials that have randomized their subjects appropriately). When we consider a patient who died of cancer detected in the first round of a screening trial, we simply won’t know whether the technology would have contributed to saving that patient’s life had the patient been enrolled in screening earlier on in the progression of their disease. As such, it is more reliable to form conclusions regarding the efficacy of a screening technology based on its results from the second round of screening onwards. Incidentally, the authors provide this data which indicates a mortality benefit (hazard ratio 0.9) from the use of mammographic screening after the first year of the trial. This indicates that mammography has contributing to lowering breast cancer mortality after the initial overly challenging cases were attended to in the first year of screening. This hazard ratio (0.9) reporting a mortality benefit from mammography after the first year of screening did not achieve a p-value below 0.05 and as such was not deemed statistically significant and was apparently ignored when establishing the study’s conclusions. However, it is doubtful that this calculation included enough breast cancer mortality samples to achieve sufficient statistical power for the statistical significance test to be reliably relied upon. Had the authors collected many more samples that continued to produce an identical hazard ratio of 0.9, the finding would have been statistically significant as it is known that the amount of separation required between two groups in order to achieve statistical significance diminishes as the number of samples increases. It is unfortunate that the total number of samples contributing to this study’s mortality calculations from cancer detected in screening rounds 2 through 5 is so limited, as this study’s mortality results (much like this study’s survival results) appear positive for mammography.
Jacob Levman, PhD
Institute of Biomedical Engineering
University of Oxford
[1] A B Miller, et al. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial, British Medical Journal, 2014;348:g366.
[2] D B Kopans, Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial, British Medical Journal, 2014;348:g366, Feb. 12th 2014.
[3] L K Tabar, Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial, British Medical Journal, 2014;348:g366, Feb. 18th 2014.
[4] A B Miller, Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial, British Medical Journal, 2014;348:g366, Feb. 17th 2014.
Competing interests: No competing interests
Dear Dr. Jerome S. Schroeder,
Please check your references.
You accuse BMJ of being one-sided in the breast screening question and cite “recently published results” that favor the intervention claiming they support your argument. However, neither the 25% breast cancer mortality reduction, nor the 4% overdiagnosis rate in Denmark that you mention is “recently published results”. The paper you allude to [1] is in fact a position paper that mostly sums up previously published results. In fact, the above mentioned results were published in two separate papers in BMJ [2,3].
We have also published results based on Danish data, including in the BMJ, but reached quite different results [4,5]. In short, the full 25% reduction was claimed to occur within the first 3 years after screening was introduced [2] and therefore cannot be related to screening, as the effect takes 5-10 years to materialise [4]. In the period where breast screening could have an effect, mortality rates declined to a similar extent in both screened and non-screened areas and we could not detect an effect of Danish breast screening in our analyses [4]. The low estimate of overdiagnosis do not fit the observed data [5] and is likely caused by a diluting effect caused by long follow-up with inclusion of all cancers detected long after screening stops. It is simply wrong when you state that the position paper shows that breast screening has lowered mastectomy rates in Denmark, as the paper contains no formal analyses of this and therefore cannot show anything about it [1]. We published data on Danish mastectomy rates in 2011 [6]. After large increase in mastectomy use in the screened areas at introduction, mastectomy rates declined in a similar fashion in both screened and non-screened areas alike due to national changes in treatment policy unrelated to screening [6]. We showed the same for Norway [7].
I would like to thank Dr. Schroeder for demonstrating so clearly to us all how emotion and good intentions can overcome a rational and courteous approach to the debate on breast screening. This can make individuals jump to conclusions; make them accept messages that they like without attention to detail; and make them be quick to dismiss messages they do not like along with those who send them and ascribe them hidden malicious motives.
1. Christiansen P, Vejborg I, Kroman N, Holten I, Garne JP, Vedsted P et al. Position paper: Breast cancer screening, diagnosis, and treatment in Denmark. Acta Oncol 2014; Early Online:1-12.
2. Njor SH, Olsen AH, Blichert-Toft M, Schwartz W, Vejborg I, Lynge E. Overdiagnosis in screening mammography in Denmark: population based cohort study. BMJ 2013;346f1064.
3. Olsen AH, Njor SH, Vejborg I, Schwarz W, Dalgaard P, Jensen MB, Tange UB, Blichert-Toft M, Rank F, Mouridsen H, Lynge E. BMJ 2005;330:220.
4. Jørgensen KJ, Zahl PH, Gøtzsche PC. Overdiagnosis in organsed breast screening in Denmark. A comparative study. BMC Womens Health 2009;9:36.
5. Jørgensen KJ, Zahl PH, Gøtzsche PC. Breast cancer mortality in organised mammography screening in Denmark. A comparative study. BMJ 2010;340:c1241.
6. Jørgensen KJ, Keen J, Gøtzsche PC. Is Mammographic Screening Justifiable Considering its Substantial Overdiagnosis Rate and Minor Effect on Mortality? Radiology 2011;260:621-7.
7. Surhke P, Mæhlen J, Schlichting E, Jørgensen KJ, Gøtzsche PC, Zahl PH. Mammography screening and surgical breast cancer treatment in Norway: comparative analysis of cancer registry data. BMJ 2011;343:d4692.
Competing interests: No competing interests
It was reassuring to have authors` response (RR 10th March 2014) to Ana Rosenguurt`s concerns about radiation exposure in mammographic screening itself (her RR 5th March 2014), agreeing that `unnecessary exposure to radiation should be avoided as far as possible`.
However, in this particular case in Uruguay, mammographic screening is compulsory for every female worker age 40-59. [1] Under these extreme circumstances where consent is denied and human rights have been violated, I think we might agree that no amount of imposed radiation is acceptable.
A petition has been raised to demand the abolition of compulsory mammography in Uruguay, demanded as a requirement of the official health card. [2] As the petition declares, denying the right to work for a woman for refusing screening for breast cancer is a policy “that is missing science and ethics”. It is to be hoped that the scientific community and citizens will rally to put an end to this abuse.
[1] Arie, S. Uruguay`s mandatory breast cancer screening for working women aged 40-59 is challenged. BMJ 2013:346:f1907 doi:10.1136/bmj.f1907
[2] Uruguay mandatory mammography – petition for presentation to the Ministry of Public Health, Uruguay. https://secure.avaaz.org/es/petition/MAMOGRAFIA_OBLIGATORIA_EN_URUGUAY_U...
Competing interests: No competing interests
Professor Dr. Peter C. Gøtzsche very wisely has synthesized in only one sentence all this issue: "If mammography screening had been a drug, it would have been withdrawn from the market" (http://www.cmaj.ca/content/183/17/1957.full). That is, drugs are expected to benefit to most of the people they are produced for and may harm only a few otherwise they are withdrawn from the market right away before a blast of lawsuits blows up.
Screening with mammography harms every healthy woman who undergoes it: the false negatives, the false positives, the overdiagnosed ones, all the true negatives round after round will accumulate radiation and all the true positives as well, because round after round mammography will produce the result with an activating agent claiming it is a detecting test for a previous condition.
It is unethical to require informed consent to such a fraudulent screening test.
Competing interests: Screening with mammography is compulsory in Uruguay for every female worker age 40-59. A petition has been set up that calls for an end to it: https://secure.avaaz.org/es/petition/MAMOGRAFIA_OBLIGATORIA_EN_URUGUAY_UN_PROBLEMA_CIENTIFICO_Y_UN_ABUSO_ETICO
Dear Dr. Godlee:
I was very disappointed that your journal once again decided to publish the unreliable results of the Canadian NBSS trial in your recent edition. Touting inaccurate analyses of inaccurate data does not make them any more believable or true. Creating sensational headlines in papers like the NY Times contributes to the confusion of patients and providers alike to the point of inaction. Your journal has been a leading mouthpiece of anti-mammography articles, often publishing papers of dubious review and merit.
One author who frequently finds a home in your journal is Peter Goztsche from the Nordic Cochrane Center. He is, perhaps, the most vocal and prolific anti-mammography voice out there.
I am sure that you saw the recently published results from Denmark's own fledgling screening programs. Denmark was reluctant to start nationwide screening in the 1990s and only 20% of the population has been getting regular screens since then (due to the influence of one of their own 'sons' in Dr. Gotzsche?). They have been rolling out nationwide screening over the last few years and the results published recently show the intelligence behind this decision. They have shown a 25% mortality decline, only a 4% over-diagnosis rate, lower mastectomy rates and higher breast conservation rates in the population that has been receiving screens. This is in direct contradiction to the articles you frequently publish claiming 'zero' mortality benefit of mammographic screening. In fact, every country which has introduced service screening programs has seen their breast cancer mortality rates drop.
I am wondering if you have heard from Dr. Gotzsche and whether or not he plans to retract his prior stance on screening and if your journal or he plans an apology for your biased stance against screening. In Denmark alone, more than 4000 women would still be alive today if they had been offered screening over the last 20 years or so. Thousands more women will die worldwide if they and their providers believe the misinformation that you are spreading.
Another thing, I thought it was interesting that, on the BMJ website, under your profile, you list no competing interests or financial incentives linked to your position as editor-in-chief. Seems to me that your position on the Advisory Board of the Nordic Cochrane Center and their prolific production of anti-mammography publications is a severe conflict of interest and one which should, at minimum, be disclosed on every document originating from that institution.
Sincerely,
Jerome S. Schroeder, MD
Breast Imaging Radiologist
Denver, CO USA
Competing interests: No competing interests
Mammography as screening test does not fit the fifth principle of Wilson and Jungner classic screening criteria:
"5. There should be a suitable test or examination."
Who set mammography as suitable?
Mammography is not a suitable test as the tool it uses is a very well known carcinogenic agent: radiation. A screening test for any cancer should avoid radiation as PSA, cervical cytology and test for fecal occult blood do. It must be selected another kind of screening test for breast cancer.
Trials on mammography are a big fraud as the test used is not suitable because it produces a tainted result: it uses an activating agent as a detecting test.
Competing interests: Screening with mammography is compulsory in Uruguay for every female worker age 40-59. I'm age 53 and I'm litigating uruguayan health authorities in order to stop violating human rights. http://www.bmj.com/content/348/bmj.g390?ijkey=c6S57MpN9FUaoz2&keytype=ref http://www.bmj.com/content/346/bmj.f1907
Screening mammography would offer survival advantage if DCIS cases were not excluded from the Canadian trial.
The debate about use of mammographic screening for breast cancer has confused many women after the recent publication by Miller et al. [1] indicating no survival benefits from mammography as part of the Canadian National Breast Screening Study. There have been many arguments far and against, some valid and some less valid. However, an important error in the trial has been ignored, correcting which the study, even in its present form, confirm the significant value of screening mammography and its survival advantage.
The Canadian trial [1] included women with only ‘invasive breast cancer’ and compared their survival in the screening and control group. The trial excluded a considerable number of women who were diagnosed with ductal carcinoma in situ (DCIS). It is important to understand the mechanics of DCIS, as by excluding this group of women, the screening arm in the trial is greatly disadvantaged. DCIS though a pre-invasive stage of breast cancer, is considered and treated as breast cancer. DCIS comprise about 25% of all invasive and non-invasive breast cancers diagnosed through screening mammography [2]. The risk of progression from DCIS to invasive breast cancer (IBC) varies with grade. Available data [3,4] suggests that about one in three patients with DCIS will develop invasive cancer over the course of 10 years. High grade DCIS are more likely to become invasive cancer after a shorter interval [5].
Now, the question arises, is there any survival difference between women who are treated for DCIS compared to those who are left alone and treated only when they develop invasive breast cancer? There have been no trials on the subject; however, ten-year survival for women who are treated for DCIS is about 100% [2] compared to 70.6% survival in women who are diagnosed and treated for IBC [1]. Had women in the Canadian trial not treated for DCIS, many of them would have developed invasive cancer and their survival would be in the range of 70% similar to other screen detected IBCs. Therefore, to ascertain the actual value of screening, women with DCIS and IBC must be considered together in the screening arm and compared with the control group. Considering 70% survival for screen detected IBCs and 100% survival for DCIS, women with screen detected breast cancer (IBC+DCIS) would have an estimated survival of around 78%. This leaves no doubt about the value of screening mammography when compared to 62.8% survival in the control group.
DCIS cases, however, do take time to progress to invasive cancers – a stage only when they could affect survival. This could potentially cause a lead-time bias in the screening group survival. However, the lead-time bias would ultimately be covered by the long follow up (25 years) in the trial. Therefore, the only logical way to find the real value of mammographic screening is by comparing survival of women with DCIS and IBC in the screening arm to those in the control arm.
References:
1. Miller AB, Wall C, Baines CJ, Sun P, To T, Narod SA. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial. BMJ 2014.348:g366 doi: 10.1136/bmj.g366.
2. Virnig BA, Shamliyan T, Tuttle TM, et al. Diagnosis and Management of Ductal Carcinoma in Situ (DCIS). Rockville (MD): Agency for Healthcare Research and Quality (US); 2009 Sep. (Evidence Reports/Technology Assessments, No. 185.) 1, Introduction. Available from: http://www.ncbi.nlm.nih.gov/books/NBK32580/
3. Page DL, Dupont WD, Rogers LW, Landenberger M. (1982). Intra- ductal carcinoma of the breast: follow-up after biopsy only. Cancer. 1982;49:751–758.
4. Page DL, Dupont WD, Rogers LW, Jensen RA, Schuyler PA. (1995). Continued local recurrence of carcinoma 15–25 years after a diagnosis of ductal carcinoma in situ of the breast treated only by biopsy. Cancer. 1995;76:1197–1200.
5. A Evans. Breast Institute, City Hospital, Nottingham, UK. Ductal carcinoma in situ (DCIS): are we overdetecting it? From Symposium Mammographicum 2004 Edinburgh, UK. 19th – 20th July 2004. Breast Cancer Res 2004, 6(Suppl 1):P23doi:10.1186/bcr842.
Competing interests: No competing interests
The work by Dr Miller et al 1 provides additional information on the outcomes of mammographic screening. There are, nonetheless, issues in the study that bear consideration on the applicability of the data.
The study design required informed consent from all participants. They were thus aware that in this trial there would be two groups – one undergoing annual mammography, and another, assigned to no mammography but placed under the care of their family doctor. In addition, those in the latter group were asked to complete four annual questionnaires. This is therefore not a blinded study, and those in the ‘no mammography’ group could perceive that they are in a disadvantaged position, resulting in a state of heightened awareness. Since they were not excluded from further diagnostic tests, symptoms of uncertain significance would prompt an assessment with a clinician earlier than if they were ignorant of the study. This could explain the smaller mean size of tumours in the control group of the Canadian study when compared with the Swedish Two-County study.2
Women who were in the control group were given annual questionnaires. This would serve as a reminder to see their family doctor for an annual clinical breast examination, which could be viewed as ‘screening’. It could be argued that this procedure is not consistent with the objective of the study which was to compare breast cancer incidence and mortality up to 25 years in women aged 40-59 who did or did not undergo mammography screening. It may be more appropriate to term the study objective as ‘a comparison between mammographic screening and clinical screening’. In the Swedish Two-County study, it may be assumed that women who were not invited for screening were unaware that a study was in progress and perhaps could be truly said to be ‘blinded’. Therefore, the results may be more representative of the effect of mammographic screening.
It has been shown that women undergoing screening have a higher breast conservation rate.3,4 This fact, coupled with a recent study by Agarwal et al,5 based on the Surveillance, Epidemiology and End-Result (SEER) data that demonstrated a higher cancer-specific survival for women who underwent breast conservation treatment (BCT), should serve as an argument for mammographic screening. Screening allows detection of smaller tumours, and intuitively affords a better chance at BCT and possibly higher survival. In line with this concept, Miller et al reported that 25 year survival for women with tumours of less than 2 cm was 77.1% while that for patients with tumours greater than 2 cm was 54.7% (hazard ratio 0.46, p<0.001). The mean size of the cancers diagnosed in the mammography arm was 1.91 cm while that for the control arm was 2.10 cm. Yet, there appeared to be no difference in cumulative mortality for the two arms. This data is perplexing and begs clarification.
Delayed diagnosis is an important cause for medical litigation against clinicians treating breast disease in a technically advanced country.6 Failure to perform a mammogram for the assessment of symptoms of uncertain clinical significance and interpretive mammographic errors contribute to diagnostic delays, leading to exposure to medical malpractice. Therefore, it is unlikely that breast screening with clinical examination alone without mammograms is a practicable alternative in today’s litigious climate. The ultimate test of the Canadian data is if it can be used for a successful medicolegal defence of diagnostic delays in the presence of technology available for mammographic screening.
References
1. Miller AB, Wall C, Baines CJ, Sun P, To T, Narod SA. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial. BMJ 2014.348:g366 doi: 10.1136/bmj.g366.
2. Tabar L, Vitak B, Chen TH, Yen AM, Cohen A, Tot T, et al. Swedish two-county trial: impact of mammographic screenin on breast cancer mortality during 3 decades. Radiology 2011;260:658-63.
3. Chuwa, EW, Yeo AW, Koong HN et al. Early detection of breast cancer through population-based mammographic screening in Asian women: a comparison study between screen detected and symptomatic breast cancer. Breast J 2009:15:133-139
4. Wang WV, Tan SM, Chow WL. The impact of mammographic breast cancer screening in Singapore: a comparison between screen-detected and symptomatic women. Asian Pacific J Cancer Prev 2011;12:2735-2740.
5. Agarwal S, Pappas L, Neumayer L, et al. Effect of Breast Conservation Therapy vs Mastectomy on Disease-Specific Survival for Early-Stage Breast Cancer. JAMA Surg doi:10.1001/jamasurg2013.3049
6. Brenner RJ. Medicolegal aspects of breast imaging: variable standards of care relating to different types of practice. Am J Roenterology 1991;156:719-23.
Competing interests: No competing interests
Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial
The screening battle has now achieved cold war proportions. Switzerland as a vanguard has pulled its screening program and others seem to be considering the same, based on responses to this article.
What happens when you don't screen? They don't screen in Iran or Pakistan or most of Asia and what is found is that the prevalence of breast cancer is up to 80% less than in Europe or USA. They find that breast cancer presents much later and the mortality figures are similar to those of EU and USA. What is starkly different is the ratio of breast cancer incidence to breast cancer mortality. In non screened countries the death rate from breast cancer is very close to the incidence rate, presumably because they present late and do not have comprehensive treatments. In the screened countries the incidence rates are multiples of the death rates because the treatments are available and also because they present earlier. If you were to take the screening out of the EU and USA the death rates would climb up to the incidence rates, as is the natural process in those countries with no screening. So screening works. It successfully reduces the death rates (as published on Cancer Research UK website) to 18 per 100,000 population from an incidence of 90 per 100,000 population in EU.
Examples are: the breast cancer incidence in East Africa is 19 per 100,000 population and the death rate is 11.4. In South Africa the incidence is 38 per 100,000 population and the death rate is 19. The incidence in South Eastern Asia is 26 per 100,000 population and the death rate is 14. In USA the incidence is 76 per 100,000 population and the death rate is 15. In Western EU the incidence is 90 per 100,000 and the death rate is 18.
Even allowing for incomplete data these figures are impressive and consistent. They suggest that if screening was introduced into third world countries the death rate would fall to 20% of the incidence rate.
The other aspect of these data is why is breast cancer so common in developed countries and much less common in third world countries. Deaths are very countable no matter what country you look at and late breast cancer is easily detected, and so the raw data of breast cancer deaths is a good surrogate for incidence in non-screened countries. This implies that the incidence actually is as low as is reported.
The three consistent robust and parallel patterns seen world wide are increasing breast cancer incidence, reduced birth rate and increased use of exogenous female hormones.1.
1. The Screech Owls of Breast Cancer. Author House. 2013.
Competing interests: No competing interests