Evidence-based or rage-based scientific debate? The case of screening mammography for premenopausal women

April 2, 2010
Manuel Vázquez Caruncho, MD

Baum stated after delivering a lecture about the U.K. breast cancer screening in the USA: "I learned a painful lesson that day: that some topics, particularly breast cancer screening, do not lend themselves to polite and rational scientific debate."

Baum stated after delivering a lecture about the U.K. breast cancer screening in the USA: "I learned a painful lesson that day: that some topics, particularly breast cancer screening, do not lend themselves to polite and rational scientific debate."(1) The irate reactions that the U.S. Preventive Services Task Force report (2) and the article by Kopans in Diagnostic Imaging(3) have been producing are good examples of the Baum complaints.

Kopans says "few of us have sufficient interest or time to review all of the data under discussion and to determine what are the actual facts," and "very few physicians, and certainly few radiologists, have taken the time to understand the data." He goes further to formally accuse those who do not share his views of "unscientific data analysis" and "misuse of science." He also states "what has been repeatedly overlooked is that truths exist."

Misuse of data? Let's look at an example: "This result [that screening is responsible for at least two thirds of the decrease of breast cancer deaths] is also shown in Berry's computer model."(3) The Berry et al article says the contribution of screening varied from 28% to 65% and the contribution variability of screening was larger than that of treatment.(4) This range of values is quite different than "at least two thirds." On the other hand, Kopans' passion leads him to accept the lesser value of therapy compared with screening in the decline of breast cancer mortality, when there is interplay between early detection and better treatments, as Berry et al have pointed out.

His article misquotes Jorgensen and Gotzsche on overdiagnosis(5) claiming they have suggested mammography finds cancers that would have "melted away" instead of quoting the correct article by Zhal et al on this topic.(6)

Kopans points accusingly to those who do not agree with him of "manipulation of facts," when the most common example of it is concealing data. As far screening is concerned, promoters usually oversell its effects by reporting the relative risk reduction. This datum has no meaning without its base, that is, the absolute risk reduction. A 30% reduction is quite impressive and has a great impact, but we can get it with absolute risk reductions of 0.075, 0.0075, and 0.00000075. Women are only told relative risk reductions. As a result, they are not well informed. Seventy-one percent believe screening reduces breast cancer deaths by 50% to 100%.(7) In a recent survey, 92% of women overestimated the benefits of mammography screening.(8) "There is no question that some organizations have engaged in some hyperbole, but radiologists involved in these debates have always made it clear that mammography screening is far from perfect and does not save all lives." In a recent commentary, one can read that USPSTF guidelines "have placed women's lives at stake" and that "false positive results […] are no reason to sacrifice the lives saved by screening mammography."(9) "Women's lives at stake" and "to sacrifice the lives" is some sort of hyperbole, isn't it?

"Randomized, controlled trials were not designed to evaluate women ages 40 to 49 separately."(10) There are two randomized controlled trials that specifically address mammography screening in women under their fifties: The Canadian NBSS1 (11) and the Age trial.(12) The Canadian trial has been harshly criticized by, among others, Kopans. Nevertheless, this trial has withstood the criticisms.(13)

The conclusion of these two trials is there is no decrease of breast cancer mortality in the screening group. Pooling the studies shows a decrease of mortality of 12% (OR Mantel-Haenzsel: 0.88; 95% CI [0.72 to 1.03]; Heterogeneity test χ2 = 0.71; df = 1; p = 0.4). Curiously enough, the control group of the Age trial showed a 20% relative decrease of mortality, suggesting the effects of improvements in diagnosis and treatment. Furthermore, Moss et al have combined the results for women 40 to 44 of the Swedish trials with those of her trial and showed a 16% reduction in mortality (0.84; 95% CI [0.69 to 1.01]).

The pooled absolute risk reduction is 0.00035 (95% CI: -0.00011 to 0.00081). That means we need to screen 2841 women over 10 years to avert a breast cancer death (95% CI: -9433 to 1233).

The Age trial is already included in several systematic reviews (2, 22, 23) and adds new information in order to update the previous results. A woman wants to know what her chances are of dying of breast cancer if screened and if not screened. These probabilities are 0.0023 and 0.0019, so the reduction of risk attributed to mammography is 4/10.000. This figure is quite a bit less impressive than a 16% risk reduction. Women also want to know what their chances are of having breast cancer. This probability is not one in eight, as is usually stated, but the incidence of breast cancer in each country; let's say 110/100.000, as that is the average estimate for the European Union.

The harms of screening are not well explained to women. Any screening implies a test (mammography in this case) to probably healthy women, so harms are frequent, no matter how mild they are. There are more than reasonable doubts about the downsides of screening in premenopausal women, as has been pointed out elsewhere.(2,5,11,16-18) Radiation risks, overdiagnosis, lead time, anxiety, and false positives are a fee to pay. The mortality excess in the screened population is particularly worrisome. It was explained on the grounds of statistical fluctuation, but this effect appeared in six trials (HIP, Two-County, Malmo, Stockholm, Canadian NBSS-1, and Edinburgh).(18) As an explanation, Demichelli et al proposed an attractive hypothesis about dormant metastases that deserves more deep research.(20)

Experts do not agree about the amount of the overdiagnosis bias (21, 22), which is estimated between 5% and 50%, if ductal carcinoma in situ is included. Women with an overdiagnosed cancer will undertake overtreatment and some of them will die or have severe side effects from surgery, radiation therapy, hormone therapy, and chemotherapy. This fact has not been properly quantified, but women must be told about it.

A very controversial topic is that of radiation-induced breast cancer. Berrington de Gonzalez and Reeves have calculated that a decade of annual two-view mammographic screening before age 40 would result in a net increase in breast cancer deaths, and that starting at age 40 could result in a material net decrease only if breast cancer mortality is reduced by about 20% or more in women screened.(18) This would be not the case if we assume the results of the two randomized trials that specifically address screening in women under 50 years of age.

False positive rates are also of concern. Screening mammography has a cultural and social component that can't be ignored and receiving a false positive result will not be the same for a U.S. woman as for a European one. European women who receive a false positive result are less likely to return for routine screening than U.S. women are.(23) A woman will also want to know how much time she would gain if her cancer were diagnosed by screening mammography. It has been calculated the potential gain would be five days per woman, as an average.(13)

The 50-year figure is arbitrary, of course, as is the 40-year one or p = 0.05 for statistical significance. Medical practice is full of these kinds of thresholds that, despite their rigidity, are useful in decision making. Age 50 is a surrogate for menopause, perhaps not the best, but it is one derived from the difficulty of determining the actual age of menopause.

From a scientific point of view, menopausal status has biological meaning. Breast cancer behaves differently before and after menopause, (23) so the actual point is screening of pre- and postmenopausal women, and 50 years is as valid a cutoff point as 5% for statistical significance.

It is undeniable that the transition to pre- and postmenopause is gradual. Smith et al(24) consider probably reasonable the 50-year threshold because: 1) The detection rates of tumors at first screening are lower in the 40 to 49 age group, even after taking into account the lower incidence of breast cancer at this age; 2) Interval cancers were considerably higher in the 40 to 49 age group; 3) Screening sensitivity is somewhat lower; 4) The mortality reduction in the 40 to 49-year group appears later than in the over-50 group; 5) Estimation of tumor progression rates indicates that tumors develop more rapidly in younger women, both in terms of growth and dissemination and in terms of transition from asymptomatic screen-detectable disease to clinical symptomatic disease; and 6) There are proportionally more ductal grade 3 carcinoma and medullary carcinoma cases in the 40 to 49 age group.

Another interesting point is the screening schedule. There are only two randomized trials that addressed this topic (25, 26), but the United Kingdom Co-ordinating Committee for Cancer Research (UKCCCR) did not include women under 50. The screening interval should be less than half of the sojourn time (27). Estimates suggest sojourn time among women aged 40 to 49 would be 1.3 to 2.5 years and 3 to 6.5 years in women aged 50 to 74 (28), so a yearly mammogram would be adequate for pre-menopausal women and a biennial mammogram for the post-menopausal ones. A recent cost-effectiveness analysis (15) concluded biennial mammography screening is cost-effective for women in the 50 to 59 age group, but not in the age 40 to 49, nor 70 to 75 groups. The incremental cost-effectiveness ratios were $29,139/quality adjusted life year (QALY) and $26,439/life year gained (LYG) for the 50 to 59 age group. They were $235,676/QALY and $237,702/LYG for the 40 to 49 group, and $235,160/QALY and $246,743/LYG for the 70 to 75 group. These results are consistent with others published elsewhere (30-32). For women in the age group 50 to 69, biennial screening is as effective as annual (15, 30), so additional costs are hardly justifiable.

Things go beyond the line when Kopans writes "many European countries, as well as Canada, do no support, or at any rate encourage, screening before the age of 50 and have lied to their populations by suggesting that the data did not show a benefit." To lie is to make a statement that one knows to be untrue with intent to deceive.

European screening programs are evidence-based and adhere to strict quality standards (33) that are far more demanding than those in the U.S.(34) Several papers have shown the differences between U.S. and European breast cancer screening. As an example, recall and open biopsy rates are higher in the U.S. for the same detection rate.(35,36)

Two trials that specifically addressed breast cancer screening in women age 40 to 49 years (11, 12) and an overview (37) failed to show a decrease in breast cancer mortality in the screening group. Cost-effectiveness analysis recommended biennial screening, as has already been pointed out.

We Europeans are very proud of our health systems and of our screening programs, where no one- despite his or her economical and social status, is denied medical care, including screening.

Many people do not share Kopans' views, or his distasteful and irate way of manifesting them. Fortunately, far from being unscientific, disagreement contributes to the advance of science.

References

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2. US Preventive Services Task Force. Screening mammography: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;151:716-26.

3. Kopans D. Why the critics of screening mammography are wrong. Diagnostic Imaging 2009;31. Availabe at: http://www.diagnosticimaging.com/display/article/113619/1493126?pageNumber=6.

4. Berry DA, Cronin KA, Plevritis SK, et al. Cancer Intervention and Surveillance Modeling Network (CISNET) Collaborators. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005 Oct 27;353(17):1784-92. 5. Jørgensen KJ, Gøtzsche PC. Overdiagnosis in publicly organised mammography screening programmes: systematic review of incidence trends. BMJ. 2009;339:b2587.

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11. Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Cancer Screening Study: 1. Breast cancer detection and death rates among women aged 40-49. Can Med Assoc J 1992;147:1459-1476.

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19. Cox B. Variation in the effectiveness of breast screening by year of follow-up. J Ntal Cancer Inst Monogr 1997;22:69-72. 20. Demichelli R, Retsky MW, Hrushesky WJM, et al. The effects of surgery on tumor growth: a century of investigations. Ann Oncol 2008;19:1821-28.

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