Financial incentives for breast cancer screening undermine informed choice

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

A variety of estimates of the benefits and harms of mammographic screening for breast cancer have been published and national policies vary. To assess the effect of screening for breast cancer with mammography on mortality and morbidity. We searched PubMed (22 November 2012) and the World Health Organization's International Clinical Trials Registry Platform (22 November 2012). Randomised trials comparing mammographic screening with no mammographic screening. Two authors independently extracted data. Study authors were contacted for additional information. Eight eligible trials were identified. We excluded a trial because the randomisation had failed to produce comparable groups.The eligible trials included 600,000 women in the analyses in the age range 39 to 74 years. Three trials with adequate randomisation did not show a statistically significant reduction in breast cancer mortality at 13 years (relative risk (RR) 0.90, 95% confidence interval (CI) 0.79 to 1.02); four trials with suboptimal randomisation showed a significant reduction in breast cancer mortality with an RR of 0.75 (95% CI 0.67 to 0.83). The RR for all seven trials combined was 0.81 (95% CI 0.74 to 0.87). 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 total 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).Total numbers of lumpectomies and mastectomies were significantly larger in the screened groups (RR 1.31, 95% CI 1.22 to 1.42), as were number of mastectomies (RR 1.20, 95% CI 1.08 to 1.32). The use of radiotherapy was similarly increased whereas there was no difference in the use of chemotherapy (data available in only two trials). If we assume that screening reduces breast cancer mortality by 15% and that overdiagnosis and overtreatment is at 30%, it means that for every 2000 women invited for screening throughout 10 years, one will avoid dying of breast cancer and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress including anxiety and uncertainty for years because of false positive findings. To help ensure that the women are fully informed before they decide whether or not to attend screening, we have written an evidence-based leaflet for lay people that is available in several languages on www.cochrane.dk. Because of substantial advances in treatment and greater breast cancer awareness since the trials were carried out, it is likely that the absolute effect of screening today is smaller than in the trials. Recent observational studies show more overdiagnosis than in the trials and very little or no reduction in the incidence of advanced cancers with screening.

1. Summary 1.1 Introduction The breast cancer screening programmes in the United Kingdom currently invite women aged 50–70 years for screening mammography every 3 years. Since the time the screening programmes were established, there has been debate, at times sharply polarised, over the magnitude of their benefit and harm, and the balance between them. The expected major benefit is reduction in mortality from breast cancer. The major harm is overdiagnosis and its consequences; overdiagnosis refers to the detection of cancers on screening, which would not have become clinically apparent in the woman's lifetime in the absence of screening. Professor Sir Mike Richards, National Cancer Director, England, and Dr Harpal Kumar, Chief Executive Officer of Cancer Research UK, asked Professor Sir Michael Marmot to convene and chair an independent panel to review the evidence on benefits and harms of breast screening in the context of the UK breast screening programmes. The panel, authors of this report, reviewed the extensive literature and heard testimony from experts in the field who were the main contributors to the debate. The nature of information communicated to the public, which too has sparked debate, was not part of the terms of reference of the panel, which are listed in Appendix 1. 1.2 Relative mortality benefit The purpose of screening is to advance the time of diagnosis so that prognosis can be improved by earlier intervention. A consequence of earlier diagnosis is that it increases the apparent incidence of breast cancer in a screened population and extends the average time from diagnosis to death, even if screening were to confer no benefit. The appropriate measure of benefit, therefore, is reduction in mortality from breast cancer in women offered screening compared with women not offered screening. In the panel's judgement, the best evidence for the relative benefit of screening on mortality reduction comes from 11 randomised controlled trials (RCTs) of breast screening. Meta-analysis of these trials with 13 years of follow-up estimated a 20% reduction in breast cancer mortality in women invited for screening. The relative reduction in mortality will be higher for women actually attending screening, but by how much is difficult to say because women who do not attend are likely to have a different background risk. Three types of uncertainties surround this estimate of 20% reduction in breast cancer mortality. The first is statistical: the 95% confidence interval (CI) around the relative risk (RR) reduction of 20% was 11–27%. The second is bias: there are a number of potential sources of distortion in the trials that have been widely discussed in the literature ranging from suboptimal randomisation to problems in adjudicating cause of death. The third is the relevance of these old trials to the current screening programmes. The panel acknowledged these uncertainties, but concluded that a 20% reduction is still the most reasonable estimate of the effect of the current UK screening programmes on breast cancer mortality. Most other reviews of the RCTs have yielded similar estimates of relative benefit. The RCTs were all conducted at least 20–30 years ago. More contemporary estimates of the benefit of breast cancer screening come from observational studies. The panel reviewed three types of observational studies. The first were ecological studies comparing areas, or time periods, when screening programmes were and were not in place. These have generated diverse findings, partly because of the major advances in treatment of breast cancer, which have a demonstrably larger influence on mortality trends than does screening, and partly because of the difficulty of excluding imbalances in other factors that could affect breast cancer mortality. The panel did not consider these studies helpful in estimating the effect of screening on mortality. The other two types of studies, case–control studies and incidence-based mortality studies, showed breast screening to confer a greater benefit than did the trials. Although these studies, in general, attempted to control for non-comparability of screened and unscreened women, the panel was concerned that residual bias could inflate the estimate of benefit. However, the panel notes that these studies' findings are in the same direction as the trials. 1.3 Absolute mortality benefit Estimates of absolute benefit of screening have varied from one breast cancer death avoided for 2000 women invited to screening to 1 avoided for about 100 women screened, about a 20-fold difference. Major determinants of that large variation are the age of women screened, and the durations of screening and follow-up. The age of the women invited is important, as mortality from breast cancer increases markedly with age. The panel therefore applied the relative mortality reduction of 20% to achieve the observed cumulative absolute risk of breast cancer mortality over the ages 55–79 years for women in the United Kingdom, assuming that women who began screening at 50 years would gain no benefit in the first 5 years, but that the mortality reduction would continue for 10 years after screening ended. This yielded the estimate that for every 235 women invited to screening, one breast cancer death would be prevented; correspondingly 180 women would need to be screened to prevent one breast cancer death. Uncertainties in the figure of a 20% RR reduction would carry through to these estimates of absolute mortality benefit. Nonetheless, the panel's estimate of benefit is in the range of one breast cancer death prevented for ∼250 women invited, rather than the range of 1 in 2000. 1.4 Overdiagnosis The major harm of screening considered by the panel was that of overdiagnosis. Given the definition of an overdiagnosed cancer, either invasive or non-invasive, as one diagnosed by screening, which would not otherwise have come to attention in the woman's lifetime, there is need for a long follow-up to assess the frequency of overdiagnosis. In the view of the panel, some cancers detected by screening will be overdiagnosed, but the uncertainty surrounding the extent of overdiagnosis is greater than that for the estimate of mortality benefit because there are few sources of reliable data. The issue for the UK screening programmes is the magnitude of overdiagnosis in women who have been in a screening programme from age 50 to 70, then followed for the rest of their lives. There are no data to answer this question directly. Any estimate will therefore be, at best, provisional. Although the definition of an overdiagnosed case, and thus the numerator in a ratio, is clear, the choice of denominator has been the source of further variability in published estimates. Different studies have used: only the cancers found by screening; cancers found during the whole screening period, both screen-detected and interval; cancers diagnosed during the screening period and for the remainder of the women's lifetime. The panel focused on two estimates: the first from a population perspective using as the denominator the number of breast cancers, both invasive and ductal carcinoma in situ (DCIS), diagnosed throughout the rest of a woman's lifetime after the age that screening begins, and the second from the perspective of a woman invited to screening using the total number of breast cancers diagnosed during the screening period as the denominator. The panel thought that the best evidence came from three RCTs that did not systematically screen the control group at the end of the screening period and followed these women for several more years. The frequency of overdiagnosis was of the order of 11% from a population perspective, and about 19% from the perspective of a woman invited to screening. Trials that included systematic screening of the control group at the end of the active part of the trial were not considered to provide informative estimates of the frequency of overdiagnosis. Information from observational studies was also considered. One method that has been used is investigation of time trends in incidence rates of breast cancer for different age groups over the period that population screening was introduced. The published results of these studies varied greatly and have been interpreted as providing either reassurance or cause for alarm. So great was the variation in results that the panel conducted an exercise by varying the assumptions and statistical methods underlying these studies, using the same data sets; estimates of overdiagnosis rates were found to vary across the range of 0–36% of invasive breast cancers diagnosed during the screening period. The panel had no reason to favour one set of estimates over another, and concluded that this method could give no reliable estimate of the extent of overdiagnosis. Were it possible to distinguish at screening those cancers that would not otherwise have come to attention from those that, untreated, would lead to death, the overdiagnosis problem could be much reduced, at least in terms of unnecessary worry and treatment. Currently this is not possible, so neither the woman nor her doctor can know whether a screen-detected cancer is an ‘overdiagnosed' case or not. In particular, DCIS, most often diagnosed at screening, does not inevitably equate to overdiagnosis – screen-detected DCIS, after wide local excision (WLE) only, is associated with subsequent development of invasive breast cancer in 10% of women within 10 years. The consequences of overdiagnosis matter, women are turned into patients unnecessarily, surgery and other forms of cancer treatment are undertaken, and quality of life and psychological well being are adversely affected. 1.5 The balance of benefit and harm The panel estimates that an invitation to breast screening delivers about a 20% reduction in breast cancer mortality. For the UK screening programmes, this currently corresponds to about 1300 deaths from breast cancer being prevented each year, or equivalently about 22 000 years of life being saved. However, this benefit must be balanced against the harms of screening, especially the risk of overdiagnosis. In the panel's view, overdiagnosed cancers certainly occur, but the frequency in a screening programme of 20 years duration is unknown. Estimates from trials of shorter duration suggest overdiagnosis of about 11% as a proportion of breast cancer incidence during the screening period and for the remainder of the woman's lifetime, or equivalently about 19% as a proportion of cancers diagnosed during the screening period. Any excess mortality stemming from the investigation and treatment of breast cancer is considered by the panel to be small and considerably outweighed by the benefits of treatment. Some other harms, including increased anxiety and discomfort caused by screening, are also acknowledged. Notionally, for 10 000 women invited to screening, from age 50 for 20 years, it is estimated that 681 cancers (invasive and DCIS) will be diagnosed, of which 129 will represent overdiagnosis (using the 19% estimate of overdiagnosis) and 43 deaths from breast cancer will be prevented. Given that the treatment for breast cancer has improved, is screening no longer relevant? The panel's view is that the benefits of screening and those of better treatments are reasonably considered independent. Uncertainty about possible interaction between the benefits of screening and of contemporary treatments is not a reason for stopping breast screening. The panel was not asked to comment on costs, both of interventions and the consequences of overdiagnosis. With accurate figures an estimate of cost-benefit could be made and compared with other interventions, but would be a significant piece of work in its own right. An individual woman cannot know whether she is one of the numbers who will benefit or be harmed from screening. If she chooses to be screened, it should be in the knowledge that she is accepting the chance of benefit, having her life extended, knowing that there is also a risk of overdiagnosis and unnecessary treatment. Similarly, a woman who declines the invitation to screening needs to recognise that she runs a slightly higher risk of dying from breast cancer. 1.6 Conclusions and recommendations Breast screening extends lives. The panel's review of the evidence on benefit – the older RCTs, and those more recent observational studies – points to a 20% reduction in mortality in women invited to screening. A great deal of uncertainty surrounds this estimate, but it represents the panel's overview of the evidence. This corresponds to one breast cancer death averted for every 235 women invited to screening for 20 years, and one death averted for every 180 women who attend screening. The panel's best estimate is that the breast screening programmes in the United Kingdom, inviting women aged 50–70 every 3 years, prevent about 1300 breast cancer deaths a year, a most welcome benefit to women and to the public health. However, there is a cost to women's well being. In addition to extending some lives by early detection and treatment, mammographic screening detects cancers, proven to be cancers by pathological testing, that would not have come to clinical attention in the woman's life, were it not for screening - called overdiagnosis. The consequence of overdiagnosis is that women have their cancer treated by surgery, radiotherapy and medication, but neither the woman nor her doctor can know whether this particular cancer would be one that could possibly lead to death, or one that would have remained undetected for the rest of the woman's life. The panel sought to estimate the level of overdiagnosis in women screened for 20 years and followed to the end of their lives. Estimates of overdiagnosis abound, from near to zero to 50%, but there is a paucity of reliable data to answer this question. There has not even been agreement on how to measure overdiagnosis. On the basis of follow-up of three RCTs, the panel estimated that in women invited to screening, about 11% of the cancers diagnosed in their lifetime constitute overdiagnosis, and about 19% of the cancers diagnosed during the period that women are actually in the screening programme; but the panel emphasises these figures are the best estimates from a paucity of reliable data. Putting together benefit and overdiagnosis from the above figures, the panel estimates that for 10 000 UK women invited to screening from age 50 for 20 years, about 681 cancers will be found of which 129 will represent overdiagnosis, and 43 deaths from breast cancer will be prevented. In round terms, therefore, for each breast cancer death prevented, about three overdiagnosed cases will be identified and treated. Of the ∼307 000 women aged 50–52 who are invited to screening each year, just >1% would have an overdiagnosed cancer during the next 20 years. Given the uncertainties around the estimates, the figures quoted give a spurious impression of accuracy. The panel concludes that the UK breast screening programmes confer significant benefit and should continue. The greater the proportion of women who accept the invitation to be screened, the greater is the benefit to the public health in terms of reduction in mortality from breast cancer. However for each woman the choice is clear: on the plus side screening confers a likely reduction in mortality from breast cancer because of early detection and treatment. On the negative side, is the knowledge that she has perhaps a 1% chance of having a cancer diagnosed, and treated with surgery and other modalities, which would never have caused problems had she not been screened. Evidence from a focus group conducted by Cancer Research UK and attended by two panel members, and in line with previous similar studies, was that this was an offer many women will feel is worth accepting: the treatment of overdiagnosed cancer may cause suffering and anxiety, but that suffering is worth the gain from the potential reduction in breast cancer mortality. Clear communication of these harms and benefits to women is of utmost importance and goes to the heart of how a modern health system should function. There is a body of knowledge on how women want information presented, and this should inform the design of information to the public. 2. Introduction 2.1 The UK NHS breast screening programmes The NHS breast cancer screening programme in England began inviting women to be screened in 1988. This followed the recommendations made by Professor Sir Patrick Forrest in his report on breast screening in 1986 (Forrest, 1986). The breast screening programmes in the United Kingdom currently invite women aged 50–70 years for a screening mammography every 3 years. The mammography is designed to detect changes in the breast tissue that may indicate the presence of cancer. The screening programme in England is currently conducting a randomised trial to ascertain whether there would be benefit in extending the age at which women are invited to 47–73 years. 2.2 Principles of screening Screening is concerned with the detection of disease at an early stage, with the expectation that treatment will be more effective if begun earlier in the disease process. Screening is therefore based on the principle of there being an effective treatment. It is well recognised that an apparent benefit of increased survival time could be illusory because of simply bringing forward the time of diagnosis without changing the course of the disease. Therefore, the appropriate way to assess benefit is to look at breast cancer mortality of screened and unscreened cohorts rather than just survival time from diagnosis (see section 3). As the principle of screening is to diagnose cases earlier, at any particular time point during the period of successive screenings, there will be more cases of breast cancer in a group of screened women compared with a similar group of unscreened women. However, it is possible that some of these additional cases may be cancers that would not otherwise have been diagnosed or caused the woman any problem during her lifetime. These cancers are referred to as overdiagnosis (see section 4). 2.3 The debate over benefits and harms of breast screening Since the screening programmes were established, there has been debate over the potential benefits and harms. Recently, the debate has focussed on the reduction in mortality attributable to screening, the numbers of women overdiagnosed, and the way that the risks and benefits are communicated to women invited for screening. The arguments have become quite polarised between those who believe that the benefit of decreased breast cancer mortality outweighs the harms and those who believe the harms outweigh the benefit. These differing views of the evidence have arisen, in part, from disagreements over the validity and applicability of the available RCTs of breast screening, and from questions about the usefulness and interpretation of observational data on breast cancer incidence and mortality. The debate over the benefits and harms of breast screening is not unique to the UK and the NHS breast screening programmes. In 2002, the International Agency for Research on Cancer at the World Health Organisation reviewed the evidence on breast screening, and put forward recommendations on further research and on implementing screening programmes (IARC, 2002). The US Preventive Services Task Force in 2009 re-examined the efficacy of different screening modalities. They recommended that women under the age of 50 not be routinely screened, and that women aged 50–74 have biennial rather than annual screens (Woolf, 2010). The Canadian Taskforce on Preventative Health Care updated their guidelines on breast screening in 2011, and concluded that the reduction in mortality associated with screening mammography is small for women aged 40–74 years at average risk of breast cancer. They also found a greater reduction in mortality for women aged ⩾50 compared with those 6550 women (aged ⩾45) per year in England. Ten per cent of the results were 4115. As there appears to be no a priori reason to favour one set of assumptions over another, the panel do not think that approaches based on extrapolation offer a robust method to estimate overdiagnosis. Several groups have compared breast cancer incidence trends over time in screened and unscreened countries or regions over the same time period (Jørgensen and Gøtzsche, 2009). The difficulty with these studies is distinguishing true overdiagnosis from the excess incidence of breast cancer that results from screening, bringing forward the time of diagnosis. Given that overdiagnosis is defined as a cancer that would not have come to attention in the woman's life span, long follow-up after cessation of screening is essential. The difficulties can be illustrated by studies of comparisons of incidence rates in regions within a single country that did or did not introduce population screening. A study from Denmark is illustrative, as only 20% of the Danish population was offered organised mammography screening over a long time-period (Jørgensen et al, 2009). Screening was introduced in Copenhagen in 1991 and in Funen in 1993 for women aged 50–69. The authors noted that the population in those areas has distributions of age and socioeconomic status comparable with the rest of Denmark. Table 2C shows the numbers of breast cancers diagnosed per 100 000 women in screened and non-screened areas of Denmark for 20 years before and 13 years after the introduction of screening in 1991. Incidence rates of breast cancer were higher in the screened areas than in the non-screened areas before screening began, suggesting some non-comparability of the areas. During the 13 years of screening, the incidence in women aged 50–69 rose both in the screened areas and the non-screened areas, but more in the screened areas. Incidence also rose in women aged 70–79. One way to estimate overdiagnosis is to compare the ratio of new cancers in screened and unscreened groups in the two periods. In the pre-screening period, the ratio was 1.08 (214/198) and for the screening period it was 1.35 (386/286). The authors say that these data indicate 35% overdiagnosis, but if we adjust for the pre-screening difference the excess is 25% (1.35/1.08=1.25). These simple calculations ignore the underlying rise in cancer incidence throughout the period. The authors used regression modelling to take account of incidence trends and age differences, giving an estimate of 33%. As noted earlier, such analyses make additional assumptions that are not verifiable. Studies such as this do not indicate the likely effect of long-term follow-up in reducing the excess in the incidence rate in the screened compared with the unscreened populations. There have been many other observational studies, but most have the type of problem illustrated here in distinguishing overdiagnosis from the expected increase in breast cancer incidence due to screening and require many assumptions to derive estimates of overdiagnosis. A recent review of 13 observational studies showed overdiagnosis to vary in the range of 0–54%. Adjustment for lead time and breast cancer risk yielded overdiagnosis estimates in the range of 1–10% (Puliti et al, 2012). The panel's judgement is that the best estimates will come from long-term follow-up of RCTs, as reviewed above. Statistical and other uncertainties As noted in section 3, it is conventional that results from statistical analyses, including meta-analyses, are presented with a measure of statistical uncertainty such as 95% confidence limits. Although these are helpful in giving an impression of the possible influence of the play of chance (given the sample sizes that are available in the studies considered), they fail to represent the uncertainties due to possible biases (internal validity of the studies) or to generalisation from the studies to a new context (external validity). So the CIs given for the estimated percentage overdiagnosis are an understatement of the uncertainty about the risk of overdiagnosis associated with the UK screening programmes. Estimates of overdiagnosis have additional uncertainties relating to which estimate to use, and the data are not available for all studies to calculate overdiagnosis in the suggested ways. Conclusion The panel believes that overdiagnosis occurs, and that women need to be aware that screening carries a risk of detecting cancers, invasive and in situ, which would not have troubled them in their lifetime. Tumours that represent overdiagnosis cannot be identified clinically and so will have to be managed according to current clinical protocols. The panel considers that the data from three of the RCTs without end-of-trial screening of controls provide the most reliable estimates of the extent of overdiagnosis, but notes that there is a rather limited amount of data and numerical estimates are subject to several uncertainties in common with estimates of mortality benefit. As noted for the estimated benefit for mortality (see section 3.2), the overdiagnosis rates estimated from old RCTs may not reflect those in current screening programmes. There is, however, no clear evidence to suggest that the current rate of overdiagnosis would be lower or higher than in the original trials. The panel thinks that the best estimate of overdiagnosis for a population invited to be screened is of the order of 11%, defined as the percentage excess incidence in the screening population above the long-term expected incidence in the absence of screening. An alternative definition addresses the answer to the question ‘if I am invited to enter into the screening programme and am given a cancer diagnosis during the screening period, what is the likelihood of overdiagnosis'? The panel views the evidence as suggesting that this probability is of the order of 19%. 4.5 Consequences of overdiagnosis As previously stated, detection of overdiagnosed cancers turns women into patients, leads to surgery and other treatments that are not therapeutically beneficial for these women and can cause harm, and adversely affects their quality of life. As cancers that would not go on to cause cancer death cannot be individually identified, they are treated according to the current treatment protocols. Figure 3D summarises the management of UK screen-detected cancers, both invasive and non-invasive, in 2010/2011 (NHS Breast Screening Programme & Association of Breast Surgery-West Midlands Cancer Intelligence Unit, 2012). One cannot, however, assume that the overdiagnosed cancers would be managed in the same proportional way as the generality of screen-detected cancers. That the patient dies before the cancer would have presented clinically, implies that such tumours: would tend to be more slowly growing, as a more rapidly growing tumour would be more likely to present clinically within a shorter time-frame; would be relatively small, as larger tumours would be more likely to present symptomatically. Thus, overdiagnosed cancers would tend to be more likely to be: DCIS (and the relative excess of DCIS in screen-detected cancers would support this), and possibly more likely to be low/intermediate rather than high grade. Grade 1 or grade 2 invasive rather than grade 3. Thus, compared with the diagram, patients with cancers that are overdiagnosed would be: relatively more likely to have been treated on the DCIS side than the invasive; and as more likely to be low/intermediate grade, less likely to have had radiotherapy; if invasive, more likely to be managed by WLE and radiotherapy than mastectomy as likely to be small if an invasive cancer, less likely to have had chemotherapy, as patients having chemotherapy are more likely to have had grade 3 and/or node-positive cancers (NHS Breast Screening Programme & Association of Breast Surgery-West Midlands Cancer Intelligence Unit, 2012); if an invasive cancer, more likely to have had endocrine therapy, as oestrogen positivity is associated with older age and lower grade invasive cancers. Evidence in support of this tendency for overdiagnosed cancers to be of potentially better prognosis, and thus given less aggressive therapy can be seen, for example, in the reports of the nature of cancers found in the two arms of randomised screening trials. Table 2D shows such data for the Malmö I trial. 4.6 Ductal carcinoma in situ (DCIS) There is evidence that breast screening has led to an increase in the identification of DCIS (IARC, 2002). It has been suggested that DCIS is a relatively benign condition that would not cause harm, and therefore diagnosis of DCIS contributes significantly to the magnitude of overdiagnosis. Definition DCIS is a malignant process that arises from the epithelial tissues of the breast, and consists of neoplastic cells, which do not, however, infiltrate beyond the limiting basement membrane, and thus remain within the ducts where they arose. Classification is based on the morphological features: architectural growth pattern and the cytological characteristics of the malignant cells. It is usually grouped by grade into high, intermediate, or low grade (IARC, 2002). Along with LCIS, it is classified as non-invasive breast cancer, and although the cells have the appearance of malignancy, they do not show invasiveness, so carcinoma in situ is not in itself a life threatening condition. The concern is that at least some have the capacity to progress to invasive malignancy. DCIS is most commonly detected mammographically as microcalcification. Less commonly, DCIS will present with a symptomatic lump. Incidence Table 2E adapted from ‘The non-invasive breast cancer report' (National Cancer Intelligence Network, 2011), shows the frequency of non-invasive breast cancer for different age groups and presentations in England for the two years 2006 and 2007. The majority (about 90%) of non-invasive cancers diagnosed are DCIS. It is apparent that the majority are screen-detected but, nevertheless, 38% were diagnosed symptomatically. Some of the symptomatic tumours may have been detected incidentally when patients presented with a different problem (e.g. microcalcifications found in the contralateral breast when the woman has presented with a benign problem in the one breast). Thus, the detection and management of non-invasive disease is not exclusively a problem of the screening programme. Nevertheless, within the screening age group (age 50–70), the majority (79%) of the DCIS is screen-detected. For 2009–2010, of all screen-detected cancers, about one in five were non-invasive, being a little higher (24%) for the prevalent round and lower (19%) for the incident rounds (The NHS Information Centre). Thus, a mammographic screening programme will detect DCIS. In some cases, (about one in five) (Evans, 2012) investigation of what is radiologically DCIS will lead to the detection of an invasive carcinoma – the larger the area of DCIS, the more likely that there will be a frankly invasive component. Natural history of DCIS Before introduction of the screening programme, DCIS was a relatively uncommon tumour. Since it is frequently a marker of associated invasive cancer, it has been investigated and usually excised, and hence it is not possible to know what would have happened if it had been left undisturbed and untreated. Given that the screening programme is diagnosing much more DCIS than presents symptomatically, the relevant questions are: How common is DCIS? As above, it represents about 1 in 5 of screen-detected cancers, but only 1 in 20 of all symptomatic cases (National Cancer Intelligence Network, 2011). In reports of small series (IARC, 2002) of women without known breast cancer who underwent postmortems (hospital-based or forensic), invasive cancer was found in about 1% and DCIS in 9%, but there was wide variation in the series, presumably reflecting differences in the women selected and methodologies for examining the breast. How often does it progress to invasive cancer? The data from trials of therapy (radiotherapy and/or tamoxifen) after WLE of DCIS shows that both interventions reduce the risk of local relapse (similar to the findings for invasive cancer after WLE). Relevant to the UK screening programme is the UK, Australia, New Zealand (UK/ANZ) trial (Cuzick et al, 2011), in which after WLE of screen-detected DCIS, without any further treatment, relapse in the breast occurred in about 19% of cases, in half of which the relapse was invasive. Progression appears to occur slowly – for example, one series of screen-detected DCIS (Wallis et al, 2012) showed the median time to invasive progression for high-grade DCIS was 76 months, and for low/intermediate grade 131 months. Is there any way of identifying those cases of DCIS that will or will not progress/relapse as invasive cancer? DCIS is classified histologically on the basis of excised specimens, and there is currently no certain means of identifying lesions that would not progress. The risk of invasive relapse is higher with high- or intermediate-grade DCIS. Low-grade DCIS seems to pursue a more indolent course, and when invasive relapse occurs it is likely to be a grade-1 tumour. There is ongoing work (Pinder et al, 2010; Reeves et al, 2012) looking at histological and molecular markers to identify those most likely to progress, especially to invasive disease. Does DCIS affect survival? The follow-up of patients with DCIS usually shows excellent survival. For example, in the UK/ANZ trial of 1701 women with a median follow-up of 12.7 years, only 179 (11%) had died, of which 39 (2% of all cases) died of breast cancer. Long-term follow-up (NHS Breast Screening Programme & Association of Breast Surgery-West Midlands Cancer Intelligence Unit, 2012) of 1603 cases of screen-detected non-invasive breast cancer (nearly all DCIS) showed a 20-year relative survival of 97.2% (95% CI 93.6–100.6), with 7.2% of the 493 deaths being due to breast cancer. However, these series are of patients who have had the DCIS treated: what is unclear is what the risk of dying of breast cancer would have been had it been left untreated. Conclusions The main question is whether DCIS is a marker of malignancy requiring active treatment or a benign condition of no clinical significance. On the one hand, DCIS (particularly high grade) can certainly serve as a marker for invasive cancer – either because it is associated with the presence of invasive disease at the time of detection, or because its presence indicates an increased risk of invasive disease developing subsequently – in about 10% of cases at 10 years after WLE only. On the other hand, autopsy series and screening programmes both demonstrate that DCIS can be found in the breast of middle-aged women at a greater frequency than presents symptomatically. Part of the explanation is time. Breast cancer has a long natural history and in patients with invasive cancer, the evolution of metastatic spread and ultimate death may take place over decades. If one also considers the progression of DCIS to invasive cancer as part of this process, the evolution is even longer. In other words, the relevant question is not whether DCIS progresses to invasive cancer (it can), but whether it might have progressed to an invasive cancer that causes symptoms within the lifetime of the women concerned. This will depend mainly on the age of the woman, her life expectancy at the point of diagnosis, and perhaps other factors that could affect progression (hormonal exposure, obesity, etc.). Current series do not show a significant impact of DCIS on survival, after treatment, even at 20 years, but increasing survival may mean that for women in their 50s and even 60s, the diagnosis of DCIS may impact on their long-term survival. Long-term data are needed. Thus, in diagnosing DCIS via a screening programme, there is a balance to be struck between the potential benefits for some women of identifying and treating a pre-invasive cancer, and the risks for others of treating something that would never have affected the woman in her lifetime. It is not simply the case that DCIS represents overdiagnosis, although it undoubtedly is a contribution to the cases of overdiagnosis. 5. Other considerations 5.1 Introduction Beside the benefit of breast screening for mortality and its harm in terms of overdiagnosis, the panel considered other relevant issues. These include additional harms through invitation, screening, diagnosis, and treatment, as well as women's perceptions and cost effectiveness. Although the panel has not made a systematic appraisal of evidence in all these areas, being outside its terms of reference (Appendix 1), it has drawn together comments on each of these issues as they should not be neglected when considering the overall impacts of breast screening. 5.2 Harms associated with breast screening Mammography Radiation exposure Mammography uses X-rays and thus exposes women to very low doses of ionising radiation that could cause breast cancers. The actual dose of radiation depends on several factors including the number of views of each breast and whether film or digital mammography is used. The Health Protection Agency (Health Protection Agency 2001) has suggested that the lifetime additional cancer risk for each mammography examination is between 1 in 1 00 000 and 1 in 10 000. Although these doses are lower than those for which cancer is directly induced (Preston et al, 2002), screening a large population on a regular basis may cause harm. The NHS Breast Screening Programme (2011) in 2006 stated that for every 14 000 women in the age range 50–70 years screened by the NHSBSP three times over a 10-year period, the associated exposure to X-rays will induce about one potentially fatal breast cancer. (NHS Breast Screening Programme & Association of Breast Surgery-West Midlands Cancer Intelligence Unit, 2012). A more recent estimate is that screening women every 3 years from age 47–73 would cause 3–6 cancers per 10 000 women screened (Berrington de Gonzalez, 2011). This risk is incorporated in estimates of the benefit of screening (see section 3). Digital mammography, which uses a lower radiation dose, is increasingly being used in the English screening programme. Therefore, it is likely that the risk of exposure will be reduced. Pain During the process of mammography, the breast is compressed and flattened in order to create a uniform density, which improves the image and reduces the radiation dose. A substantial proportion of women find this painful and some studies (Nelson et al, 2009; Gøtzsche and Nielsen, 2011) have shown that the pain and discomfort of mammography deters them from attending for further screening (Gøtzsche and Nielsen, 2011). The assessment process Figure 4 summarises the process and numbers for women recalled after routine screening mammograms Figure 4. Many women take part in the screening programme; it is often argued that for many the benefit will be reassurance (Welch et al, 2011). With that reassurance, however, must come the knowledge that all screening tests have errors of false positives and false negatives. The mammogram may sometimes appear to show an abnormality that requires further investigation to determine whether or not it is a cancer-requiring treatment or fail to detect a cancer that is present. False-positive mammogram In Figure 4 2522 women (i.e., 3105 recalled minus the 583 diagnosed with cancer=2522: 3.36% of all the women screened) were recalled and found not to have cancer. This is called a false-positive result. Of the women recalled and found not to have cancer, the majority (1744/2522=69%) had only further imaging (mammography, ultrasound) but a minority (778/2522=31%) had a biopsy, which was core biopsy under local anaesthetic in all except 2.3% (57/2522) who had a formal biopsy under general anaesthetic. The latter group represents only 0.076% (57/75 057) of all women screened. Numerous studies have assessed the psychological impact of a false-positive result on women (Brett et al, 1998; Brett and Austoker, 2001). The studies' results are conflicting but a recent systematic review of the literature (Bond et al, 2012) concluded that, in the population at general risk of breast cancer, a false-positive result can cause breast cancer-specific psychological distress, which may endure for up to 3 years. The degree of distress is associated with the level of invasiveness of subsequent assessment. Some studies found that the distress caused by a false-positive result deterred some women from re-attending for breast screening, which would reduce any benefit they would otherwise have got from being offered screening in the first place. The level of distress can be mitigated by providing women with clearly worded information about the recall and appropriate support from clinical staff in before and during assessment (Bond et al, 2012). False-negative results No screening test is completely accurate and sometimes mammography will not detect a cancer. This may because the cancer is not mammographically visible or develops between screening rounds and women are warned of this possibility in the screening literature. When women present with an interval cancer, the previous mammograms are reviewed blind to assess whether a suspicious abnormality was visible on the previous screening mammogram. If so, such cases are classified as a true false-negative mammogram, that is, the suspicious abnormality was missed at the first screen. For women attending at three yearly intervals, the false-negative rate is 0.2/1000 women screened (Lawrence, 2012; c.f. the cancer detection rate by screening of 7.8 cancers/1000 women screened). Diagnostic testing Core biopsy carries a risk of local haemorrhage and, rarely, reaction to local anaesthetics. Open surgical biopsy involves a general anaesthetic but it is regarded as a low-risk procedure. Psychological consequences of a positive diagnosis The psychological consequences of a breast cancer diagnosis and subsequent treatment have been well documented. In terms of harms of screening, these consequences are particularly relevant to those women who have been overdiagnosed. Although these women will not know that the cancer would not have caused them any harm they will have suffered unnecessary psychological trauma associated with a cancer diagnosis Two studies (Yousaf et al, 2005; Schairer et al, 2006) have shown a small but significant increased risk of suicide in patients diagnosed with breast cancer. The risk increases with advancing stage of the disease and therefore may be less relevant for those who are overdiagnosed. However, two further studies (Jamison et al, 1978; de Leo et al, 1991) have found suicidal ideation to be present in some patients post-mastectomy. Although these risks are small they should not be overlooked when assessing the benefits and harms of breast screening. Potential morbidity and mortality from treatment Breast surgery As with any surgical procedure, there are hazards from the anaesthetic and the surgical procedure itself. Although the surgery can be extensive (especially if it involves reconstructive surgery as well), the surgery is elective, patients are assessed pre-operatively, serious complications are rare. The most extensive surgery is mastectomy and reconstruction for which the mortality is estimated to be <0.3% (The NHS Information Centre). In contrast, following mastectomy, 10% of patients will have some sort of complication (e.g. infection, fluid accumulation) (The NHS Information Centre). Radiotherapy Acutely, radiotherapy can cause skin reactions and uncommonly radiation pneumonitis. Both of these are short-lived and usually not severe. Radiotherapy can cause other long-term harms (Early Breast Cancer Trialists' Collaborative Group (EBCTCG), 2005). There is, at 15 years, a small excess risk of non-breast cancer mortality (15.9 vs 14.6%, an absolute difference of 1.3%). This is mainly due to heart disease (so seen more in left- than right-sided cases because more of the heart is irradiated), lung, and oesophageal cancers. These estimates are derived from trials of radiotherapy performed mostly during or before the 1970s; since then radiotherapy techniques have changed especially with the introduction of CT planning, so reducing the volume of heart and lung irradiated, which should reduce, but not eliminate, such complications. Data from the Surveillance Epidemiology and End Results (SEER) database (Giordano et al, 2005) shows that the risk of death from ischaemic heart disease due to radiotherapy has diminished from 1973 to 1989 (risk from right-sided tumours unchanged, left sided decreased). The last published Oxford overview (Clarke et al, 2005) showed that there is a reduction in mortality from the reduction in local recurrence of invasive cancer by radiotherapy. Essentially, for every four recurrences prevented at 5 years, there will be one death prevented at 15 years. For illustration, the local recurrence rate in the radiotherapy START trial (in which many patients had screen-detected cancers) was 3.5% at 5 years, which, given radiotherapy reduces local recurrence by about two-thirds, would correspond to a 5-year local recurrence rate of about 10.5% without radiotherapy. This gain of 7% in local control should correspond to a reduction in mortality of just under 2%. Adjuvant hormone therapy The most extensive experience is with tamoxifen. Trials of adjuvant tamoxifen for 5 years have shown that for patients with hormone receptor-positive breast cancer, breast cancer mortality is reduced by about 33% (Early Breast Cancer Trialists' Collaborative Group (EBCTCG) 2005), translating into an absolute reduction in mortality at 10 years of 5.3% and 12.2% for node-negative and node-positive patients, respectively. Tamoxifen does have some long-term hazards in that it carries an increased risk of uterine cancer and thromboembolic disease. Their effect on mortality is of the order of 0.2% per decade and is outweighed by the modest but positive effect of tamoxifen on ischaemic heart disease (possibly because it lowers cholesterol) (Dewar et al, 1992). Aromatase inhibitors are increasingly used instead of tamoxifen, but their overall effect on mortality is very similar to that of tamoxifen. Cytotoxic chemotherapy Adjuvant cytotoxic chemotherapy reduces both overall and breast cancer-specific mortality. Use of an anthracycline- or taxane-containing regime yields a RR reduction of about one third in breast cancer mortality (Peto et al, 2012). The absolute benefit depends on the risk profile but will often be of the order of 6–7% at 10 years. There are acute toxicities associated with giving chemotherapy — such as alopecia, nausea and vomiting, which are all unpleasant but non-fatal. Acute neutropenic sepsis can be fatal but this is a rare event in the adjuvant setting. There is an increased risk of thromboembolism. Mortality rates during adjuvant chemotherapy have been reported at around 0.3% (Cameron et al, 2003). The main long-term risks are (Azim et al, 2011): Cardiac: Anthracyclines can cause a cardiomyopathy, the incidence being dose related and increasing with age. Trials suggest an absolute excess mortality of up to 1%, but this may be an underestimate as the incidence of cardiac failure may be higher and can occur many years after treatment. Second cancers: The main risk with chemotherapy, particularly anthracycline-based, appears to be acute myeloid leukaemia and myelodysplastic syndrome. At standard doses, the risk is probably of the order of 0.5% but may be higher if the doses (especially of alkylating agents and anthracyclines) are increased. Neurotoxicity and premature menopause: Both are very real causes of morbidity but not of mortality. Conclusion We know that within the NHS screening programmes, of patients found to have invasive or non-invasive cancer, 99% have surgery (of whom 5.7% have mastectomy and immediate reconstruction), 72% have radiotherapy, 72% have adjuvant hormone therapy, and 27% adjuvant chemotherapy (NHS Breast Screening Programme & Association of Breast Surgery-West Midlands Cancer Intelligence Unit, 2012). From the above, assuming a worst case scenario, it would be reasonable to assume no adverse mortality effect for hormone therapy, no net effect of radiotherapy on mortality, a maximum of 0.2 per 1000 dying because of surgery (0.3% of those having reconstruction) and 1.3 per 1000 dying because of chemotherapy (0.5% of the 27% who have chemotherapy), giving an adverse mortality rate of 0.15%. For patients who have an ‘overdiagnosed' cancer, the risk is likely to be lower as it is unlikely that they would have received chemotherapy (see section 4). The panel concludes that the excess mortality from the investigation and treatment of invasive breast cancer is small and outweighed by the benefits of the treatment. For DCIS, the benefits of radiotherapy or hormone therapy are in terms of recurrence rather than a reduction in mortality, but the absolute risks of such treatment in terms of mortality are likely to be very small. For patients with screen-detected breast cancer, there is no evidence that these risks are any greater than in the symptomatic population, but for women diagnosed with a breast cancer, that if it were certain would never be symptomatic, there is nevertheless a real, but very small, mortality risk from being screened. 5.3 Women's perceptions of screening The development of new information to accompany cancer screening invitations was not in scope for this review and is being dealt with separately. Women's perspectives on overdiagnosis and whether they see it as a key issue in their screening decisions had not previously been investigated, so Cancer Research UK commissioned some qualitative research to investigate this. The findings, from one focus group attended by panel members, are presented briefly here for information (Appendix 5), but academic papers, focusing on a larger sample of qualitative research, will follow publication of this report. These women understood the concept of screening and most had attended. Although they understood breast cancer, and many knew people who had had it, they had little concept of DCIS and overdiagnosis. Their opinions are not mainly informed by the screening leaflet, and it would appear many do not read it in detail. Thus, informing women about screening will involve much more than simply re-writing the leaflet. 5.4 Cost-effectiveness of breast screening It was not in the panel's remit to review the data relating to the costs or the cost-effectiveness of breast cancer screening. The Department of Health in England has provided funds of about £100 million per year to deliver the current screening programme (NHS Breast Screening Programme, 2012). If one were to take the well-founded cost-effectiveness approach such as that employed by the National Institute for Health and Clinical Excellence (NICE) when reviewing a health technology, it would be important to establish the costs not only of the intervention, but of all subsequent interventions, both in those invited to be screened and those not offered screening. No such data are available for any of the randomised trials, and thus this panel is not in a position to consider the full costs of a breast screening programme, including the financial costs to the NHS of any overdiagnosed cancers. Thus, although it has been estimated that the UK NHSBSP comes within the NICE cost/quality-adjusted life year threshold of £20 000–30 000 (Advisory Committee on Breast Cancer Screening, 2006), the panel is not able to comment on this, as it has not been able to scrutinise the costs of treatment with and without screening, including the costs of treating the cancers that are overdiagnosed. We can, however, make general comparisons with other interventions and see that, in terms of lives saved per year, breast cancer screening is of a similar order of magnitude as cervical screening, bowel cancer screening using faecal occult blood testing and, the use of statins (Table 3). 6. Conclusions and recommendations 6.1 Recommendations for further research The panel's review of the randomised trials of breast screening leads to the following recommendations about future research priorities: An individual participant data meta-analysis of the breast screening trials is in progress. This should help resolve some (but not all) of the concerns that have been raised about individual trials and their combined interpretation. The panel supports this enterprise, and is disappointed that it had already not been done a long time ago. The impact of breast screening outside the ages 50–69 years is very uncertain. The panel supports the principle of the ongoing trial in the United Kingdom for randomising women under age 50 and above age 70 to be invited for breast screening. The panel's review of overdiagnosis leads to their support for further research into DCIS, in particular: A proposed study to examine the need for treatment of low-grade DCIS Continued support for the Sloane project, which has an extensive database of screen-detected cases of DCIS, and the long-term follow-up of these cases may well improve our understanding of this condition (The Sloane Project 2010). Current mammographic screening techniques now detect many more cases of DCIS than in the trials. The appropriate treatment of these is uncertain, because there is limited information on their natural history (section 4.6). The panel supports studies to elucidate the appropriate treatment of screen-detected DCIS. Work on improved screening and pathological techniques that can predict prognosis more effectively. The panel also supports: A re-evaluation of the cost-effectiveness of the NHS breast cancer screening programme that takes into account the conclusion of this report. 6.2 Conclusions Breast screening extends lives. The panel's review of the evidence on benefit – the older RCTs, and those more recent observational studies judged to be relevant – point to a 20% reduction in mortality in women invited to screening. A great deal of uncertainty surrounds this estimate but it represents the panel's overview of the evidence. This corresponds to one breast cancer death averted for every 235 women invited to screening, and one death averted for every 180 women who attend screening. The breast screening programmes in the United Kingdom, inviting women aged 50–70 every 3 years, probably prevent about 1300 breast cancer deaths a year, equivalent to about 22 000 years of life being saved; a most welcome benefit to women and to the public health. But there is a cost to women's well-being. In addition to extending lives by early detection and treatment, mammographic screening detects cancers, proven to be cancers by pathological testing, that would not have come to clinical attention in the woman's life were it not for screening - called overdiagnosis. The consequence of overdiagnosis is that women have their cancer treated by surgery, and in many cases radiotherapy and medication, but neither the woman nor her doctor can know whether this particular cancer would be one that would have become apparent without screening and could possibly lead to death, or one that would have remained undetected for the rest of the woman's life. The answer the panel sought was to the question of the level of overdiagnosis in women screened for 20 years and followed to the end of their lives. Estimates abound of overdiagnosis, from near to zero to 50%, but there are no reliable data to answer this question. There has not even been agreement on how to measure it. On the basis of follow-up of three RCTs, the panel estimated that in women invited to screening, about 11% of the cancers diagnosed in their lifetime constitute overdiagnosis, and about 19% of the cancers diagnosed during the period that women are actually in the screening programme. However, the panel emphasises, these figures are the best estimates from a paucity of reliable data. Any excess mortality stemming from investigation and treatment of breast cancer is considered by the panel to be minimal and considerably outweighed by the benefits of treatment. Putting together benefit and overdiagnosis from the above figures, the panel estimates that for 10 000 UK women invited to screening from age 50 for 20 years, about 681 cancers will be found of which 129 will represent overdiagnosis, and 43 deaths from breast cancer will be prevented. In round terms, therefore, for each breast cancer death prevented about three overdiagnosed cases will be identified and treated. Of the ∼307 000 women aged 50–52 who are invited to screening each year, just over 1% would have an overdiagnosed cancer during the next 20 years. Given the uncertainties around the estimates, the figures quoted give a spurious impression of accuracy. 6.3 Policy recommendations The panel concludes that the UK breast screening programmes confer significant benefit and should continue. The greater the proportion of women who accept the invitation to be screened, the greater is the benefit to population health in terms of reduction in mortality from breast cancer. However, for each woman the choice is clear: on the plus side, screening confers reduction in the risk of mortality from breast cancer because of early detection and treatment. On the negative side, is the knowledge that she has perhaps a 1% chance of having a cancer diagnosed and treated that would never have caused problems had she not been screened. Evidence from a focus group the panel conducted, and in line with previous similar studies, was that screening was an offer many women will feel is worth accepting: the treatment of overdiagnosed cancer may cause suffering and anxiety but that suffering is worth the gain from the potential reduction in breast cancer mortality. Clear communication of these harms and benefits to women is of utmost importance and goes to the heart of how a modern health system should function. There is a body of knowledge on how women want information presented, and this should inform the design of information to the public.