Screening for breast cancer—balancing the debate

Reducing breast cancer burden

The incidence of breast cancer has risen by 50% since 1980, although age standardised mortality is thankfully falling (by 35%).8 The reduced mortality is mainly down to a valiant concentration on therapeutics, research, and practice and a strong commitment to rationalise cancer services in the NHS. But screening has had its effect too: both on the rise in incidence and on the fall in mortality. Quantifying these relative effects when much else is changing simultaneously is where the problems arise. Reducing incidence must be the primary goal, with reducing mortality an important but secondary end point. Mammography unavoidably increases incidence considerably by bringing the diagnosis forward but also by diagnosing cancer that would never become apparent and by false positive results. The last two result in overdiagnosis and overtreatment and have no effect on mortality. Thus real mortality reductions attributable to mammography must be large and secure to justify this possible harm.

Early breast cancer and DCIS

Enthusiasm for breast screening has uncovered a disease hitherto much less common and correspondingly poorly studied: ductal carcinoma in situ (DCIS). Mammography may also detect invasive tumours that are not going to cause any trouble during the rest of a woman’s life. And mammography itself is minimally carcinogenic. We do not know enough about DCIS to know how to treat it optimally, and we have imprecise measures of the extent of overtreatment.

DCIS represents about 20% of screen detected cancers.8 The population incidence shoots up above the age of 50. Half of women with DCIS detected will develop invasive disease,9 as far as we know. Previously most were treated with mastectomy; nowadays more are treated with lumpectomy and radiotherapy. Around 15% of women with treated DCIS, have a recurrence within 10 years; hence treatment can be withheld only when the prognosis is more specific than it can be now—for example, by more reliably taking account of grade or necrotic tendency. This is a dilemma for women,10 both in deciding whether to go for routine mammography in the first place and in what to do when confronted with a diagnosis of DCIS.

Overdiagnosis

If we assume the US estimates of effect are correct and apply them to UK death rates, then over 15 years the rate of prevented deaths in a screened population ranges from 0.06% of women at age 40 to 0.40% at age 60. We need then to be able compare these estimates reliably with risks of overdiagnosis, including some DCIS. An overdiagnosed case is one in which a cancer is detected and treated that would never have presented clinically. Clearly this is an unobservable entity in individual women. The only way to estimate the extent of overdiagnosis, just as for reductions in mortality, is to compare the number of accumulated cases of breast cancer in a screened population with that in a comparable unscreened population over a long period. The difference between the two groups after a long period would provide an estimate of the extent of overdiagnosis.

Evidence from randomised trials is essential here for many reasons. Use of hormone replacement therapy has changed greatly since the 1980s, mainly because it was shown to increase the risk of breast cancer.11 It also affects the sensitivity and specificity of mammography.12 Obesity has also increased, and that too increases risk of breast cancer among postmenopausal women. If use of hormone replacement therapy and obesity are associated with the uptake of screening, which is highly likely,13 then unscrambling that confounding will be impossible. Sophisticated modelling will not help either.

A recent analysis from the Nordic Cochrane Centre claims that overdiagnosis constitutes one third of breast cancers detected in screening programmes.14 And in 2006 Zackrisson et al, who followed up 43 283 women aged 45-69 in the Malmo randomised trial of mammographic screening, estimated that 10% of cancers in the screening group were overdiagnosed after 15 years of follow-up.15 This is 0.93% of screened women. There were 150 more women diagnosed with cancer in the screened group than in the randomised control group at the end of the trial’s original 10 year follow-up, and 115 after 25 years.16

More recently, Duffy and colleagues have responded to these varying estimates of overdiagnosis in screening programmes by analysing the Swedish Two County Trial of 55 985 women aged 40-74.17 They argue that the lives saved by screening greatly outnumber overdiagnosed cases, estimating overdiagnosis to be 0.43% and lives saved as 0.88% at 20 years (table⇓). However, the US task force estimates give a figure for lives saved of about 0.4% for women over 60 with optimistic assumptions. The 0.88% is likely to be a “random high” because the two counties trial observed an unusually large reduction in mortality. The estimate of overdiagnosis from this trial is very low (0.43% is roughly approximately 0.30% at 15 years) compared with that of Zackrisson et al (0.30% v 0.93%). But it is higher than the authors have previously estimated from multistage modelling, which is important because these original modelling analyses were crucial in designing the NHS screening programme.

But it is misleading to accept Duffy et al’s estimate as if it comes from a randomised trial. They estimate overdiagnosis by comparing incidence observed with regression estimates of the trend in incidence before the control group was offered screening and give no direct comparison of the observed diagnosed cases over time in the two groups. Other things also need clarifying: why did they not discuss Zackrisson et al’s15 estimate of overdiagnosis in their report when they did criticise the Nordic Cochrane Centre, and why did they not discuss DCIS?

The Nordic Cochrane Centre has responded at considerable length,18 providing substantive justification and pointing to possible conflicts of interest in Duffy et al’s publication. Duffy et al’s response dismisses this as “off topic” and comments that they “do not have the leisure” to fully enumerate the centre’s inaccuracies. And still Zackrisson is not discussed.

The US task force estimates, from five trials in which the control group did not receive mammography, that the excess incidence of invasive and ductal carcinoma in situ is between 0.007% and 0.073% a year.19 These are approximately equivalent to 0.10% and 0.73% at 15 years, with UK incidence data. The low figure comes from a 1960s trial that is probably less relevant now, and the high figure is from Zackrisson et al. Apart from this two Canadian trials are the most informative, being recent and with 13 years’ follow-up. Among women aged 50-59, the cumulative excess risk (and hence overdiagnosis) in the screened arm of these trials was 0.34%. Hence the estimate from Zackrisson does look high. But the Canadian trial used here compared annual mammography and physical examination with annual physical examination, not a control group and found no mortality reduction associated with mammography.20 Physical examination in both groups could therefore attenuate the effect on overdiagnosis of mammography.

Sorting out the evidence

Mammography does save lives, more effectively among older women, but does cause some harm. Do the benefits justify the risks? The misplaced propaganda battle seems to now rest on the ratio of the risks of saving a life compared with the risk of overdiagnosis, two very low percentages that are imprecisely estimated and depend on age and length of follow-up. Duffy et al say this ratio is about 2 (0.88%/0.43%) whereas Zackrisson et al put it at about 0.2 (0.18/0.93). So are women more likely to be overdiagnosed than to have their life saved by screening mammography? Even if women knew the answer balancing the two would be deeply problematic, but such differences in estimates for this ratio are unacceptable (table⇑).

Estimates of rates of overdiagnosis are less secure than estimates of mortality because they were not the primary outcome measure, and consequently estimation is possible in only three randomised studies. The US task force, using estimated averages, says that the studies are too heterogeneous to combine statistically.

Arguments that polarise are unhelpful and render women, many with strong preferences, more helpless. For too long they have been misled and confused by too much agenda driven analyses of these data. What is required now is a full examination of all the data, preferably individual patient data, from all the recent studies, by dispassionate epidemiologists to get the best estimates in the UK screening setting. Synthesis of observed data from trials and the screening service could surely now be put to better use by, for example, the National Institute for Health and Clinical Excellence, with collaboration, in six months.

Meanwhile the NHS screening programme needs to be really clear about these uncertainties when communicating with women, and organisers of current trials need to be clear about how much of this uncertainty will be addressed, with what precision, and by when. More importantly, we all need to understand better how a national programme of such importance could exist for so long with so many unanswered questions. Maybe the breast screening service exists on its face validity plus concomitant scientific polarisation in the face of uncertainty? That would be irresponsible.