Harms from breast cancer screening outweigh benefits if death caused by treatment is included

Each new intake of medical students to my surgical “firm” started off with a tutorial where I posed a rhetorical question: “Why do we screen for cancer?” To which the inevitable answer would be, “To catch it early, sir.” Wrong. The question should be reframed, as “Does screening for cancer improve length or quality of life?” All other outcomes are surrogates.

The clinical trials of screening for breast cancer that informed the recent Marmot review1 made no attempt to measure quality of life, but a surrogate for that might be mastectomy rate in screened compared with unscreened populations. On that measure alone, screening fails: the hazard ratio for mastectomy of 1.2 favours the unscreened population.2

So, does screening improve length of life? Sadly, the Marmot committee chose to duck that one and rely on another surrogate outcome measure, cause specific mortality, with the rather lame excuse that the trials weren’t powered to detect any impact on all cause mortality. Well shame on them, I say. The ProtecT trial of prostate specific antigen screening for prostate cancer gives equal weight to cause specific and all cause mortality by accepting that overdiagnosis and overtreatment might lead to an increase in all cause mortality.3 Here I estimate the additional non-breast cancer deaths that might be the consequence of screening for breast cancer.

The CRC1 trial was published in the BMJ in 1989.4 Patients were randomised to mastectomy with or without radiotherapy. This cohort of 2800 women was recruited contemporaneously with those in the old randomised trials of screening by mammography. Note in figure 1 of this paper that the 10 year survival was about 55%. Also, after about eight years of follow-up the curves for deaths other than breast cancer begin to separate, favouring those women who avoided radiotherapy.

In 2008, nearly 20 years later, I coauthored a paper in the Lancet reporting an update of the ATAC trial, which compared adjuvant tamoxifen with adjuvant anastrozole for postmenopausal women with early breast cancer.5 The 10 year survival in that cohort was 80% (five year survival was approximately 90%).

The two key points are that, as systemic therapy improves, the window for the impact of screening narrows substantially,6 and as overdiagnosis rates increase then the importance of the relatively rare lethal toxicities of treatment increase.

If we accept the Marmot estimate of reduction in cause specific mortality of 20%, then, as adjuvant systemic therapy developed over the years since the data accumulated to provide this estimate, we would now have to screen 2500 women for 10 years to avoid one breast cancer death (box 1). This estimate is much lower than in the Marmot report, which dismissed the impact of improvements in treatment.

Now consider overdiagnosis. The most important and comprehensive examination to date was recently published, a few weeks after the Marmot report.7 Bleyer and Welch estimate that about 30% of all cancers, or 50% of those detected by screening, are overdiagnosed each year in the United States. This is similar to that reported by the Nordic Cochrane Centre.2 In absolute terms this is 70 000 cases a year of women told that they have breast cancer, yet their pathology will not become life threatening. The UK has a fifth of the population of the US, and if the NHS breast screening programme (NHSBSP) widens its age limits to match the US, 14 000 more women a year would be exposed to the risks of treatment with no hope of benefit.

The Early Breast Cancer Trialists’ Collaborative Group overview of trials involving radiation estimated a relative risk of 1.78 for deaths from lung cancer and 1.27 for deaths from myocardial infarction in the irradiated group.8 These data were relevant when women were recruited into the old screening trials, and despite reassurances that they don’t apply today, I remain concerned. The left anterior descending coronary artery is in the field of treatment and remains at risk despite recent advances.9 This can have devastating long term consequences on cardiopulmonary function among breast cancer survivors.10 As recently as October 2012 the British Institute of Radiology organised a conference on this topic.

For these reasons, any estimates of benefits and harms based on trials reported 20 to 25 years ago, as described in the Marmot report, are irrelevant to the modern practice of medicine. It is exceptionally difficult to calculate the benefit to harm ratios based on all the developments in the past 25 years since the NHSBSP started, but my crude estimate is that for every 10 000 women invited for screening, three to four deaths from breast cancer are avoided (see box 1).

If each of those were translated into total lives saved from all causes then I would remain content but, unfortunately, when 10 000 are screened along the way about 120 to 140 cases will be overdiagnosed with the current age group invited.7 Four fifths of these women would receive radiotherapy and would be at an increased risk of dying of ischaemic heart disease and lung cancer. Knowing the background risks (box 2) and multiplying these by the factors 1.27 and 1.78 gives us increases of 2% for lung cancer and 1.33% for myocardial infarction. Adding that to all cause mortality rates I crudely estimate that an additional one to three deaths might be expected from other causes for every breast cancer death avoided.14