Breast cancer mortality and overdiagnosis after implementation of population-based screening in Denmark.

INTRODUCTION: Service breast cancer screening is difficult to evaluate because there is no unscreened control group. Due to a natural experiment, where 20% of women were offered screening in two regions up to 17 years before other women, Denmark is in a unique position. We utilized this opportunity to assess outcome of service screening. MATERIALS AND METHODS: Screening was offered in Copenhagen from 1991 and Funen from 1993 to women aged 50-69 years. We used difference-in-differences methodology with a study group offered screening; a historical control group; a regional control group; and a regional-historical control group, comparing breast cancer mortality and incidence, including ductal carcinoma in situ, between study and historical control group adjusted for changes in other regions, and calculating ratios of rate ratios (RRR) with 95% confidence intervals (CI). Data came from Central Population Register; mammography screening databases; Cause of Death Register; and Danish Cancer Register. RESULTS: For breast cancer mortality, the study group accumulated 1,551,465 person-years and 911 deaths. Long-term breast cancer mortality in Copenhagen was 20% below expected in absence of screening; RRR 0.80 (95% CI 0.71-0.90), and in Funen 22% below; RRR 0.78 (95% CI 0.68-0.89). Combined, cumulative breast cancer incidence in women followed 8+ years post-screening was 2.3% above expected in absence of screening; RRR 1.023 (95% CI 0.97-1.08). DISCUSSION: Benefit-to-harm ratio of the two Danish screening programs was 2.6 saved breast cancer deaths per overdiagnosed case. Screening can affect only breast cancers diagnosed in screening age. Due to high breast cancer incidence after age 70, only one-third of breast cancer deaths after age 50 could potentially be affected by screening. Increasing upper age limit could be considered, but might affect benefit-to-harm ratio negatively.

Outcome of breast cancer screening in Denmark.

BACKGROUND: In Denmark, national roll-out of a population-based, screening mammography program took place in 2007-2010. We report on outcome of the first four biennial invitation rounds. METHODS: Data on screening outcome were retrieved from the 2015 and 2016 national screening quality reports. We calculated coverage by examination; participation after invitation; detection-, interval cancer- and false-positive rates; cancer characteristics; sensitivity and specificity, for Denmark and for the five regions. RESULTS: At the national level coverage by examination remained at 75-77%; lower in the Capital Region than in the rest of Denmrk. Detection rate was slightly below 1% at first screen, 0.6% at subsequent screens, and one region had some fluctuation over time. Ductal carcinoma in situ (DCIS) constituted 13-14% of screen-detected cancers. In subsequent rounds, 80% of screen-detected invasive cancers were node negative and 40% ≤10 mm. False-positive rate was around 2%; higher for North Denmark Region than for the rest of Denmark. Three out of 10 breast cancers in screened women were diagnosed as interval cancers. CONCLUSIONS: High coverage by examination and low interval cancer rate are required for screening to decrease breast cancer mortality. Two pioneer local screening programs starting in the 1990s were followed by a decrease in breast cancer mortality of 22-25%. Coverage by examination and interval cancer rate of the national program were on the favorable side of values from the pioneer programs. It appears that the implementation of a national screening program in Denmark has been successful, though regional variations need further evaluation to assure optimization of the program.

Mammographic density in birth cohorts of Danish women: a longitudinal study.

BACKGROUND: Breast cancer is the leading malignant disease among western women with incidence increasing over time. High mammographic density is a well-established risk factor for breast cancer. We explored trends in mammographic density across birth cohorts to gain further insight into possible time trends in women's mammographic density that might explain the historical increase in breast cancer incidence. METHODS: Data derived from two mammography screening programs in Denmark from 1991 to 2001, including on average 41,091 women from Copenhagen and 52,938 women from Funen aged 50-69. Mammographic density was assessed qualitatively (fatty or mixed/dense) by senior screening radiologists. The proportion of women with mixed/dense mammographic density was calculated by age at screening, screening period, and birth cohort. The Generalized Estimating Equations were used to calculate odds ratios and 95% confidence intervals. All statistical tests were two-sided. RESULTS: The proportion of women with mixed/dense mammographic density increased from 45% among women born in the 1920s to 75-80% among women born in the 1940s. In Copenhagen, the age-adjusted odds ratio (95% CI) of mixed/dense mammographic density in women born in 1941-42 was 2.48 (2.22-2.76) compared with women born in 1921-22. In Funen, the age-adjusted odds ratio of mixed/dense mammographic density in women born in 1946-47 was 5.89 (5.32-6.51) compared with women born in 1924-25. Hormone use had a greater impact on mammographic density in birth cohorts of the 1920s compared with those of the 1940s. CONCLUSIONS: We found suggestive evidence of a birth cohort pattern in mammographic density and an attenuated impact of hormone use in younger compared with older birth cohorts suggesting that postmenopausal mammographic density could be linked to changing exposures accumulated over time in women's lives.

Seventeen-years overview of breast cancer inside and outside screening in Denmark.

BACKGROUND: Long-term data on breast cancer detection in mammography screening programs are warranted to better understand the mechanisms by which screening changes the breast cancer pattern in the population. We aimed to analyze 17 years of breast cancer detection rates inside and outside screening in two Danish regions, emphasizing the influence of organizational differences of screening programs on the outcomes. MATERIAL AND METHODS: We used data from two long-standing population-based mammography screening programs, Copenhagen and Fyn, in Denmark. Both programs offered biennial screening to women aged 50-69 years. We identified targeted, eligible, invited and participating women. We calculated screening detection and interval cancer rates for participants, and breast cancer incidence in non-screened women (= targeted women excluding participants) by biennial invitation rounds. Tumor characteristics were tabulated for each of the three groups of cancers. RESULTS: Start of screening resulted in a prevalence peak in participants, followed by a decrease to a fairly stable detection rate in subsequent invitation rounds. A similar pattern was found for breast cancer incidence in non-screened women. In Fyn, non-screened women even had a higher rate than screening participants during the first three invitation rounds. The interval cancer rate was lower in Copenhagen than in Fyn, with an increase over time in Copenhagen, but not in Fyn. Screen-detected cancers showed tumor features related with a better prognosis than tumors detected otherwise, as more than 80% were smaller than 20 mm and estrogen receptor positive. CONCLUSION: Data from two long-standing population-based screening programs in Denmark illustrated that even if background breast cancer incidence and organization were rather similar, performance indicators of screening could be strongly influenced by inclusion criteria and participation rates. Detection rates should be interpreted with caution as they may be biased by selection into the screening population.

Mammography screening in Denmark.

Mammography screening is offered healthy women, and a high standard on professional and organizational level is mandatory not only in the screening programme but even in the diagnostic work-up and treatment. The main goal is to achieve a substantial reduction in disease specific mortality, but it is not possible to evaluate the effect on mortality until several years later, and continuously monitoring of the quality of all aspects of a screening programme is necessary. Based on other European guidelines, 11 quality indicators have been defined, and guidelines concerning organizational requirements for a Danish screening programme as well as recommendations for the radiographic and radiological work have been drawn up.

Morbidity as a Predictor for Participation in the Danish National Mammography Screening Program: A Cross-Sectional Study.

PURPOSE: In this cross-sectional study, we evaluated the association between morbidity and participation in the prevalence round of the Danish national mammography screening program. PATIENTS AND METHODS: Morbidity was assessed by the Charlson Comorbidity Index (CCI) score (0, 1-2, and ≥3) and by 19 individual diagnoses. We retrieved data on participation from The Danish Quality Database of Mammography Screening and on diagnoses from The Danish National Patient Registry. We estimated prevalence proportion ratios (PR) with 95% confidence intervals (CI). RESULTS: In total, 519,009 (79.8%) women participated in the first national breast cancer screening round. Relative to women with a CCI score of 0, the adjusted PRs were 0.96 (95% CI: 0.95-0.96) for a CCI score of 1-2 and 0.80 (95% CI: 0.79-0.81) for a CCI score of ≥3. Compared with no disease, the PRs for a diagnosis of the most prevalent, but less severe diseases, chronic pulmonary disease, cerebrovascular disease, diabetes I and II were 0.93 (95% CI: 0.93-0.94), 0.96 (95% CI: 0.94-0.96), and 0.96 (95% CI: 0.95-0.97), respectively. Among women with low prevalent, but most severe diseases, the PRs were 0.69 (95% CI: 0.60-0.81) for AIDS and 0.73 (95% CI: 0.70-0.76) for metastatic solid tumor. CONCLUSION: Women with a high CCI score or one severe chronic condition are less likely to participate in breast cancer screening compared to women without disease. However, these women account for a small proportion of all non-participating women. Thus, it might be most beneficial to maximize breast cancer screening participation in women with less severe although more common morbidities.

Impact of chronic diseases on effect of breast cancer screening.

BACKGROUND: Although breast cancer screening reduces breast cancer mortality at the population level, subgroups of women may benefit differently. We investigated the impact of health status on the effect of breast cancer screening. METHODS: The study included 181 299 women invited in two population-based screening programs in Denmark and 1 526 446 control subjects, followed from April 1981 to December 2014. Poisson regressions were used to compare the observed breast cancer mortality rate in women invited to screening with the expected rate in the absence of screening among women with and without chronic diseases. Chronic diseases were defined as any diagnosis in the Charlson Comorbidity Index during 4 years before the first invitation to screening. RESULTS: Almost 10% of women had chronic diseases before first invitation to screening. Whereas we observed a reduction in breast cancer mortality following invitation to screening of 28% (95% CI, 20% to 35%) among women without chronic diseases, only a 7% (95% CI, -39% to 37%) reduction was seen for women with chronic diseases (P-value for interaction = .22). For participants, the reduction, corrected for selection bias, was 35% (95% CI 16% to 49%) for women without, and 4% (95% CI -146% to 62%) for women with chronic diseases (P-value for interaction = .43). CONCLUSION: Our data indicate a marginal effect of mammography screening on breast cancer mortality in women with chronic diseases. If our results are confirmed in other populations, the presence of chronic diseases will be an important factor to take into consideration in personalized screening.

Minimizing misclassification of hormone users at mammography screening.

The aim of the study was to retrospectively determine the impact of comparing current mammograms with prior mammograms on risk of misclassification especially for hormone users. Data on mammography screening were retrieved for 1993-2005 from Fyn, Denmark. At first screen, two projections were made; at subsequent screens, one projection for fatty and two projections for mixed/dense breasts. Until June 3, 2002, 2-year-old mammograms were used for comparison, and later 4-year-old mammograms. Prescription drug data were used to identify hormone, hormone therapy (HT), use. False positive risk and interval cancer proportion dependency on age, hormone use, screen number, projection and prior mammogram were tested with logistic regression. Controlled for breast density, current HT-users had a lower risk of a false positive test 0.69 (95%CI 0.55-0.86) and a lower interval cancer proportion 0.66 (95%CI 0.45-0.99) when 4-year-old instead of 2-year-old mammograms were used for comparison. The use of 4-year-old instead of 2-year-old mammograms for comparison lowered the risk of false positive test in never users, but otherwise age of comparison mammogram had no impact on classification of never and past users of HT. The study indicated that misclassification at screening mammography in current users of HT can be reduced considerably, when the screening mammograms are viewed with the mammograms taken 4 years earlier. It should be stressed that these results come from a single clinic, and replication in other observational and/or experimental studies is warranted.

Socio-demographic determinants of participation in mammography screening.

Our objective was to use individual data on socio-demographic characteristics to identify predictors of participation in mammography screening and control to what extent they can explain the regional difference. We used data from mammography screening programmes in Copenhagen, 1991-1999, and Funen, 1993-2001, Denmark. Target groups were identified from the Population Register, screening data came from the health authority, and socio-demographic data from Statistics Denmark. Included were women eligible for at least 3 screens. The crude RR of never use versus always use was 3.21 (95%CI, 3.07-3.35) for Copenhagen versus Funen, and the adjusted RR was 2.55 (95%CI, 2.43-2.67). The adjusted RR for never use among women without contact to a primary care physician was 2.50 (95% CI, 2.31-2.71) and 2.89 (95% CI, 2.66-3.14), and for women without dental care 2.94 (95% CI, 2.77-3.12) and 2.88 (95% CI, 2.68-3.10) for Copenhagen and Funen, respectively. Other important predictive factors for nonparticipation were not being married and not being Danish. In conclusion, to enhance participation in mammography screening programmes special attention needs to be given to women not using other primary health care services. All women in Copenhagen, irrespective of their socio-demographic characteristics, had low participation. Screening programmes have to find ways to handle this urbanity factor.

Performance of systematic and non-systematic ('opportunistic') screening mammography: a comparative study from Denmark.

OBJECTIVES: Evaluation and comparison of the performance of organized and opportunistic screening mammography. METHODS: Women attending screening mammography in Denmark in 2000. The study included 37,072 women attending organized screening. Among these, 320 women were diagnosed with breast cancer during follow-up. Opportunistic screening was attended by 2855 women with 26 women being diagnosed with breast cancer. Data on women attending screening were linked with information on cancer status. Each woman was followed with respect to diagnosis of breast cancer (invasive as well as in situ) for a period of two years. Screening outcome and cancer status during follow-up were combined to assess whether the result of the examination was true-positive, true-negative, false-positive or false-negative. Based on this classification, age-adjusted sensitivity and specificity of organized and opportunistic screening were calculated. RESULTS: Defining BI-RADS(trade mark) 4-5 as a positive screening outcome, the overall sensitivity of opportunistic screening was 33.6% and the specificity was 99.1%. Using BI-RADS(trade mark) 3-5 as positive, the sensitivity was 37.4% and the specificity was 97.9%. Organized screening (which was not categorized according to BI-RADS(trade mark)) had an overall sensitivity of 67.2% and a specificity of 98.4%. CONCLUSION: Our study showed a considerably higher sensitivity in organized screening than in opportunistic screening, while the specificity was fairly similar in the two settings. The findings support implementation of population-based breast screening programmes, as recommended in the 'European guidelines for quality assurance in breast cancer screening and diagnosis'.

Predicting the risk of a false-positive test for women following a mammography screening programme.

OBJECTIVES: The objectives of this study was to provide a simple estimate of the cumulative risk of a false-positive test for women participating in mammography screening. To test the method, we used data from two well-established, organized mammography screening programmes offering biennial screening to women aged 50-69 years in Copenhagen and Fyn, Denmark. METHODS: We defined the outcome from a screen as being either a false-positive test or not a false-positive test. We then tested whether the outcomes from subsequent screens were independent, and afterwards estimated the risk over 10 screens of a false-positive test, i.e. the risk of getting at least one false-positive test for a woman participating in all 10 screens typically offered in Europe. RESULTS: The outcomes of subsequent screens were found to be independent. After completion of screening rounds 3-5, the risk of a false-positive test over 10 screens was predicted to be 15.8-21.5% for a woman participating in the programme in Copenhagen, and 8.1-9.6% for a woman participating in the programme in Fyn. CONCLUSIONS: Our study showed that a relatively robust prediction of the risk of a false-positive test over 10 screens can be calculated in a simple way relatively early after the start of a mammography screening programme.

Decline in breast cancer mortality: how much is attributable to screening?

OBJECTIVES: When estimating the decline in breast cancer mortality attributable to screening, the challenge is to provide valid comparison groups and to distinguish the screening effect from other effects. In Funen, Denmark, multidisciplinary breast cancer management teams started before screening was introduced; both activities came later in the rest of Denmark. Because Denmark had national protocols for breast cancer treatment, but hardly any opportunistic screening, Funen formed a "natural experiment", providing valid comparison groups and enabling the separation of the effect of screening from other factors. METHODS: Using Poisson regression we compared the observed breast cancer mortality rate in Funen after implementation of screening with the expected rate without screening. The latter was estimated from breast cancer mortality in the rest of Denmark controlled for historical differences between Funen/rest of Denmark. As multidisciplinary teams were introduced gradually in the rest of Denmark from 1994, the screening effect was slightly underestimated. RESULTS: Over 14 years, women targeted by screening in Funen experienced a 22% (95% confidence interval 11%-32%) reduction in breast cancer mortality associated with screening (a reduction in breast cancer mortality rate from 61 to 47 per 100,000). The estimated reduction for participants corrected for selection bias was 28% (13%-41%). Excluding deaths in breast cancer cases diagnosed after end of screening, these numbers became 26% and 31%, respectively. CONCLUSIONS: There is additional benefit in reducing breast cancer mortality from the early detection of breast cancer through mammographic screening over and above the benefits arising from improvements in treatment alone.

Overdiagnosis in screening mammography in Denmark: population based cohort study.

OBJECTIVE: To use data from two longstanding, population based screening programmes to study overdiagnosis in screening mammography. DESIGN: Population based cohort study. SETTING: Copenhagen municipality (from 1991) and Funen County (from 1993), Denmark. PARTICIPANTS: 57,763 women targeted by organised screening, aged 56-69 when the screening programmes started, and followed up to 2009. MAIN OUTCOME MEASURES: Overdiagnosis of breast cancer in women targeted by screening, assessed by relative risks compared with historical control groups from screening regions, national control groups from non-screening regions, and historical national control groups. RESULTS: In total, 3279 invasive breast carcinomas and ductal carcinomas in situ occurred. The start of screening led to prevalence peaks in breast cancer incidence: relative risk 2.06 (95% confidence interval 1.64 to 2.59) for Copenhagen and 1.84 (1.46 to 2.32) for Funen. During subsequent screening rounds, relative risks were slightly above unity: 1.04 (0.85 to 1.27) for Copenhagen and 1.14 (0.98 to 1.32) for Funen. A compensatory dip was seen after the end of invitation to screening: relative risk 0.80 (0.65 to 0.98) for Copenhagen and 0.67 (0.55 to 0.81) for Funen during the first four years. The relative risk of breast cancer accumulated over the entire follow-up period was 1.06 (0.90 to 1.25) for Copenhagen and 1.01 (0.93 to 1.10) for Funen. Relative risks for participants corrected for selection bias were estimated to be 1.08 for Copenhagen and 1.02 for Funen; for participants followed for at least eight years after the end of screening, they were 1.05 and 1.01. A pooled estimate gave 1.040 (0.99 to 1.09) for all targeted women and 1.023 (0.97 to 1.08) for targeted women followed for at least eight years after the end of screening. CONCLUSIONS: On the basis of combined data from the two screening programmes, this study indicated that overdiagnosis most likely amounted to 2.3% (95% confidence interval -3% to 8%) in targeted women. Among participants, it was most likely 1-5%. At least eight years after the end of screening were needed to compensate for the excess incidence during screening.

Existing data sources for clinical epidemiology: the Danish Quality Database of Mammography Screening.

The Danish Quality Database of Mammography Screening (DKMS) was established in 2007, when screening was implemented on a nationwide basis and offered biennially to all Danish women aged 50-69 years. The primary aims of the database are to monitor and evaluate the quality of the screening program and - after years of follow-up - to evaluate the effect of nationwide screening on breast cancer-specific mortality. Here, we describe the database and present results for quality assurance from the first round of national screening. The steering committee for the DKMS defined eleven organizational and clinical quality indicators and standards to monitor the Danish breast cancer screening program. We calculated the relevant proportions and ratios with 95% confidence intervals for each quality indicator. All indicators were assessed on a national and regional level. Of 670,039 women invited for mammography, 518,823 (77.4%) participated. Seventy-one percent of the women received the result of their mammography examination within 10 days of screening, and 3% of the participants were recalled for further investigation. Among all detected cancers, 86% were invasive cancers, and the proportion of women with node negative cancer was 67%. There were 36% women with small cancers, and the ratio of surgery for benign lesions to malignant lesions was 1:6.3. A total of 80% of women with invasive cancers were treated with breast conserving therapy. Screening interval and interval cancers were not relevant in the first round, and data regarding radiation dose were not available at the time of evaluation. Overall, the quality indicators showed satisfactory quality in the first round of national breast cancer screening in Denmark. The DKMS is a potentially valuable tool for improving quality and conducting research in the field of breast cancer screening.

Type of hormone therapy and risk of misclassification at mammography screening.

OBJECTIVE: Current users of hormone therapy (HT) are known to have a lower accuracy of mammography screening than do never users. We studied whether the risk of misclassification depends on type of hormone, administration, regimen, and dose of the therapy. METHODS: We linked data from mammography screening registers with drug prescription registers from Fyn, Denmark to identify current and never HT users among screening participants. We compared false-positive risks and interval cancer proportions between current users of different HT preparations, taking women's age, breast density, screen number, and age of comparison mammogram into account. RESULTS: Estrogen therapy users had a significantly higher false-positive risk when the administration was by injection instead of oral (relative risk [RR], 2.37; 95% CI, 1.37-4.09). Women using sequential estrogen plus progestogen therapy had a significantly higher false-positive risk (RR, 1.94; 95% CI, 1.16-3.26) and a nonsignificantly higher interval cancer proportion (RR, 4.29; 95% CI, 0.69-26.53) when the administration of both hormones was transdermal instead of oral. Using tibolone instead of comparable hormones gave a nonsignificantly lower false-positive risk and a nonsignificantly higher interval cancer proportion. CONCLUSIONS: Our data showed increased risks of misclassification at mammography screening among women using estrogen injections or transdermal, sequential estrogen plus progestogen. Tibolone seems to offer no advantage regarding accuracy of screening mammography.

[Fine needle aspiration cytology of mammography screening]. / Finnålsaspirationscytologi ved mammografiscreening.

INTRODUCTION: In the year 2000 a quality assurance programme for the preoperative breast diagnostics was introduced in Denmark. The programme was based on the "European guidelines for quality assurance in breast cancer screening and diagnosis" where - among other measures - five cytological diagnostic classes were introduced. The aim of this study was to evaluate the quality assurance programme in a screening population to determine whether fine needle aspiration cytology (FNAC) as first choice remains a useful tool in the preoperative diagnostics, or if needle core biopsy should be the first-choice treatment. MATERIAL AND METHODS: 767 women had FNAC performed from a total of 783 lesions at the Mammography Clinic, University Hospital Odense. All FNACs were compared with the final histology diagnosis. Nine statistical parameters were calculated according to the European guidelines. RESULTS: A total of 66% of the 783 FNACs had a malignant cytology diagnosis, which in 99% of the cases turned out to be the correct diagnosis. Four lesions were false positives all of which represented benign proliferative breast diseases. The surgical procedures in these cases were either excisional biopsy or lumpectomy. The values of eight of the nine mutually dependent statistical parameters of quality scored within the recommended threshold values. Specificity was the only parameter that fell outside the recommended threshold values. CONCLUSION: Although specificity in our study is lower than recommended, we find that the use of FNAC as first-choice in triple diagnostics is a useful tool.

Does educational level determine screening participation?

The objective of this study was to test the hypothesis that nonparticipation in organized mammography screening is due to insufficient understanding of the information in the invitation letter by relating educational level to user pattern. Data from two Danish mammography screening programmes in Copenhagen, 1991-1999, and Funen, 1993-2001 were taken for this study. The Danish Central Population Register was used to define target groups; screened participation data were provided by the health authority, and data on highest obtained education came from Statistics Denmark. Data on all breast imaging in 2000 outside organized screening were provided by radiology clinics. Included were all women eligible for at least three screens, and participation was classified into four mutually exclusive user groups. Organized mammography screening programmes in Copenhagen and Funen, Denmark were used as field of this study. Main outcome measures were age-adjusted relative risks (RR) and 95% confidence intervals (CI) of 'never use' versus 'always use' of screening by educational level, using women with secretarial/sales education as baseline. The RR of 'never use' was 1.65 (95% CI: 1.37-1.99) in Copenhagen and 1.93 (95% CI: 1.42-2.62) in Funen for academics, 1.60 (95% CI: 1.48-1.73) in Copenhagen and 1.26 (95% CI: 1.14-1.39) Funen for women with lower primary educational level. Taking other breast imaging into account, the RR was 1.60 (95% CI: 1.32-1.95) for academics in Copenhagen, and 1.90 (95% CI: 1.75-2.07) for women with lower primary education. In conclusion, our results did not support the hypothesis that lack of understanding the information in the invitation letter explains nonparticipation. 'Never use' was not inversely associated with the level of education, but showed a U-shaped association, even when use of breast imaging outside organized screening was taken into account.

[Mammography screening--advantages and disadvantages]. / Screening for cancer mammae--fordele og ulemper.

Mammography screening involves advantages as well as disadvantages. Intensive research in this area is being carried out both internationally and in Denmark. As mammography screening becomes nationwide in Denmark in 2007, it is crucial to closely monitor the advantages as well as the disadvantages, their extent and the possibility of optimizing the balance between them. The effect of a screening programme on breast cancer mortality is not likely to be evident until several years after starting the programme, and it is necessary to define process indicators for close monitoring of the programme.