Anne Helene Olsen

Absolute numbers of lives saved and overdiagnosis in breast cancer screening, from a randomized trial and from the Breast Screening Programme in England

Objectives To estimate the absolute numbers of breast cancer deaths prevented and the absolute numbers of tumours overdiagnosed in mammographic screening for breast cancer at ages 50–69 years. Setting The Swedish Two-County randomized trial of mammographic screening for breast cancer, and the UK Breast Screening Programme in England, ages 50–69 years. Methods We estimated the absolute numbers of deaths avoided and additional cases diagnosed in the study group (active study population) of the Swedish Two-County Trial, by comparison with the control group (passive study population). We estimated the same quantities for the mortality and incidence rates in England (1974–2004 and 1974–2003, respectively). We used Poisson regression for statistical inference. Results A substantial and significant reduction in breast cancer mortality was associated with screening in both the Two-County Trial (P < 0.001) and the screening programme in England (P < 0.001). The absolute benefits were estimated as 8.8 and 5.7 breast cancer deaths prevented per 1000 women screened for 20 years starting at age 50 from the Two-County Trial and screening programme in England, respectively. The corresponding estimated numbers of cases overdiagnosed per 1000 women screened for 20 years were, respectively, 4.3 and 2.3 per 1000. Conclusions The benefit of mammographic screening in terms of lives saved is greater in absolute terms than the harm in terms of overdiagnosis. Between 2 and 2.5 lives are saved for every overdiagnosed case.

Breast cancer mortality in Copenhagen after introduction of mammography screening: cohort study

Abstract Objectives To evaluate the effect on breast cancer mortality during the first 10 years of the mammography service screening programme that was introduced in Copenhagen in 1991. Design Cohort study. Setting The mammography service screening programme in Copenhagen, Denmark. Participants All women ever invited to mammography screening in the first 10 years of the programme. Historical, national, and historical national control groups were used. Main outcome measures The main outcome measure was breast cancer mortality. We compared breast cancer mortality in the study group with rates in the control groups, adjusting for age, time period, and region. Results Breast cancer mortality in the screening period was reduced by 25% (relative risk 0.75, 95% confidence interval 0.63 to 0.89) compared with what we would expect in the absence of screening. For women actually participating in screening, breast cancer mortality was reduced by 37%. Conclusions In the Copenhagen programme, breast cancer mortality was reduced without severe negative side effects for the participants.

Overdiagnosis, Sojourn Time, and Sensitivity in the Copenhagen Mammography Screening Program

Abstract:u2003 The goal of this research was to estimate the overdiagnosis at the first and second screens of the mammography screening program in Copenhagen, Denmark. This study involves a mammography service screening program in Copenhagen, Denmark, with 35,123 women screened at least once. We fit multistate models to the screening data, including preclinical incidence of progressive cancers and nonprogressive (i.e., overdiagnosed) cancers. We estimated mean sojourn time as 2.7 years (95% confidence interval [CI] 2.2–3.1) and screening test sensitivity as 100% (95% CI 99.8–100). Overdiagnosis was estimated to be 7.8% (95% CI 0.3–26.5) at the first screen and 0.5% (95% CI 0.02–2.1) at the second screen. This corresponds to 4.8% of all cancers diagnosed among participants during the first two invitation rounds and following intervals. A modest overdiagnosis was estimated for the Copenhagen screening program, deriving almost exclusively from the first screen. The CIs were very broad, however, and estimates from larger datasets are warranted.u2002

Breast density and outcome of mammography screening: a cohort study

The purpose of this study was to investigate the effect of breast density on breast cancer (BC) mortality in a mammography screening programme. The cohort included 48u2009052 women participating in mammography screening in Copenhagen, Denmark, where biennial screening is offered to women aged 50–69 years. We collected information for the years 1991–2001 on screening outcome, incident BCs (screen-, interval-, and later detected), and BC deaths. Breast density was dichotomised into fatty (F) and mixed/dense (M/D) breasts. Screening sensitivity was measured as the odds ratio of interval versus screen-detected cancer for dense versus F breasts. Poisson regression was used to estimate the ratios for BC incidence, case fatality, and mortality between women with M/D and F breasts. For women with M/D breasts, the odds ratio of an interval cancer was 1.62 (95% confidence interval, CI, 1.14–2.30), and the age-adjusted rate ratios were 2.45 (95% CI 2.14–2.81) for BC incidence, 0.60 (95% CI 0.43–0.84) for case fatality, and 1.78 (95% CI 1.17–2.72) for BC mortality. The study shows that BC in women with M/D breasts is more frequent, but on average less severe, than in women with F breasts.

Complexities in the estimation of overdiagnosis in breast cancer screening

There is interest in estimating and attributing temporal changes in incidence of breast cancer in relation to the initiation of screening programmes, in particular to estimation of overdiagnosis of breast cancer as a result of screening. In this paper, we show how screening introduces complexities of analysis and interpretation of incidence data. For example, lead time brings forward time- and age-related increases in incidence. In addition, risk factors such as hormone replacement therapy use have been changing contemporaneously with the introduction of screening. Although we do not indicate exactly how such complexities should be corrected for, we use some simple informal adjustments to show how they may account for a substantial proportion of increased incidence, which might otherwise erroneously have been attributed to overdiagnosis. We illustrate this using an example of analysis of breast cancer incidence data from Sweden.

Breast cancer incidence after the start of mammography screening in Denmark

Mammography screening may lead to overdiagnosis of asymptomatic breast cancers, that would otherwise not have given rise to clinical symptoms. This aspect was studied in three regional screening programmes in Denmark, which started in Copenhagen municipality, Fyn county, and Frederiksberg municipality in 1991, 1993, and 1994, respectively. In these regions, we compared time trends in incidence of invasive breast cancer with the rest of Denmark. Since the number of clinical mammograms was relatively low, it was reasonable to assume that the breast cancer incidence outside the three screening regions represented the incidence of a population with low-intensity opportunistic screening. In Copenhagen and Fyn, a prevalence peak in incidence was seen during the first invitation round. During the subsequent invitation rounds, the incidence dropped to a level in line with the incidence expected without screening. The pattern was different in the small municipality of Frederiksberg, where the sensitivity was low during the first invitation round. Inclusion of screen-detected ductal carcinoma in situ cases did not change these results. The experiences from Copenhagen and Fyn show that organised mammography screening can operate without overdiagnosis of breast cancer.

Estimating the benefits of mammography screening : The impact of study design

Background: Mammography screening is justifiable only if it leads to reduction in breast cancer mortality. However, evaluation of routine screening is not straightforward, as no unscreened control group is available. We report here on a cohort study of the effect of routine mammography on breast cancer mortality, and illustrate how variations in the analytic approach can affect the conclusions. Methods: We used data from the mammography screening program in Copenhagen, Denmark, for the period 1991–2001. We used local historical, concurrent regional, and historical regional control groups, and included only deaths from breast cancers diagnosed during the observation periods. We examined the impact of various control groups, of including all breast cancer deaths, and of using individual data versus routine statistics. Results: Combining all 3 control groups gave an estimated 25% reduction in breast cancer mortality. The estimate was 20% using only a local historical control group, and 9% using only a concurrent regional control group. Including all breast cancer deaths resulted in an estimate of 21% reduction in breast cancer mortality. Using routine statistics and a concurrent regional control group resulted in an estimated increase of 6% in breast cancer mortality. Conclusion: Estimated changes in breast cancer mortality following the introduction of routine mammography ranged from a 25% reduction (based on the best methodology) to a 6% increase with a less rigid study design. The estimated effect of routine mammography on breast cancer mortality is thus highly dependent on study design.

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.

Reply: Overdiagnosis of breast cancer in Denmark

Sir, n nAs observed by Dr Zahl, it is correct that the cumulative risk in breast cancer incidence increased during the observed period. Indeed, breast cancer incidence has increased steadily in Denmark since the 1960s (Sundhedsstyrelsen, 2003). Assuming linearity in the cumulative risk, we performed a simple least-squares estimation of the trend in breast cancer incidence in the period before screening for both Copenhagen and Fyn. Assuming this trend would have continued if screening had not been introduced, the expected cumulative risk for Copenhagen in 1993–95 was 6.6% and the observed cumulative risk was 6.1% (95% CI 5.3–6.8%). For Fyn the expected cumulative risk for 1996–97 was 5.9%, whereas the observed cumulative risk was 6.6% (95% CI 5.9–7.3%). For both Fyn and Copenhagen the expected cumulative risk was within the 95% confidence interval. Therefore, we see no reason to conclude that overdiagnosis is taking place. n nIf the underlying increase in the incidence before screening was partly due to opportunistic screening, this would not affect the conclusions since the increase in the number of clinical mammography examinations continued after the introduction of screening (Olsen et al, 2003). n nIt is correct that bringing the time of diagnosis forward should result in a lower incidence in the age group 70–74, and we plan to look at this effect for Copenhagen and Fyn. But whereas entry into the screening programmes is well defined, exit is not. In the second invitation round in Copenhagen, women in the age group 70–71 were invited. In Fyn, women over 70 can participate if they ask for it. This will dilute the effect, and therefore we have not yet performed this analysis. n nAs mentioned in the article (Olsen et al, 2003), inclusion of screen-detected DCIS did not change the picture. Note that the proportion of DCIS detected in the Danish screening programmes is small compared to that in many other programmes, due to a deliberately conservative attitude towards supposedly benign microcalcifications (Vejborg et al, 2002). n nWe will follow the further development of breast cancer incidence in Denmark.

Cancer mortality in the 50 - 69 year age group before and after screening

seem to imply that our data from the randomized trials are not empirical. Furthermore, it is not important for the ratio whether one looks at invited or attending women, as both benefits and harms increase among attendees. Duffy et al. claim that only 37% of breast cancers are screen-detected, based on a 200-word conference abstract where the sum of the relevant percentages is only 72%. They conclude that our estimate implies that virtually all screen-detected cancers are overdiagnosed, which they consider ‘absurd and frankly incredible’. However, it is well known that between one-half and two-thirds of cancers are detected through screening, e.g. 68% of cancers were screendetected in the relevant age groups in the UK in 2006, not 37%. Duffy et al. substantially overestimate benefits and underestimate harms. We also note that no conflicts of interest were declared. Tabár founded Mammography Education Inc, Arizona in 1980, which still exists, and in 1999, he declared an income of five million SEK in Sweden, which is an extraordinary amount according to Nordic standards. We believe that such an important conflict of interest should be declared.