The Nordic Cochrane Centre's comments on "Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. Lancet 2012 Oct 30."

(http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961611-0/fulltext)

1 November 2012

The independent UK Panel's report is a step in the right direction, as it has narrowed down the uncertainty about breast screening. The Panel estimated that one breast cancer death is prevented for every 3 overdiagnosed and overtreated cases. In contrast, researchers with a conflict of interest in relation to mammography screening have recently published estimates that are 6 to 7.5 times more positive than those from the Panel. Statistician Stephen Duffy - who has been very influential in the NHS Breast Screening Programme - and colleagues estimated in 2010 that between 2 and 2.5 lives are saved for every overdiagnosed woman.1 In 2012, the EUROSCREEN working group, which has Duffy as one of its coordinators, estimated that 7 to 9 lives are saved for every 4 overdiagnosed women.2 We have shown why these estimates are false.3-6

The estimate in our Cochrane review of mammography screening7 is that one breast cancer death is avoided for every 10 overdiagnosed cases, i.e. a 3 times less positive estimate than that of the UK Panel.

We believe the Cochrane estimate comes closer to the truth than the Panel's estimate and shall explain why. The Panel did not to pay attention to the most important issues described in the written testimony the Nordic Cochrane Centre submitted to the Panel before Peter Gøtzsche gave oral testimony on 8 March 2012.8

Our Cochrane review from 2009 was the source of the data for the Panel's estimation that screening reduces breast cancer mortality by 20%. However, the Panel did not differentiate between the more reliable and the less reliable trials, as we did, but combined them. We assessed the reliability of the trials using standard Cochrane criteria and found that the four best trials did not show a significant reduction in breast cancer mortality at 13 years (relative risk (RR) 0.90, 95% confidence interval (CI) 0.79 to 1.02). We tentatively suggested an effect of 15%, but doubted whether there was any effect at all, which is clear from the abstract of our Cochrane review:

"We found that breast cancer mortality was an unreliable outcome that was biased in favour of screening, mainly because of differential misclassification of cause of death. The trials with adequate randomisation did not find an effect of screening on cancer mortality, including breast cancer, after 10 years (RR 1.02, 95% CI 0.95 to 1.10) or on all-cause mortality after 13 years (RR 0.99, 95% CI 0.95 to 1.03)."

Thus, the overall estimate of the effect is not robust. This is an important finding that should have been considered by the Panel. Instead of paying attention to this, the Panel introduces an assumption that is clearly wrong. The Panel says that, "Although adjudication of the cause of death has been one of the major criticisms of some of the trials, the Panel does not think that it would exaggerate the estimates of relative risk obtained from individual trials, or from a meta-analysis of trials."

It is unconvincing that the Panel does not "think" that assessment of cause of death is a problem. We have documented in our report submitted to the Panel,8 in our Cochrane review7 and elsewhere9 that it is a huge problem, which inevitably biases the trials in favour of screening, even when blinded endpoint commmittees have been used.7 Misclassification of cause of death often concerns other cancers, and it is therefore important to point out that screening did not decrease cancer mortality (including breast cancer), although this would have been expected if screening had an effect.7

Another example of an erroneous assumption is when the Panel says that, "In the absence of data to the contrary, the Panel concluded that the benefits of screening and those of better treatments are likely to be independent, and thus that the estimates of the relative reduction in breast cancer mortality achieved with screening are similar now to when the trials were undertaken."

This is another gross error and the assumption is clearly not true. Imagine if the improvements in treatment that have been introduced since the trials were done meant that everyone would be cured by the treatment. Then screening could have no effect. But one needs not go to such extremes. Imagine a woman who would have died without screening in the old days but now lives so much longer that she dies of a heart attack. Also for such women, screening can have no effect.

Thus, we cannot use the old randomised trials to tell us what a likely effect of screening is today. We have to look at more recent, good observational studies. It is inexcusable that the Panel decided to ignore observational studies completely. Recent, rigorous observational studies have failed to show an effect of screening.8

An equally important omission is that the Panel did not discuss recent studies on the size and stages of cancers. These studies have shown that screening has not reduced the occurrence of large cancers or cancers in stages III or IV per 100,000 women.10,11 That was the whole rationale for screening, and if it doesn't happen, screening cannot work.

Other important problems in the Panel's report

1. "The Panel noted that all-cause mortality is not an appropriate outcome for trials of breast screening because the trials were not designed with sufficient power for this outcome."

Whether an outcome is appropiate or not has nothing to do with whether the trials had sufficient power to study it. What matters is whether the outcome is reliable, and since mortality from breast cancer is not reliable, we need to look at other outcomes. As stated above, screening did not reduce total mortality. It did not reduce mortality from all cancers (incl. breast cancer) either, although the trials collectively had power to detect such a difference if it existed. This suggests that women don't live longer if they go to screening.

2. "The Panel applied a relative reduction of 20% to achieve the observed cumulative absolute risk of breast cancer mortality within the ages 55-79 years in the UK."

This substantial extrapolation of the results from the trials, which ran for only 5-9 years, is not appropriate. Data from Denmark - which has an ideal control group, as 80% of the country was not screened for 17 years - failed to find any effect of screening on breast cancer mortality.12

3. "The Panel thinks that the best estimate of overdiagnosis for a population invited to be screened is roughly 11%."

The Panel based its estimate of overdiagnosis on trials that ran for only 7-9 years and, furthermore, the Panel did not include all the data (data from younger women were left out from the Malmö trial) and even diluted their estimate substantially by adding cancers to both groups detected up 15 years (in Malmö) after screening stopped. The estimate of overdiagnosis in the Cochrane review was 29%, and observational studies have found 33% overdiagnosis in Denmark (which, as noted, has an ideal control group) and 52% in a systematic review of countries with organised screening programmes.13

4. The Panel concludes that "Breast screening extends lives."

As noted above, it has never been shown that women live longer, on average, if they go to screening. It is also important to be aware that some of the healthy overdiagnosed women will die from their treatment, which is usually radiotherapy and sometimes chemotherapy. Also for this reason, it is unacceptable to use breast cancer mortality as the outcome; we should use total mortality and total cancer mortality (as radio- and chemotherapy cause cancer).

5. The Panel concludes that, "the UK breast screening programmes confer significant benefit and should continue. For each woman, the choice is clear."

It is a value judgment whether the benefits are greater than the harms and scientists cannot make this judgment on behalf of the women. The women should decide for themselves, after adequate and honest information, and the choice is not at all clear. Some women will say no to screening, which many already did before the Panel's report.

To help women make informed decisions about screening, The Nordic Cochrane Centre produced a screening leaflet, which it published in the BMJ in 2009 alongside a critique of the leaflet from the NHS Breast Screening Programme,14 which is still vastly inadequate and misleading.4 The Nordic Cochrane Centre's leaflet was updated in 2012 and now exists in 14 languages on our website (www.cochrane.dk). It has been translated by volunteers who felt that also in their country, women were not being honestly informed about breast screening.

Peter C Gøtzsche
Professor and director, DrMedSci, MD, MSc

References

  1. Duffy SW, Tabár L, Olsen AH, et al. Absolute numbers of lives saved and overdiagnosis in breast cancer screening, from a randomised trial and from the breast screening programme in England. J Med Screen 2010;17:25-30.
  2. EUROSCREEN Working Group. Summary of the evidence of breast cancer service screening outcomes in Europe and first estimate of the benefit and harm balance sheet. J Med Screeen 2012;19 Suppl 1:5-13, DOI: 10.1258/jms.2012.012077.
  3. Gøtzsche PC, Jørgensen KJ, Zahl P- H. Breast screening: why estimates differ by a factor of 20-25. J Med Screen 2010;17:158-9.
  4. Gøtzsche PC, Jørgensen KJ. The Breast Screening Programme and misinforming the public. J R Soc Med 2011;104:361-9.
  5. Gøtzsche PC. Mammography screening: truth, lies and controversy. London: Radcliffe Publishing; 2012.
  6. Gøtzsche PC. Why the results from the EUROSCREEN Working Group are false. 2012 Oct 11. http://www.cochrane.dk/screening/EuroScreen-2012-critique.pdf.
  7. Gøtzsche PC, Nielsen M. Screening for breast cancer with mammography. Cochrane Database Syst Rev 2009;4:CD001877.
  8. Gøtzsche PC. Benefit and harms of mammography screening, and invitations to screening. Written statement for the UK hearing on mammography screening, 8 March 2012. 2012 Feb 27. http://www.cochrane.dk/screening/Statement for UK Panel.pdf.
  9. Gøtzsche PC. Relation between breast cancer mortality and screening effectiveness: systematic review of the mammography trials. Dan Med Bull 2011;58:A4246.
  10. Autier P, Boniol M, Middleton R, et al. Advanced breast cancer incidence following population-based mammographic screening. Ann Oncol 2011;22:1726-35.
  11. Kalager M, Adami HO, Bretthauer M, et al. Overdiagnosis of invasive breast cancer due to mammography screening: results from the Norwegian screening program. Ann Intern Med 2012;156:491-9.
  12. Jørgensen KJ, Zahl P-H, Gøtzsche PC. Breast cancer mortality in organised mammography screening in Denmark: comparative study. BMJ 2010;340:c1241.
  13. Jørgensen KJ, Gøtzsche PC. Overdiagnosis in publicly organised mammography screening programmes: systematic review of incidence trends. BMJ 2009;339:b2587.
  14. Gøtzsche P, Hartling OJ, Nielsen M, et al. Breast screening: the facts - or maybe not. BMJ 2009;338:446-8.