Acta Oncologica, 2014; 53: 433–444
REVIEW ARTICLE
Position paper: Breast cancer screening, diagnosis, and treatment in Denmark
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PEER CHRISTIANSEN1, ILSE VEJBORG2, NIELS KROMAN3, IBEN HOLTEN4, JENS PETER GARNE5, PETER VEDSTED6, SUSANNE MØLLER7 & ELSEBETH LYNGE8 1Breast
and Endocrine Section, Department of Surgery P, Aarhus University Hospital, Aarhus, Denmark, of Radiology, Copenhagen University Hospital, Copenhagen, Denmark, 3Department of Breast Surgery, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, 4Department of Prevention and Documentation, Danish Cancer Society, Copenhagen, Denmark,5Department of Breast Surgery, Aalborg University Hospital, Aalborg, Denmark, 6The Research Unit for General Practice, Danish Research Centre for Cancer Diagnosis in Primary Care (CaP), School of Public Health, Aarhus University, Aarhus, Denmark, 7DBCG Data Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark and 8Department of Public Health, University of Copenhagen, Copenhagen, Denmark
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ABSTRACT Background. During the last decades the diagnosis, treatment, and prognosis of breast cancer have changed and improved in Denmark. The first mammography screening programme started in 1991. However, for many years only about 20% of Danish women aged 50–69 were offered screening. The national roll-out of screening took place in 2008–2010. Material and methods. Based on published Danish data, this overview describes the status of diagnosis and treatment, and the screening programme. For further evaluating the potential overdiagnosis and overtreatment, additional Danish Breast Cancer Cooperative Group (DBCG) data are included. Results and conclusion. Using incidence-based mortality method, reduction in breast cancer mortality was estimated to be 25% in the target group of women after 10 years of screening in Copenhagen; an outcome comparable to that of randomised controlled trials. A recent Danish study has indicated overdiagnosis to be around 4%. Others have estimated overdiagnosis to be 33%. National DBCG data showed that the rude breast cancer incidence increased during the period 1990–2011 from 126 to 206 per 100 000. The incidence was almost constant for women younger than 50 years. In regions not offering screening, the incidence increased with 3% per year for women aged 50–69 years with similar trends for small and large tumours. After introduction of screening the increase in the age group 50–69 years was confined to small tumours ⱕ 20 mm, and most pronounced for node negative patients. From the 1990s, the use of breast conserving surgery has increased from around 25% to 69% in 2010. Screening has not increased the number of mastectomies. Breast cancer treatment in Denmark is evidence based and in agreement with international recommendations. After the introduction of mammography screening the absolute number of patients with a more advanced stage at diagnosis and the absolute number of patients undergoing mastectomy have decreased. Breast cancer is the most frequent malignancy among women in most western countries. In Denmark, the incidence of breast cancer has increased steadily though being fairly stable during 2002–2006 with 4000 new cases per year [1], while the rates have gone down in some other countries. During the last decades the treatment options for breast cancer have widened and the prognosis has improved significantly, but still
the disease has a considerable mortality, and in Denmark the relative survival is lower than in most other comparable countries [2]. A reduction in the number of women contracting breast cancer is not expected within the nearest future, and therefore a reduction in breast cancer mortality depends on better treatment results. A shortcut is treatment at an earlier stage of the disease. This can be achieved by
Correspondence: P. Christiansen, Breast and Endocrine Section, Department of Surgery P, Aarhus University Hospital, Tage-Hansens Gade 2, 8000 Aarhus, Denmark. E-mail: [email protected]. (Received 7 March 2013 ; accepted 27 November 2013) ISSN 0284-186X print/ISSN 1651-226X online © 2014 Informa Healthcare DOI: 10.3109/0284186X.2013.874573
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mammography screening, which leads to an earlier diagnosis, although criticism has been raised questioning the reduction in breast cancer mortality and focusing on overdiagnosis and overtreatment. The aim of this work is, based on published data, to describe the status of diagnosis and treatment of breast cancer and to present the mammography screening programme in Denmark. In order to further evaluate the extent of potential overdiagnosis and overtreatment; some additional data from the database of the Danish Breast Cancer Cooperative Group (DBCG) are presented in this position paper.
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Breast cancer treatment in Denmark The organisation of breast cancer treatment in Denmark is described in the Supplementary addendum available online at http://informahealthcare.com/doi/ abs/10.3109/0284186X.2013.874573. The survival of breast cancer patients has improved steadily over the last 30 years [3] (Figure 1). A constant improvement of the prognosis according to period of the primary diagnosis is apparent. Thus, the five-year overall survival increased from 65% for patients diagnosed in 1977–1981 to approximately 75–80% for those diagnosed in 2002–2006. Nevertheless, breast cancer survival in Denmark is low relative to otherwise comparable countries. This is partly explained by a relatively unfavourable stage distribution at time of diagnosis, as documented previously in studies comparing Sweden and Denmark [4,5]. More recently it has been further elucidated in a comparison of breast cancer survival and mortality in six countries: UK, Canada, Australian, Norway, Sweden, and Denmark [6]. However, although results at large were poorer in Denmark, both one- and three-year survival by stage were at the average of the other five countries.
Figure 1. Five- and 10-year crude overall survival of Danish breast cancer patients.
Mammography screening in Denmark Organised mammography screening with biennial screening to women aged 50–69 years started in Denmark in 1991 in the municipality of Copenhagen (with the municipality of Frederiksberg included from 1994), and in 1993 in the county of Funen. Together these three areas covered around 20% of the target population of women aged 50–69 years. The rest of women were not offered organised screening. Still opportunistic screening was rare [7]. In 2001, organised mammography screening was introduced in Bornholm and in 2004 in the county of West Zealand. From 2007 to 2010 the national roll-out of the organised screening programme took place. A detailed description of the programme is included in the Supplementary addendum available online at http://informahealthcare.com/doi/ abs/10.3109/0284186X.2013.874573. Quality assurance of mammography screening in Denmark Surrogate, or short-term, measures are used to monitor the quality of mammography screening. These measures are based on data from the randomised controlled trials on correlations between short-term outcomes and long-term effect on breast cancer mortality. The effect from screening stems from its ability to antedate diagnosis ensuring the diagnosis of smaller tumours and less axillary spread. Therefore, the frequency of small tumour size ⬍ 10 mm and number of cases with negative axilla are useful examples of surrogate measures, as is the number of cases diagnosed in the interval between scheduled screens. Surrogate measures from the two longstanding organised mammography screening programmes in Denmark are depicted in Table I [8]. Overall the two programmes performed very similar, though with a higher participation rate in the semirural Funen as compared to the capital of Copenhagen. The Funen programme deliberately kept the recall rate low, which resulted in a somewhat lower detection rate and higher interval cancer rate than in Copenhagen but still within acceptable ranges. The European commission has published: “European guidelines for quality assurance in breast cancer screening and diagnosis” [9]. In these guidelines 39 performance indicators are suggested for use in quality assurance, covering administrative measures as well at radiological, pathological, and surgical aspects. To assure the quality of the national mammography screening programme the National Board of Health and the Danish Regions in 2007 initiated a Danish Database for Quality Assurance of Mammography Screening. A steering committee has been appointed with the responsibility to define national
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Table I. Summary of outcome measures from the two long-standing organised mammography screening programmes in Denmark.
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Indicator Invitation round Participation rate First Subsequent Recall rate First Subsequent Detection rate First per 1000 per year Subsequent per 1000 per year First % of expected Interval cancer rate First per 1000 per year Subsequent per 1000 per year First % of expected Interval/(detected ⫹ interval) % First Subsequent Invasive % of screen detected Node negative % of invasive screen detected ⬍ 10 mm % of invasive screen detected
1991–2008 Copenhagen
1993–2005 Funen
EU Acceptable1
EU Desirable1
71% 62%
85% 82%
⬎ 70%2 ⬎ 70%2
⬎ 75%2 ⬎ 75%2
6.8% 2.8%
2.7% 1.5%
⬍ 7% ⬍ 5%
⬍ 5% ⬍ 3%
5.79 3.20 4.4 X IR
4.47 2.79 4.0 X IR
NA NA 3 X IR
NA NA ⬎ 3 X IR
0.97 1.36 0.34 X IR
1.08 1.33 0.42 X IR
NA NA 0.4 X IR
NA NA ⬍ 0.4 X IR
0.14 0.30 85% 74% 41%
0.19 0.32 88% 68% 35%
NA NA 90% 75%3 ⱖ 25%3
NA NA 80–90% ⬎ 75%3 ⱖ 30%3
IR, breast cancer incidence rate in the absence of screening; NA, not available. et al. 2006 [10]; 2Proportion of women invited that attend for screening. Danish proportions calculated as proportion of women eligible for screening that attended for screening; 3Proportion at subsequent regular screening examinations. Danish proportions calculated as proportion at subsequent invitation rounds.
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quality indicators and work out national clinical guidelines. Each of the five regions is obliged to send specified data to the database and yearly reports are published on 11 quality indicators. Data after the first round of the national programme showed that the stipulated levels for the various quality indicators were largely met [10], which is expected to lead to a fulfilment of the primary goal of reducing breast cancer mortality (Table II).
Evaluation of mammography screening programmes Mammography screening should be evaluated based on its balance between benefits and harms. The long-term purpose of mammography screening is to decrease breast cancer mortality. This effect is complicated to measure, as the majority of women dying from breast cancer in the first years after the introduction of a screening programme will have
Table II. National Mammography Screening Programme in Denmark. First screening round (2007–2010). Summary of indicator results calculated on a national basis. Indicator 1. Glandular dose (PMMA1 thickness at 4.5 cm) 2. Participation in % of invited in % of target 3. Re-invited within the specified screening interval of 2 years ⫾ 3 months 4. Recalled for assessment 5. Interval cancers 6. Invasive cancers (IC in % of IC⫹ DCIS) 7. Node negative cancers 8. Small cancers (tumour size ⱕ 10 mm) 9. Benign vs. malignant operation ratio 10. Breast conserving surgery (for IC⫾ DCIS) 11. Time to written answer (ⱕ 10 working days)
Standard ⬍ 2.0 mGy ⬎ 75%
National Results (95% CI)
ⱖ 98%
Data not available2 77.4% (77.3–77.5) 76.0% (75.9–76.1) Not calculated3
⬍ 5% ⬍ 30% ⱖ 80 & ⱕ 90% ⬎ 70% ⱖ 25% ⱕ 1:4 ⬎ 50% ⬎ 95%
3.0% (2.9–3.0) Not calculated3 86.4% (85.3–87.3) 67.4% (65.9–68.9) 36.4% (34.7–38.1) 1:6.3 80.2% (78.9–81.4) 71.1% (71.0–71.3)
DCIS, ductal carcinoma in situ; IC, invasive cancers. methacrylate or polymethyl-2-methylpropanoate (PMMA) is the unit used for standardised glandular dose calculation; 2Data not available in first screening round; 3Not relevant in first screening round. 1polymethyl
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been diagnosed with breast cancer prior to the start of the programme. Also, improvement in adjuvant therapy and treatment for disseminated disease will complicate measurements; as such improvements can cause fewer deaths and/or postponement of death of breast cancer, even in the absence of screening. A concern in mammography screening is overdiagnosis, i.e. the diagnosis of breast cancer cases that would otherwise not have become clinical manifest in the women’s lifetime. The main benefit of screening is reduction in breast cancer mortality. The main harm is overdiagnosis and hence overtreatment.
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Reduction in breast cancer mortality Mammography screening was implemented in routine health care based on results from randomised controlled trials showing a reduction in breast cancer mortality in the screening arms of the trials as compared with the control arms. For the trial data, the International Agency for Research on Cancer concluded in 2002 that “there is sufficient evidence for the efficacy of screening women aged 50–69 years by mammography as the sole screening modality in reducing mortality from breast cancer”. The effect was estimated to be a 25% reduction in invited women and a 35% reduction in participating women [11]. The US Preventive Services Task Force concluded in 2009 that the trial data showed a 14% reduction in breast cancer mortality for women offered screening at age 50–59 years, and a 32% reduction for women offered screening at age 60–69 years [12]. Considering data from the majority of trials and all age groups, the UK Independent Panel on Breast Cancer Screening recently concluded that mammography screening decreased breast cancer mortality by 20% [13]. Routine health care might, however, not always reach the same results as seen in randomised controlled trials. It is therefore important to monitor the outcome of routine screening [9]. Ideally, this should be carried out comparing women offered screening with women in an unexposed control group, but this is a complicated task when all women are offered screening. Three approaches have been used in the monitoring of routine screening. First, time trends in breast cancer mortality, but this is not a sensitive approach because during the first many years after start of screening a large proportion of breast cancer deaths will still occur in women diagnosed with breast cancer before screening started. Furthermore, it is difficult to do proper adjustment for better treatment by time. Second, case-control studies where screening participation of breast cancer deaths are compared with screening participation of population controls. This type of studies is, however, sensitive to a possible
selection bias in screening participation. Third, cohort studies including only deaths from breast cancer in cases diagnosed after start of screening. This approach is also called “incidence-based mortality” or “refined mortality” studies. The third type is the least biased approach for evaluating routine screening. The best incidence-based mortality studies derive from settings where it has been possible to compare breast cancer mortality in the screening region with that of both historical and regional controls. Such studies have been performed in Sweden, Finland, and Norway. Data from Finland show a decrease in breast cancer mortality of 28% [14], data from Sweden show a decrease of 13–18%, but these results were highly depending on the estimated lead time [15,16]. Data from Norway showed an 11% decrease [17], where it should be taken into account that Norway had considerable opportunistic mammography activity prior to the organised programme [18]. As screening started in Copenhagen in 1991 and in Funen in 1993, and the national roll-out of screening took place only from 2007 onwards, Denmark offers one of the best opportunities for evaluating the outcome of screening. During the first 10 years of the Copenhagen programme, the breast cancer mortality in screening targeted women decrease by 25% compared with what would have been expected in the absence of screening [19]. The estimate for participating women was a 35% reduction. This study used an incidence-based mortality method, and the expected breast cancer mortality in the absence of screening was estimated from the mortality in Copenhagen prior to screening controlled for contemporary changes in the mortality in Danish non-screening regions [19]. In the period prior to screening, Copenhagen had an excess breast cancer mortality compared to the rest of Denmark; this excess disappeared after start of screening in Copenhagen. Data from Funen are currently being analysed following the same methodology. The breast cancer mortality following the start of the Danish programmes has been evaluated based on time trends in breast cancer mortality in both screening and non-screening regions [20]. This study compared the slope of the mortality trend in a pre-screening period with that of a post-screening period leaving out the first seven years after start of screening. There was no difference in these slopes, and the authors concluded that they were unable to see an effect of the screening programme in breast cancer mortality. As this study did not use the incidence-based mortality method, a considerable part of breast cancer deaths in the post-screening period derived from cases diagnosed prior to screening. Furthermore, changes occurred during the seven years left out of the analysis.
A review supplied with Danish Breast Cancer Cooperative Group data
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Overdiagnosis The breast cancer incidence rate is changed when screening is introduced. The first screen leads to a prevalence peak which will be two times the background incidence if all women are screened in a twoyear period and lead time is assumed to be three years [21]. During the subsequent screens an artificial aging is expected, as breast cancer cases will be diagnosed at an earlier age. After end of screening a compensatory drop is expected. Overdiagnosis occurs if there is an excess cumulative incidence from the total of these three phases. Most randomised controlled trials started screening in the control group immediately after end of the trials. Overdiagnosis can therefore not be assessed from these trials. However, the Malmö trial did not screen the control group in women reaching age 70 before the start of service screening. For women screened at aged 45– 79 years and followed past screening age this trial showed an excess cumulative breast cancer incidence of 10% [22]. The control groups were not screened either in the Canadian trial targeted women aged 40–49 [23] and 50–59 years [24], respectively. Based on data from these three trials, the UK Panel concluded that mammography screening lead to an 11% overdiagnosis [13]. However, the overdiagnosis in the Malmö trial was concentrated to women screened past the age of 70 years with too short further life-expectancy to include the entire compensatory dip in breast cancer incidence after the end of screening [25]. Thus, overdiagnosis was probably estimated too high. Similarly, the overdiagnosis in the Canadian trials might be less than estimated, as women in these trials are expected to have attended routine screening after the end of the trials. Most estimations of overdiagnosis have been based on the outcome of routine screening. This type of study encompasses two problems. First, to identify a suitable control group. Second, to get a sufficiently long follow-up period so the measured cumulative incidence reflects the prevalence peak, the artificial aging, and the compensatory drop. As these two conditions are difficult to fulfil, studies of overdiagnosis have so far mostly involved also some type of modelling. From the Netherlands the lifetime overdiagnosis has been estimated to 2.8% for invited and 4.0% for participating women [26]. For the UK, the relative excess risk up to age 75 was estimated to be 11% [27], while another study estimated the relative excess risk in screening ages to 4–7% [28]. Smaller studies from Italy [29,30] and the early phase of the Copenhagen screening programme [31] show similar results. To assess the possible occurrence of overdiagnosis early after start of the programmes, the breast
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cancer incidence for women aged 50–69 years was followed from before screening until some subsequent screening rounds had been completed [21]. As expected, this study showed a clear prevalence peak, but the incidence in the subsequent screening rounds were within the 95% confidence intervals of the trend expected based on the pre-screening data. This methodology is crude, as it does not entail the follow-up of screened cohorts to post-screening age. Nevertheless, these crude data indicated that if overdiagnosis occurred it would be of relatively modest size [21]. The study from Copenhagen fitting multi state models on the screening data indicated a 7% overdiagnosis based on small numbers [31]. Another analysis of overdiagnosis in Denmark used breast cancer incidence in women aged 50–69 years and looked for the compensatory drop in women aged 70–79 years. The authors concluded that screening was associated with 33% overdiagnosis [32]. This study had a number of limitations, the main thing being that the birth cohorts in the age group 50–69 years were born later than the birth cohorts in the age group 70–79 years, and breast cancer incidence in Denmark has increased steadily across birth cohorts. A cohort study of women invited for screening in Copenhagen and Funen and followed both during the prevalence peak, the artificial aging and the compensatory drop was very recently published by Njor et al. [33]. They assessed the relative risk of being diagnosed with breast cancer in women targeted by the screening programmes as compared to women in the same regions prior to screening and controlled for the contemporary development in breast cancer incidence in non-screening regions. The relative risk of breast cancer was increased during the prevalence screening and slightly above unity in the subsequent screening rounds, and a compensatory dip was seen after the end of invitation to screening. For the entire period the relative risk was 1.04 for all targeted women and 1.02 for targeted women followed for at least eight years after screening. Trends in disease stage in primary breast cancer in Denmark 1990–2011 (not previously published results from DBCG) DBCG data for all of Denmark show that the crude breast cancer incidence has gradually increased from 1990 to 2011; from 126 per 100 000 (95% CI 121–131 per 100 000) to 206 per 100 000 (95% CI 200–212 per 100 000). For the age group 50–69 years, the incidence increased in non-screening regions from 1990 up until the roll-out of national screening in 2008–2010. In the old screening regions, Copenhagen and Funen, the incidence fluctuated around a
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stable level from 1990 to 2011 (Figure 2). Prior to the roll-out of national screening, i.e. up to 2006–2007, the increase in incidence in non-screening regions was observed for both small (0–10 and 11–20 mm) and larger tumours (above 20 mm) (Figure 3A1–3). After the roll-out, the increase in the age group 50–69 years was confined almost to small tumours, though with a small temporary increase in larger tumours in 2008 and 2009. For the age group 70 years of age and older (70⫹), the incidence continued to increase, for both small and larger tumours. In early screening regions, the tumours were generally smaller dominated by tumours up to 2 cm in size (Figure 3B1–3). Up to 2006–2007 the increase in breast cancer incidence in the non-screened areas included both patients with and without lymph node metastases (Figure 4A1–3). Throughout the period 1990–2011, the incidence of node positive among younger patients was fairly constant over time and similar between early and late screening regions (Figure 4A1 and B1). For women 50 years and older in late screening regions, (Figure 4A2) an increase in incidence was seen up to 2006–2007 for both node positive and node negative tumours. For the 50–69 age group in late screening regions, the prevalence peak in 2008– 2009 was dominated by node negative patients, and after 2010–2011 the incidence of node positive tumours declined to 98 per 100 000 per year (95% CI 92–104 per 100 000), which was below the rate of 117 per 100 000 per year (95% CI 113–121 per 100 000) in 2001–2007. For the age group 50–69 years in early screening regions node negative patients were much more frequent than node positive patients in the age group 50–69 years (Figure 4B2). Concerning treatment strategy, marked changes were observed during the period 1990–2011. In the 1990s mastectomy was performed in most patients. In the new millennium, gradually more patients were
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treated with breast conserving surgery (BCS) which is now the most frequent operation (Figure 5). The most pronounced increase in the rate of BCS was observed for the age group 50–69 years from 2006–2007 onwards in in the non-screened regions (Figure 5A2). Although a small temporary increase was seen in 2008–2009, use of mastectomy has otherwise decreased markedly. Up to 2004 registration of DCIS has been incomplete [34]. For the age group 50–69 years a marked increase was seen in the DCIS incidence from 2004 to 2008–2009, where after it decreased (Figure 6). Most DCIS patients were treated with BCIS, but a small increase in mastectomy was also observed during that period. Discussion This review of breast cancer treatment in Denmark based on studies published in peer-reviewed scientific journals supplemented with previously unpublished data from DBCG, clearly documented that during the last decades breast cancer diagnosis and treatment in Denmark have been centralised to dedicated units and that treatment has been in accordance with the international standards. The survival and prognosis of Danish breast cancer patients seem worse than in comparable countries, but there are strong indications that this is caused by a less favourable stage distribution in Denmark. Stage by stage, the Danish survival seems to be fully comparable with the best international standard. Until recently, mammography screening was offered to only one fifth of Danish women, despite the fact that women invited to screening experienced a reduction in breast cancer mortality, comparably to the results of the randomised controlled trials. It is not possible yet to measure the long-term effect on breast cancer mortality of the national roll-out of
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Figure 2. Breast cancer incidence rates 1990–2011 in Denmark according to age. (A) The whole country except Copenhagen and Funen. (B) Copenhagen and Funen, where mammography screening was introduced early (1991 and 1993, respectively).
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A review supplied with Danish Breast Cancer Cooperative Group data (A1)
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Figure 3. Breast cancer incidence rates 1990–2011 in Denmark according to tumour size. (A1–3) The whole country except Copenhagen and Funen. (B1–3) Copenhagen and Funen, where mammography screening was introduced early (1991 and 1993, respectively). A1 and B1: age group up to 49 years; A2 and B2: 50–69 years; A3 and B3: age group 70 ⫹ years.
mammography screening in 2007–2010, but the present data indicate a more favourable stage distribution, fewer patients undergoing mastectomy and axillary clearance, and more patients undergoing less mutilating surgical breast conserving treatment and sentinel lymph node biopsy. The present data give no indication of an increase in number of mastectomies. Based on the data presented in this review, the outcome for Danish breast cancer patients is expected to improve within the next years. Improved staging plays an important part in this progress. Previous studies have documented that a significantly better
relative survival for Swedish as compared to Danish breast cancer patients could be attributed mainly to a better stage distribution in Sweden [4,5], but in both studies there seem to be an additional effect favouring Swedish inhabitants, an effect that persisted after adjustment for differences in the general population-based death rates.These studies included breast cancer patients diagnosed in the 1980s or 1990s, at which time breast cancer treatment was probably more centralised in Sweden than in Denmark, and this might in part explain the difference. The later changes in organisation of breast
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Figure 4. Breast cancer incidence rates 1990–2011 in Denmark according to lymph node status. (A1–3) The whole country except Copenhagen and Funen. (B1–3) Copenhagen and Funen, where mammography screening was introduced early (1991 and 1993, respectively). A1 and B1: age group up to 49 years; A2 and B2: 50–69 years; A3 and B3: age group 70 ⫹ years.
cancer treatment in Denmark should eliminate this difference, and indeed the newest data support that stage by stage Danish breast cancer patients treated in the period 2000–2007 have as good a prognosis as patients treated in Sweden and in other countries included in international comparison [6]. Therefore, it is anticipated that after roll-out of mammography screening, Danish breast cancer patients will within the next years have the same prognosis as patients treated in our neighbouring countries. The effect of screening can be seen from a national perspective or from the perspective of the individual
woman attending screening. It is extremely important to be very specific when addressing this issue. The national perspective is of interest from an economic and political point of view in terms of reducing population mortality and morbidity, and estimating the price of saving lives and reducing morbidity. However, for the woman having to decide whether or not to attend screening, the question is what difference it makes for her. Recently, the EUROSCREEN Working Group published key outcome data from European population-based mammography screening programmes. The focus was on the benefit
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Figure 5. Breast cancer incidence rates 1990–2011 in Denmark according to type of surgery. (A1–3) The whole country except Copenhagen and Funen. (B1–3) Copenhagen and Funen, where mammography screening was introduced early (1991 and 1993, respectively). A1 and B1: age group up to 49 years; A2 and B2: 50–69 years; A3 and B3: age group 70 ⫹ years.
in reduction in breast cancer mortality and on the harms, in terms of overdiagnosis (increase in breast cancer incidence) and false-positive screening results [35]. Screened women were estimated to expect 38– 48% reduction in breast cancer mortality, 6.7% increase in breast cancer incidence, and 3–17% cumulative risk of a false-positive test. In a balance sheet [35] the main results were summarised for
every 1000 women screened for 20 years: 71 breast cancer cases diagnosed, 7–9 lives saved, four cases of overdiagnosis, and 200 women recalled for further assessment, of which 30 having some kind of surgery. Thus, the estimated number of breast cancer deaths avoided by screening far exceeded the estimated number of overdiagnosed breast cancer cases. Based on the Danish results so far, a similar effect is expected
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Figure 6. In situ breast cancer incidence rates 2004–2011 in Denmark according to type of surgery. A: age group up to 49 years; B: 50–69 years; C: age group 70 ⫹ years.
on breast cancer mortality and false-positive tests, but the overdiagnosis is expected to be lower than reported in the European overview. The EUROSCREEN report was very recently followed by a review from The Independent UK Panel on Breast Cancer Screening [13]. Benefits and harms were considered mainly based on results from the randomised controlled trials. Although the final conclusion was that “breast cancer screening extends lives”, the panel found the balance between benefits and harms somewhat more unfavourable than did the EUROSCREEN group [35]. The Panel esti-
mated that for 10 000 invited women offered screening for 20 years, 680 cancers would be discovered, of which 75 (11%) would be overdiagnosed. Fortythree breast cancer deaths would be prevented. Much effort has gone into the discussion on overdiagnosis, and the magnitude of this has been emphasised by a very recent publication from US based on SEER data claiming that in US overdiagnosis accounts for more than 70 000 women per year or 31% of all newly diagnosed breast cancer cases [36]. The authors had no data on the trend in incidence in women not offered screening but estimated this to be up to 0.5% per year, equivalent to twice the increase in incidence for women 40 years of age or younger, and added a correction for effect of hormone replacement treatment (HRT). For women above the age of 40 years, they observed an increase in incidence from 112 per 100 000 in 1976– 1978 to 234 per 100 000 in 2006–2008 (4% per year), and attributed most of this increase to overdiagnosis. For Denmark, we have observed an annual increase in breast cancer incidence of approximately 3% across all age groups in women not offered screening. Recent long-term follow-up data from the early Danish screening programmes [33] indicate overdiagnosis to be 10 times lower than reported from the US [36]. Surely, overdiagnosis is a matter of concern, but it should be put in the right perspective. Overdiagnosed cases will be patients with early manifestations of breast cancer or in situ carcinoma detected at screening, typically undergoing less mutilating treatment regiments (BCS and sentinel lymph node biopsy). These cases are “overdiagnosed” because they are less aggressive slow progressing types of breast cancer that would otherwise not have surfaced during the woman’s lifetime, or because the woman dies from other causes within a relatively short time after diagnosis. In comparing breast cancer incidence in women having undergone three screens with those having undergone one screen only, Zahl et al. [37], suggested also that some early breast cancers would regress without treatment. The paper led to much debate and the interpretation of the results was questioned, suggesting instead differences between the cohorts in use of HRT [38], or simply reflecting artificial ageing. It cannot be ruled out that spontaneous regression of breast cancer occurs, as has also been reported in a few casuistic cases, but it is hard to see the evidence for this to be of quantitative significance. Especially as untreated clinically detected breast cancer seems to regress only very rarely [39,40]. If spontaneous regression indeed is occurring in some cases, we are unfortunately not able to select the tumours expected to have such a favourable prognosis.
A review supplied with Danish Breast Cancer Cooperative Group data Theoretically, predictive factors such as size and hormone receptor status could be evaluated in randomised controlled trials, as suggested recently [41], but in our view, such a study would be unethical and inclusion of patients would be very hard if at all possible. Therefore we have to accept the possibility that some screen-detected patients, but most likely few, are unnecessarily treated in order to give better results for the majority of women with breast cancer.
[8]
[9]
[10]
[11]
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Conclusions Breast cancer treatment in Denmark is evidence based and the recommendations are in agreement with international recommendations. Mammography screening seems to reduces the absolute number of patients with a more advanced stage at diagnosis, and the absolute number of patients undergoing mastectomy.
[12]
[13] [14]
[15]
Acknowledgements Thanks to statistician Karsten Bjerre who helped by making most of the figures. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References [1] NORDCAN database [Internet]. [cited 2012 Mar 8]. Available from: http//www-dep.iarc.fr/nordcan.htm. [2] Coleman MP, Forman D, Bryant H, Butler J, Rachet B, Maringe C, et al. Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995–2007 (the International Cancer Benchmarking Partnership): An analysis of population-based cancer registry data. Lancet 2011; 377:127–38. [3] Mouridsen HT, Bjerre KD, Christiansen P, Jensen M-B, Møller S. Improvement of prognosis in breast cancer in Denmark 1977–2006, based on the nationwide reporting to the DBCG Registry. Acta Oncol 2008;47:525–36. [4] Christensen LH, Engholm G, Ceberg J, Hein S, Perfekt R, Tange UB, et al. Can the survival difference between breast cancer patients in Denmark and Sweden 1989 and 1994 be explained by patho-anatomical variables? – a populationbased study. Eur J Cancer 2004;40:1233–43. [5] Jensen AR, Garne JP, Storm HH, Engholm G, Möller T, Overgaard J. Does stage at diagnosis explain the difference in survival after breast cancer in Denmark and Sweden? Acta Oncol 2004;43:719–26. [6] Walters S, Maringe C, Butler J, Rachet B, Barrett-Lee P, Bergh J, et al. Breast cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK, 2000–2007: A population-based study. Br J Cancer 2013;108:1195–208. [7] Jensen A, Olsen AH, von Euler-Chelpin M, Helle Njor S, Vejborg I, Lynge E. Do nonattenders in mammography
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REVIEW ARTICLE
Position paper: Breast cancer screening, diagnosis, and treatment in Denmark
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PEER CHRISTIANSEN1, ILSE VEJBORG2, NIELS KROMAN3, IBEN HOLTEN4, JENS PETER GARNE5, PETER VEDSTED6, SUSANNE MØLLER7 & ELSEBETH LYNGE8 1Breast
and Endocrine Section, Department of Surgery P, Aarhus University Hospital, Aarhus, Denmark, of Radiology, Copenhagen University Hospital, Copenhagen, Denmark, 3Department of Breast Surgery, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, 4Department of Prevention and Documentation, Danish Cancer Society, Copenhagen, Denmark,5Department of Breast Surgery, Aalborg University Hospital, Aalborg, Denmark, 6The Research Unit for General Practice, Danish Research Centre for Cancer Diagnosis in Primary Care (CaP), School of Public Health, Aarhus University, Aarhus, Denmark, 7DBCG Data Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark and 8Department of Public Health, University of Copenhagen, Copenhagen, Denmark
2Department
ABSTRACT Background. During the last decades the diagnosis, treatment, and prognosis of breast cancer have changed and improved in Denmark. The first mammography screening programme started in 1991. However, for many years only about 20% of Danish women aged 50–69 were offered screening. The national roll-out of screening took place in 2008–2010. Material and methods. Based on published Danish data, this overview describes the status of diagnosis and treatment, and the screening programme. For further evaluating the potential overdiagnosis and overtreatment, additional Danish Breast Cancer Cooperative Group (DBCG) data are included. Results and conclusion. Using incidence-based mortality method, reduction in breast cancer mortality was estimated to be 25% in the target group of women after 10 years of screening in Copenhagen; an outcome comparable to that of randomised controlled trials. A recent Danish study has indicated overdiagnosis to be around 4%. Others have estimated overdiagnosis to be 33%. National DBCG data showed that the rude breast cancer incidence increased during the period 1990–2011 from 126 to 206 per 100 000. The incidence was almost constant for women younger than 50 years. In regions not offering screening, the incidence increased with 3% per year for women aged 50–69 years with similar trends for small and large tumours. After introduction of screening the increase in the age group 50–69 years was confined to small tumours ⱕ 20 mm, and most pronounced for node negative patients. From the 1990s, the use of breast conserving surgery has increased from around 25% to 69% in 2010. Screening has not increased the number of mastectomies. Breast cancer treatment in Denmark is evidence based and in agreement with international recommendations. After the introduction of mammography screening the absolute number of patients with a more advanced stage at diagnosis and the absolute number of patients undergoing mastectomy have decreased. Breast cancer is the most frequent malignancy among women in most western countries. In Denmark, the incidence of breast cancer has increased steadily though being fairly stable during 2002–2006 with 4000 new cases per year [1], while the rates have gone down in some other countries. During the last decades the treatment options for breast cancer have widened and the prognosis has improved significantly, but still
the disease has a considerable mortality, and in Denmark the relative survival is lower than in most other comparable countries [2]. A reduction in the number of women contracting breast cancer is not expected within the nearest future, and therefore a reduction in breast cancer mortality depends on better treatment results. A shortcut is treatment at an earlier stage of the disease. This can be achieved by
Correspondence: P. Christiansen, Breast and Endocrine Section, Department of Surgery P, Aarhus University Hospital, Tage-Hansens Gade 2, 8000 Aarhus, Denmark. E-mail: [email protected]. (Received 7 March 2013 ; accepted 27 November 2013) ISSN 0284-186X print/ISSN 1651-226X online © 2014 Informa Healthcare DOI: 10.3109/0284186X.2013.874573
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mammography screening, which leads to an earlier diagnosis, although criticism has been raised questioning the reduction in breast cancer mortality and focusing on overdiagnosis and overtreatment. The aim of this work is, based on published data, to describe the status of diagnosis and treatment of breast cancer and to present the mammography screening programme in Denmark. In order to further evaluate the extent of potential overdiagnosis and overtreatment; some additional data from the database of the Danish Breast Cancer Cooperative Group (DBCG) are presented in this position paper.
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Breast cancer treatment in Denmark The organisation of breast cancer treatment in Denmark is described in the Supplementary addendum available online at http://informahealthcare.com/doi/ abs/10.3109/0284186X.2013.874573. The survival of breast cancer patients has improved steadily over the last 30 years [3] (Figure 1). A constant improvement of the prognosis according to period of the primary diagnosis is apparent. Thus, the five-year overall survival increased from 65% for patients diagnosed in 1977–1981 to approximately 75–80% for those diagnosed in 2002–2006. Nevertheless, breast cancer survival in Denmark is low relative to otherwise comparable countries. This is partly explained by a relatively unfavourable stage distribution at time of diagnosis, as documented previously in studies comparing Sweden and Denmark [4,5]. More recently it has been further elucidated in a comparison of breast cancer survival and mortality in six countries: UK, Canada, Australian, Norway, Sweden, and Denmark [6]. However, although results at large were poorer in Denmark, both one- and three-year survival by stage were at the average of the other five countries.
Figure 1. Five- and 10-year crude overall survival of Danish breast cancer patients.
Mammography screening in Denmark Organised mammography screening with biennial screening to women aged 50–69 years started in Denmark in 1991 in the municipality of Copenhagen (with the municipality of Frederiksberg included from 1994), and in 1993 in the county of Funen. Together these three areas covered around 20% of the target population of women aged 50–69 years. The rest of women were not offered organised screening. Still opportunistic screening was rare [7]. In 2001, organised mammography screening was introduced in Bornholm and in 2004 in the county of West Zealand. From 2007 to 2010 the national roll-out of the organised screening programme took place. A detailed description of the programme is included in the Supplementary addendum available online at http://informahealthcare.com/doi/ abs/10.3109/0284186X.2013.874573. Quality assurance of mammography screening in Denmark Surrogate, or short-term, measures are used to monitor the quality of mammography screening. These measures are based on data from the randomised controlled trials on correlations between short-term outcomes and long-term effect on breast cancer mortality. The effect from screening stems from its ability to antedate diagnosis ensuring the diagnosis of smaller tumours and less axillary spread. Therefore, the frequency of small tumour size ⬍ 10 mm and number of cases with negative axilla are useful examples of surrogate measures, as is the number of cases diagnosed in the interval between scheduled screens. Surrogate measures from the two longstanding organised mammography screening programmes in Denmark are depicted in Table I [8]. Overall the two programmes performed very similar, though with a higher participation rate in the semirural Funen as compared to the capital of Copenhagen. The Funen programme deliberately kept the recall rate low, which resulted in a somewhat lower detection rate and higher interval cancer rate than in Copenhagen but still within acceptable ranges. The European commission has published: “European guidelines for quality assurance in breast cancer screening and diagnosis” [9]. In these guidelines 39 performance indicators are suggested for use in quality assurance, covering administrative measures as well at radiological, pathological, and surgical aspects. To assure the quality of the national mammography screening programme the National Board of Health and the Danish Regions in 2007 initiated a Danish Database for Quality Assurance of Mammography Screening. A steering committee has been appointed with the responsibility to define national
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Table I. Summary of outcome measures from the two long-standing organised mammography screening programmes in Denmark.
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Indicator Invitation round Participation rate First Subsequent Recall rate First Subsequent Detection rate First per 1000 per year Subsequent per 1000 per year First % of expected Interval cancer rate First per 1000 per year Subsequent per 1000 per year First % of expected Interval/(detected ⫹ interval) % First Subsequent Invasive % of screen detected Node negative % of invasive screen detected ⬍ 10 mm % of invasive screen detected
1991–2008 Copenhagen
1993–2005 Funen
EU Acceptable1
EU Desirable1
71% 62%
85% 82%
⬎ 70%2 ⬎ 70%2
⬎ 75%2 ⬎ 75%2
6.8% 2.8%
2.7% 1.5%
⬍ 7% ⬍ 5%
⬍ 5% ⬍ 3%
5.79 3.20 4.4 X IR
4.47 2.79 4.0 X IR
NA NA 3 X IR
NA NA ⬎ 3 X IR
0.97 1.36 0.34 X IR
1.08 1.33 0.42 X IR
NA NA 0.4 X IR
NA NA ⬍ 0.4 X IR
0.14 0.30 85% 74% 41%
0.19 0.32 88% 68% 35%
NA NA 90% 75%3 ⱖ 25%3
NA NA 80–90% ⬎ 75%3 ⱖ 30%3
IR, breast cancer incidence rate in the absence of screening; NA, not available. et al. 2006 [10]; 2Proportion of women invited that attend for screening. Danish proportions calculated as proportion of women eligible for screening that attended for screening; 3Proportion at subsequent regular screening examinations. Danish proportions calculated as proportion at subsequent invitation rounds.
1Perry
quality indicators and work out national clinical guidelines. Each of the five regions is obliged to send specified data to the database and yearly reports are published on 11 quality indicators. Data after the first round of the national programme showed that the stipulated levels for the various quality indicators were largely met [10], which is expected to lead to a fulfilment of the primary goal of reducing breast cancer mortality (Table II).
Evaluation of mammography screening programmes Mammography screening should be evaluated based on its balance between benefits and harms. The long-term purpose of mammography screening is to decrease breast cancer mortality. This effect is complicated to measure, as the majority of women dying from breast cancer in the first years after the introduction of a screening programme will have
Table II. National Mammography Screening Programme in Denmark. First screening round (2007–2010). Summary of indicator results calculated on a national basis. Indicator 1. Glandular dose (PMMA1 thickness at 4.5 cm) 2. Participation in % of invited in % of target 3. Re-invited within the specified screening interval of 2 years ⫾ 3 months 4. Recalled for assessment 5. Interval cancers 6. Invasive cancers (IC in % of IC⫹ DCIS) 7. Node negative cancers 8. Small cancers (tumour size ⱕ 10 mm) 9. Benign vs. malignant operation ratio 10. Breast conserving surgery (for IC⫾ DCIS) 11. Time to written answer (ⱕ 10 working days)
Standard ⬍ 2.0 mGy ⬎ 75%
National Results (95% CI)
ⱖ 98%
Data not available2 77.4% (77.3–77.5) 76.0% (75.9–76.1) Not calculated3
⬍ 5% ⬍ 30% ⱖ 80 & ⱕ 90% ⬎ 70% ⱖ 25% ⱕ 1:4 ⬎ 50% ⬎ 95%
3.0% (2.9–3.0) Not calculated3 86.4% (85.3–87.3) 67.4% (65.9–68.9) 36.4% (34.7–38.1) 1:6.3 80.2% (78.9–81.4) 71.1% (71.0–71.3)
DCIS, ductal carcinoma in situ; IC, invasive cancers. methacrylate or polymethyl-2-methylpropanoate (PMMA) is the unit used for standardised glandular dose calculation; 2Data not available in first screening round; 3Not relevant in first screening round. 1polymethyl
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been diagnosed with breast cancer prior to the start of the programme. Also, improvement in adjuvant therapy and treatment for disseminated disease will complicate measurements; as such improvements can cause fewer deaths and/or postponement of death of breast cancer, even in the absence of screening. A concern in mammography screening is overdiagnosis, i.e. the diagnosis of breast cancer cases that would otherwise not have become clinical manifest in the women’s lifetime. The main benefit of screening is reduction in breast cancer mortality. The main harm is overdiagnosis and hence overtreatment.
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Reduction in breast cancer mortality Mammography screening was implemented in routine health care based on results from randomised controlled trials showing a reduction in breast cancer mortality in the screening arms of the trials as compared with the control arms. For the trial data, the International Agency for Research on Cancer concluded in 2002 that “there is sufficient evidence for the efficacy of screening women aged 50–69 years by mammography as the sole screening modality in reducing mortality from breast cancer”. The effect was estimated to be a 25% reduction in invited women and a 35% reduction in participating women [11]. The US Preventive Services Task Force concluded in 2009 that the trial data showed a 14% reduction in breast cancer mortality for women offered screening at age 50–59 years, and a 32% reduction for women offered screening at age 60–69 years [12]. Considering data from the majority of trials and all age groups, the UK Independent Panel on Breast Cancer Screening recently concluded that mammography screening decreased breast cancer mortality by 20% [13]. Routine health care might, however, not always reach the same results as seen in randomised controlled trials. It is therefore important to monitor the outcome of routine screening [9]. Ideally, this should be carried out comparing women offered screening with women in an unexposed control group, but this is a complicated task when all women are offered screening. Three approaches have been used in the monitoring of routine screening. First, time trends in breast cancer mortality, but this is not a sensitive approach because during the first many years after start of screening a large proportion of breast cancer deaths will still occur in women diagnosed with breast cancer before screening started. Furthermore, it is difficult to do proper adjustment for better treatment by time. Second, case-control studies where screening participation of breast cancer deaths are compared with screening participation of population controls. This type of studies is, however, sensitive to a possible
selection bias in screening participation. Third, cohort studies including only deaths from breast cancer in cases diagnosed after start of screening. This approach is also called “incidence-based mortality” or “refined mortality” studies. The third type is the least biased approach for evaluating routine screening. The best incidence-based mortality studies derive from settings where it has been possible to compare breast cancer mortality in the screening region with that of both historical and regional controls. Such studies have been performed in Sweden, Finland, and Norway. Data from Finland show a decrease in breast cancer mortality of 28% [14], data from Sweden show a decrease of 13–18%, but these results were highly depending on the estimated lead time [15,16]. Data from Norway showed an 11% decrease [17], where it should be taken into account that Norway had considerable opportunistic mammography activity prior to the organised programme [18]. As screening started in Copenhagen in 1991 and in Funen in 1993, and the national roll-out of screening took place only from 2007 onwards, Denmark offers one of the best opportunities for evaluating the outcome of screening. During the first 10 years of the Copenhagen programme, the breast cancer mortality in screening targeted women decrease by 25% compared with what would have been expected in the absence of screening [19]. The estimate for participating women was a 35% reduction. This study used an incidence-based mortality method, and the expected breast cancer mortality in the absence of screening was estimated from the mortality in Copenhagen prior to screening controlled for contemporary changes in the mortality in Danish non-screening regions [19]. In the period prior to screening, Copenhagen had an excess breast cancer mortality compared to the rest of Denmark; this excess disappeared after start of screening in Copenhagen. Data from Funen are currently being analysed following the same methodology. The breast cancer mortality following the start of the Danish programmes has been evaluated based on time trends in breast cancer mortality in both screening and non-screening regions [20]. This study compared the slope of the mortality trend in a pre-screening period with that of a post-screening period leaving out the first seven years after start of screening. There was no difference in these slopes, and the authors concluded that they were unable to see an effect of the screening programme in breast cancer mortality. As this study did not use the incidence-based mortality method, a considerable part of breast cancer deaths in the post-screening period derived from cases diagnosed prior to screening. Furthermore, changes occurred during the seven years left out of the analysis.
A review supplied with Danish Breast Cancer Cooperative Group data
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Overdiagnosis The breast cancer incidence rate is changed when screening is introduced. The first screen leads to a prevalence peak which will be two times the background incidence if all women are screened in a twoyear period and lead time is assumed to be three years [21]. During the subsequent screens an artificial aging is expected, as breast cancer cases will be diagnosed at an earlier age. After end of screening a compensatory drop is expected. Overdiagnosis occurs if there is an excess cumulative incidence from the total of these three phases. Most randomised controlled trials started screening in the control group immediately after end of the trials. Overdiagnosis can therefore not be assessed from these trials. However, the Malmö trial did not screen the control group in women reaching age 70 before the start of service screening. For women screened at aged 45– 79 years and followed past screening age this trial showed an excess cumulative breast cancer incidence of 10% [22]. The control groups were not screened either in the Canadian trial targeted women aged 40–49 [23] and 50–59 years [24], respectively. Based on data from these three trials, the UK Panel concluded that mammography screening lead to an 11% overdiagnosis [13]. However, the overdiagnosis in the Malmö trial was concentrated to women screened past the age of 70 years with too short further life-expectancy to include the entire compensatory dip in breast cancer incidence after the end of screening [25]. Thus, overdiagnosis was probably estimated too high. Similarly, the overdiagnosis in the Canadian trials might be less than estimated, as women in these trials are expected to have attended routine screening after the end of the trials. Most estimations of overdiagnosis have been based on the outcome of routine screening. This type of study encompasses two problems. First, to identify a suitable control group. Second, to get a sufficiently long follow-up period so the measured cumulative incidence reflects the prevalence peak, the artificial aging, and the compensatory drop. As these two conditions are difficult to fulfil, studies of overdiagnosis have so far mostly involved also some type of modelling. From the Netherlands the lifetime overdiagnosis has been estimated to 2.8% for invited and 4.0% for participating women [26]. For the UK, the relative excess risk up to age 75 was estimated to be 11% [27], while another study estimated the relative excess risk in screening ages to 4–7% [28]. Smaller studies from Italy [29,30] and the early phase of the Copenhagen screening programme [31] show similar results. To assess the possible occurrence of overdiagnosis early after start of the programmes, the breast
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cancer incidence for women aged 50–69 years was followed from before screening until some subsequent screening rounds had been completed [21]. As expected, this study showed a clear prevalence peak, but the incidence in the subsequent screening rounds were within the 95% confidence intervals of the trend expected based on the pre-screening data. This methodology is crude, as it does not entail the follow-up of screened cohorts to post-screening age. Nevertheless, these crude data indicated that if overdiagnosis occurred it would be of relatively modest size [21]. The study from Copenhagen fitting multi state models on the screening data indicated a 7% overdiagnosis based on small numbers [31]. Another analysis of overdiagnosis in Denmark used breast cancer incidence in women aged 50–69 years and looked for the compensatory drop in women aged 70–79 years. The authors concluded that screening was associated with 33% overdiagnosis [32]. This study had a number of limitations, the main thing being that the birth cohorts in the age group 50–69 years were born later than the birth cohorts in the age group 70–79 years, and breast cancer incidence in Denmark has increased steadily across birth cohorts. A cohort study of women invited for screening in Copenhagen and Funen and followed both during the prevalence peak, the artificial aging and the compensatory drop was very recently published by Njor et al. [33]. They assessed the relative risk of being diagnosed with breast cancer in women targeted by the screening programmes as compared to women in the same regions prior to screening and controlled for the contemporary development in breast cancer incidence in non-screening regions. The relative risk of breast cancer was increased during the prevalence screening and slightly above unity in the subsequent screening rounds, and a compensatory dip was seen after the end of invitation to screening. For the entire period the relative risk was 1.04 for all targeted women and 1.02 for targeted women followed for at least eight years after screening. Trends in disease stage in primary breast cancer in Denmark 1990–2011 (not previously published results from DBCG) DBCG data for all of Denmark show that the crude breast cancer incidence has gradually increased from 1990 to 2011; from 126 per 100 000 (95% CI 121–131 per 100 000) to 206 per 100 000 (95% CI 200–212 per 100 000). For the age group 50–69 years, the incidence increased in non-screening regions from 1990 up until the roll-out of national screening in 2008–2010. In the old screening regions, Copenhagen and Funen, the incidence fluctuated around a
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stable level from 1990 to 2011 (Figure 2). Prior to the roll-out of national screening, i.e. up to 2006–2007, the increase in incidence in non-screening regions was observed for both small (0–10 and 11–20 mm) and larger tumours (above 20 mm) (Figure 3A1–3). After the roll-out, the increase in the age group 50–69 years was confined almost to small tumours, though with a small temporary increase in larger tumours in 2008 and 2009. For the age group 70 years of age and older (70⫹), the incidence continued to increase, for both small and larger tumours. In early screening regions, the tumours were generally smaller dominated by tumours up to 2 cm in size (Figure 3B1–3). Up to 2006–2007 the increase in breast cancer incidence in the non-screened areas included both patients with and without lymph node metastases (Figure 4A1–3). Throughout the period 1990–2011, the incidence of node positive among younger patients was fairly constant over time and similar between early and late screening regions (Figure 4A1 and B1). For women 50 years and older in late screening regions, (Figure 4A2) an increase in incidence was seen up to 2006–2007 for both node positive and node negative tumours. For the 50–69 age group in late screening regions, the prevalence peak in 2008– 2009 was dominated by node negative patients, and after 2010–2011 the incidence of node positive tumours declined to 98 per 100 000 per year (95% CI 92–104 per 100 000), which was below the rate of 117 per 100 000 per year (95% CI 113–121 per 100 000) in 2001–2007. For the age group 50–69 years in early screening regions node negative patients were much more frequent than node positive patients in the age group 50–69 years (Figure 4B2). Concerning treatment strategy, marked changes were observed during the period 1990–2011. In the 1990s mastectomy was performed in most patients. In the new millennium, gradually more patients were
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treated with breast conserving surgery (BCS) which is now the most frequent operation (Figure 5). The most pronounced increase in the rate of BCS was observed for the age group 50–69 years from 2006–2007 onwards in in the non-screened regions (Figure 5A2). Although a small temporary increase was seen in 2008–2009, use of mastectomy has otherwise decreased markedly. Up to 2004 registration of DCIS has been incomplete [34]. For the age group 50–69 years a marked increase was seen in the DCIS incidence from 2004 to 2008–2009, where after it decreased (Figure 6). Most DCIS patients were treated with BCIS, but a small increase in mastectomy was also observed during that period. Discussion This review of breast cancer treatment in Denmark based on studies published in peer-reviewed scientific journals supplemented with previously unpublished data from DBCG, clearly documented that during the last decades breast cancer diagnosis and treatment in Denmark have been centralised to dedicated units and that treatment has been in accordance with the international standards. The survival and prognosis of Danish breast cancer patients seem worse than in comparable countries, but there are strong indications that this is caused by a less favourable stage distribution in Denmark. Stage by stage, the Danish survival seems to be fully comparable with the best international standard. Until recently, mammography screening was offered to only one fifth of Danish women, despite the fact that women invited to screening experienced a reduction in breast cancer mortality, comparably to the results of the randomised controlled trials. It is not possible yet to measure the long-term effect on breast cancer mortality of the national roll-out of
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Figure 2. Breast cancer incidence rates 1990–2011 in Denmark according to age. (A) The whole country except Copenhagen and Funen. (B) Copenhagen and Funen, where mammography screening was introduced early (1991 and 1993, respectively).
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Figure 3. Breast cancer incidence rates 1990–2011 in Denmark according to tumour size. (A1–3) The whole country except Copenhagen and Funen. (B1–3) Copenhagen and Funen, where mammography screening was introduced early (1991 and 1993, respectively). A1 and B1: age group up to 49 years; A2 and B2: 50–69 years; A3 and B3: age group 70 ⫹ years.
mammography screening in 2007–2010, but the present data indicate a more favourable stage distribution, fewer patients undergoing mastectomy and axillary clearance, and more patients undergoing less mutilating surgical breast conserving treatment and sentinel lymph node biopsy. The present data give no indication of an increase in number of mastectomies. Based on the data presented in this review, the outcome for Danish breast cancer patients is expected to improve within the next years. Improved staging plays an important part in this progress. Previous studies have documented that a significantly better
relative survival for Swedish as compared to Danish breast cancer patients could be attributed mainly to a better stage distribution in Sweden [4,5], but in both studies there seem to be an additional effect favouring Swedish inhabitants, an effect that persisted after adjustment for differences in the general population-based death rates.These studies included breast cancer patients diagnosed in the 1980s or 1990s, at which time breast cancer treatment was probably more centralised in Sweden than in Denmark, and this might in part explain the difference. The later changes in organisation of breast
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Figure 4. Breast cancer incidence rates 1990–2011 in Denmark according to lymph node status. (A1–3) The whole country except Copenhagen and Funen. (B1–3) Copenhagen and Funen, where mammography screening was introduced early (1991 and 1993, respectively). A1 and B1: age group up to 49 years; A2 and B2: 50–69 years; A3 and B3: age group 70 ⫹ years.
cancer treatment in Denmark should eliminate this difference, and indeed the newest data support that stage by stage Danish breast cancer patients treated in the period 2000–2007 have as good a prognosis as patients treated in Sweden and in other countries included in international comparison [6]. Therefore, it is anticipated that after roll-out of mammography screening, Danish breast cancer patients will within the next years have the same prognosis as patients treated in our neighbouring countries. The effect of screening can be seen from a national perspective or from the perspective of the individual
woman attending screening. It is extremely important to be very specific when addressing this issue. The national perspective is of interest from an economic and political point of view in terms of reducing population mortality and morbidity, and estimating the price of saving lives and reducing morbidity. However, for the woman having to decide whether or not to attend screening, the question is what difference it makes for her. Recently, the EUROSCREEN Working Group published key outcome data from European population-based mammography screening programmes. The focus was on the benefit
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Figure 5. Breast cancer incidence rates 1990–2011 in Denmark according to type of surgery. (A1–3) The whole country except Copenhagen and Funen. (B1–3) Copenhagen and Funen, where mammography screening was introduced early (1991 and 1993, respectively). A1 and B1: age group up to 49 years; A2 and B2: 50–69 years; A3 and B3: age group 70 ⫹ years.
in reduction in breast cancer mortality and on the harms, in terms of overdiagnosis (increase in breast cancer incidence) and false-positive screening results [35]. Screened women were estimated to expect 38– 48% reduction in breast cancer mortality, 6.7% increase in breast cancer incidence, and 3–17% cumulative risk of a false-positive test. In a balance sheet [35] the main results were summarised for
every 1000 women screened for 20 years: 71 breast cancer cases diagnosed, 7–9 lives saved, four cases of overdiagnosis, and 200 women recalled for further assessment, of which 30 having some kind of surgery. Thus, the estimated number of breast cancer deaths avoided by screening far exceeded the estimated number of overdiagnosed breast cancer cases. Based on the Danish results so far, a similar effect is expected
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Figure 6. In situ breast cancer incidence rates 2004–2011 in Denmark according to type of surgery. A: age group up to 49 years; B: 50–69 years; C: age group 70 ⫹ years.
on breast cancer mortality and false-positive tests, but the overdiagnosis is expected to be lower than reported in the European overview. The EUROSCREEN report was very recently followed by a review from The Independent UK Panel on Breast Cancer Screening [13]. Benefits and harms were considered mainly based on results from the randomised controlled trials. Although the final conclusion was that “breast cancer screening extends lives”, the panel found the balance between benefits and harms somewhat more unfavourable than did the EUROSCREEN group [35]. The Panel esti-
mated that for 10 000 invited women offered screening for 20 years, 680 cancers would be discovered, of which 75 (11%) would be overdiagnosed. Fortythree breast cancer deaths would be prevented. Much effort has gone into the discussion on overdiagnosis, and the magnitude of this has been emphasised by a very recent publication from US based on SEER data claiming that in US overdiagnosis accounts for more than 70 000 women per year or 31% of all newly diagnosed breast cancer cases [36]. The authors had no data on the trend in incidence in women not offered screening but estimated this to be up to 0.5% per year, equivalent to twice the increase in incidence for women 40 years of age or younger, and added a correction for effect of hormone replacement treatment (HRT). For women above the age of 40 years, they observed an increase in incidence from 112 per 100 000 in 1976– 1978 to 234 per 100 000 in 2006–2008 (4% per year), and attributed most of this increase to overdiagnosis. For Denmark, we have observed an annual increase in breast cancer incidence of approximately 3% across all age groups in women not offered screening. Recent long-term follow-up data from the early Danish screening programmes [33] indicate overdiagnosis to be 10 times lower than reported from the US [36]. Surely, overdiagnosis is a matter of concern, but it should be put in the right perspective. Overdiagnosed cases will be patients with early manifestations of breast cancer or in situ carcinoma detected at screening, typically undergoing less mutilating treatment regiments (BCS and sentinel lymph node biopsy). These cases are “overdiagnosed” because they are less aggressive slow progressing types of breast cancer that would otherwise not have surfaced during the woman’s lifetime, or because the woman dies from other causes within a relatively short time after diagnosis. In comparing breast cancer incidence in women having undergone three screens with those having undergone one screen only, Zahl et al. [37], suggested also that some early breast cancers would regress without treatment. The paper led to much debate and the interpretation of the results was questioned, suggesting instead differences between the cohorts in use of HRT [38], or simply reflecting artificial ageing. It cannot be ruled out that spontaneous regression of breast cancer occurs, as has also been reported in a few casuistic cases, but it is hard to see the evidence for this to be of quantitative significance. Especially as untreated clinically detected breast cancer seems to regress only very rarely [39,40]. If spontaneous regression indeed is occurring in some cases, we are unfortunately not able to select the tumours expected to have such a favourable prognosis.
A review supplied with Danish Breast Cancer Cooperative Group data Theoretically, predictive factors such as size and hormone receptor status could be evaluated in randomised controlled trials, as suggested recently [41], but in our view, such a study would be unethical and inclusion of patients would be very hard if at all possible. Therefore we have to accept the possibility that some screen-detected patients, but most likely few, are unnecessarily treated in order to give better results for the majority of women with breast cancer.
[8]
[9]
[10]
[11]
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Conclusions Breast cancer treatment in Denmark is evidence based and the recommendations are in agreement with international recommendations. Mammography screening seems to reduces the absolute number of patients with a more advanced stage at diagnosis, and the absolute number of patients undergoing mastectomy.
[12]
[13] [14]
[15]
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