Introduction
Since the introduction of mammography screening in many countries, a substantialincrease in the incidence of breast cancers has been observed, raising concern about thepotential for overdiagnosis of breast cancer due to screening. However, no consensus hasbeen reached on the extent of such overdiagnosis. An overdiagnosed breast cancer isdefined as one which is screen-detected, and would never have presented clinically in awoman's lifetime in the absence of screening [
1]. In addition to overdiagnosis and consequent overtreatment, screening resultsin additional years lived with breast cancer due to the advancement of time ofdiagnosis. Estimates of overdiagnosis in previous studies vary considerably. Comparisonsof expected breast cancer incidence extrapolated from rates before the introduction ofscreening with that observed after have resulted in estimates of overdiagnosis rangingfrom 4% [
2] to 52% [
3] of all diagnosed breast cancers. Variations between estimates reflect themethodological challenges faced when estimating overdiagnosis. A drop in breast cancerincidence is observed in the age group immediately above that invited for screening dueto the advancement of diagnosis of these cases by screening. Studies that do not accountfor this compensatory drop tend to have a higher estimate of overdiagnosis. Estimateswill also vary depending on whether or not
in situ cancers are included [
1,
4].
Simulation modelling is a popular tool for estimating the extent of overdiagnosis due toscreening; it requires estimates of the mean duration of pre clinical cancer states(mean sojourn time), the screening test sensitivity (STS), and the background incidenceof breast cancer in the absence of screening. De Koning
et al. applied this approach to Dutch screening data for women aged 50 to 74, andestimated that 3% of all cancers and 8% of screen-detected cancers were overdiagnosed [
5].
Most estimates of overdiagnosis are based on data for women aged 50 years and over, asyounger women are currently not eligible for screening in most countries. The extensionof the age range of screening programmes to include younger women is under debate, butlittle is known on the extent of overdiagnosis due to screening in these women. Also,evidence suggest that younger women tend to have breast cancers that progress faster andlower mammography STS, mostly due to higher breast density, than older women [
6‐
9], which may be favourable with regards to overdiagnosis.
In this study, we model data from a trial of mammographic screening for breast cancerstarting at age 40 (Age trial) conducted in the UK, using data collected from the startof the trial in 1991 until 31st December 2010, in order to estimate, in women aged 40 to49:
1.
the STS of mammography for invasive and in situ breast cancers, that is the probability of a mammographic screen detecting a cancer that is in the preclinical state,
2.
the mean sojourn time (MST), that is the mean duration, in years, for a cancer from first becoming detectable by screening to clinical diagnosis, of the screen-detectable preclinical breast cancer states: progressive in situ, non-progressive in situ, and invasive,
3.
the proportion of screen-detected in situ cancers that are non-progressive,
4.
the proportion of breast cancers diagnosed that would not have presented clinically in the absence of screening after accounting for a compensatory drop in incidence.
Results
Estimates from the parameter estimation model are shown in Table
4. The median and 95% CI for the invasive and
in situ mammography STSwere 90.0% (72.0 to 98.9) and 81.7% (43.4 to 99.0), respectively. Model estimates forthe MST in the screen-detectable PIBC state was 0.84 years (0.64 to 1.21), which, addedto the MST in the screen-detectable PIS state, 0.11 years (0.05 to 0.19), gave a meanwindow of 0.95 years for a cancer to be detected via screening before arisingclinically. For screen-detectable NPIS, the MST was 1.29 years (0.41 to 3.44). Theestimated proportion of screen-detected
in situ cancers that werenon-progressive was 55% (25-77) in the prevalent and 40% (22 to 60) in incidentscreens.
Table 4
Model estimates of breast cancer screening and progression parameters in womenaged 40 to 49 years
Screening test sensitivity (%)
| |
Invasive | 90.0 | (72.0-98.9) |
In-situ | 81.7 | (43.4-99.0) |
Mean sojourn time (years)
| |
Invasive | 0.84 | (0.64-1.21) |
Progressive in situ | 0.11 | (0.05-0.19) |
Non-progressive in situ | 1.29 | (0.41-3.44) |
% of screen-detected
in situ
that is non-progressive
| |
Prevalent screen | 55 | (25-77) |
Incident screens | 40 | (22-60) |
Results of the overdiagnosis model are given in Table
5. In ourbase-case analysis, 16,030 breast cancers were diagnosed between the ages of 40 and 49years in women offered screening, in contrast with 15,425 in women not offered anyscreening, a surplus of 605 cases, equivalent to 6.2% of screen-detected and 3.8% of allcases. However, in ages 50 to 54, where screening is not offered in both simlulatedgroups, 541 additional cases were diagnosed in women not offered screening previously,resulting in a total of 64 overdiagnosed cases equivalent to 0.7% of screen-detectedcases and 0.4% of all cancers diagnosed within ages 40 to 49 years.
Table 5
Comparison of the number of cancers detected for 1,000,000 women in annualscreening between ages 40 to 49 years versus no screening versus.
Screen-detected
| | | | | | |
Invasive | 7772 | - | - | - | 7772 | - |
Progressive in situ | 1145 | - | - | - | 1145 | - |
Non-progressive in situ | 874 | - | - | - | 874 | - |
Clinically detected
| | | | | | |
Invasive | 5693 | 14 089 | 7680 | 8151 | 13 373 | 22 240 |
Non-progressive in situ | 546 | 1336 | 658 | 728 | 1204 | 2064 |
All cancers
| 16 030 | 15 425 | 8338 | 8879 | 24 368 | 24 304 |
Overdiagnosis
| | | | | |
Absolute number | 605 | -541 | 64 |
% of screen-detected | 6.2 | | | 0.7 |
% of cancers diagnosed within ages 40 to 49 | 3.8 | | | 0.4 |
Estimates of overdiagnosis in our sensitivity analysis ranged from 0.5 to 2.9% ofscreen-detected cancers and 0.3% to 2.2% of all cancers diagnosed within ages 40 to 49years. The highest impact on overdiagnosis was observed when increasing the MST, whereasincreasing the STS had a smaller impact on overdiagnosis (Table
6).
Table 6
Overdiagnosis of breast cancer due to annual screening in women aged 40 to 49years.
Base-case | 0.7 | 0.4 |
Long MST | 2.7 | 2.0 |
Short MST | 0.5 | 0.3 |
High sensitivity | 0.7 | 0.4 |
Low sensitivity | 0.5 | 0.3 |
High sensitivity, long MST | 2.9 | 2.2 |
Low sensitivity, long MST | 2.7 | 1.6 |
Model fit
When compared to data from the Age trial, the parameter estimation model accuratelypredicted the screen-detected invasive cancers for the first six screens, butunderestimated those for the last two screens (Table
7). Forscreen-detected
in situ cancers, model predictions were accurate for thefirst five screens, but underestimated the observed number for the last threescreens. The number of invasive interval cancers were overestimated for the firstscreen, and underestimated in the last three screens. The expected number of
insitu interval cancers were underestimated for the last screen only. For allscreens combined, the model slightly underestimated the number of screen-detectedinvasive cancers. Expected values from the overdiagnosis models were within the rangeof estimates from the parameter estimation model, and had a similar fit to theobserved data in the intervention arm. The fit of the expected numbers of cancers inthe control arm was good, with a slight overprediction overall of approximately2%.
Table 7
Fit of model estimates to data observed in a trial of annual mammographicscreening starting age 40 in the UK.
| |
Intervention arm (offered annual screening)
| |
| |
Screen-detected cancers
| |
1
| 31 | 28(22-34) | 32 | 6 | 7(3-12) | 7 |
2
| 20 | 18(16-20) | 19 | 3 | 5(2-8) | 5 |
3
| 16 | 17(15-19) | 18 | 3 | 5(2-7) | 5 |
4
| 15 | 17(15-18) | 17 | 5 | 5(2-6) | 5 |
5
| 16 | 15(13-17) | 16 | 4 | 5(2-6) | 4 |
6
| 13 | 14(13-15) | 15 | 7 | 3(2-6) | 4 |
7
| 19 | 14(12-15) | 14 | 9 | 3(2-6) | 4 |
8
| 21 | 11(10-12) | 12 | 6 | 3(2-4) | 3 |
Total
| 151 | 134(116-150) | 143 | 43 | 36(17-55) | 37 |
Interval cancers
|
1
| 7 | 19(16-23) | 16 | 2 | 1.4(0.6-2.6) | 2 |
2
| 17 | 17(14-19) | 14 | 2 | 1.3(0.5-2.4) | 1 |
3
| 17 | 15(13-18) | 13 | 0 | 1.2(0.5-2.2) | 1 |
4
| 17 | 13(11-15) | 13 | 1 | 1(0.4-1.9) | 1 |
5
| 10 | 12(10-14) | 12 | 0 | 0.9(0.4-1.7) | 1 |
6
| 16 | 12(10-13) | 11 | 1 | 0.9(0.4-1.7) | 1 |
7
| 18 | 10(8-11) | 11 | 1 | 0.7(0.3-1.4) | 1 |
8
| 11 | 4(3-5) | 9 | 2 | 0.2(0.1-0.5) | 1 |
Total
| 113 | 102(85-118) | 99 | 9 | 7.6(3.2-14.4) | 9 |
Control arm (not offered screening)
|
40
| 52 | -1 | 69 | 1 | - | 5 |
41
| 115 | - | 111 | 8 | - | 7 |
42
| 115 | - | 124 | 7 | - | 9 |
43
| 129 | - | 133 | 7 | - | 12 |
44
| 138 | - | 147 | 15 | - | 13 |
45
| 161 | - | 155 | 16 | - | 12 |
46
| 161 | - | 160 | 12 | - | 10 |
47
| 165 | - | 165 | 7 | - | 11 |
48
| 172 | - | 166 | 13 | - | 12 |
Total
| 1208 | - | 1230 | 86 | - | 91 |
Discussion
In this study, we aimed to quantify the overdiagnosis of breast cancer attributable toscreening women aged 40 to 49 years annually by first estimating screening parameters ina six-state Markov model using data from a trial of annual mammographic screeningstarting age 40 conducted in the UK. In women aged 40 to 49 years in the UK, weestimated that only 0.3% to 2.2% of all cancers were overdiagnosed.
An implicit assumption of the Markov process is that the time to transition isdistributed exponentially. This distribution has been used in many instances previouslyand has been shown to have a good fit to progression models for breast cancer, as wellas other cancers [
11,
12,
16]. We assumed that all
in situ cancers that arose in the absence ofscreening were non-progressive. In reality, a proportion of
in situ casesdetected in the absence of screening may be progressive. However, this proportion couldnot be estimated when relaxing this assumption.
Estimates from our overdiagnosis model suggest a 5% reduction in the detection ofinvasive cancers as a result of screening. Previously, three screening trials (theTwo-County, Stockholm, and Goteborg trials) showed a non-significant reduction of 5% to10% in the incidence of invasive breast cancer when comparing the incidence in thescreened and control groups [
17]. Also, we assumed that all invasive cancers had an
in situ precursor, which may not be the case [
18]. Hence, our model may have overestimated the number of invasive cancersdetected in their
in situ precursor state. However, it is unlikely that thiswould affect our estimates of overdiagnosis as both
in situ and invasive breastcancers were included in our calculations.
Our results showed that the STS for
in situ cancers was approximately 10% lowerthan for invasive cancers, probably due to the larger size of invasive tumours [
19]. Although no previous studies estimated the STS of
in situ cancersseparately, previous estimates of the STS for preclinical breast cancer ranged from 69%to 100% [
6‐
8,
13], consistent with our 90% STS estimate for PIBC. In the Age trial, two-viewmammograms were performed at prevalence screen, and one-view at incident screens unlessindicated otherwise. When estimated separately, we found a 10% difference in prevalent(95%, 79 to 100) and incident STS (85%, 69 to 95). However, this model did not show anyimprovement in fit, and could not estimate the difference in STS for
in situ and invasive breast cancer, which are more important parameters with regards tooverdiagnosis due to screening. In addition, the STS of mammography is likely toincrease with increasing age [
9]; it was not possible to incorporate this in the current model, but oursensitivity analysis found that increasing the sensitivity had limited impact on theestimate of overdiagnosis. Estimates of MST and STS are necessarily related. Thecorrelation between STS and MST in our model was 0.75 and their distribution showed nosign of bimodality. The sensitivity analysis addressed the correlated nature of STS andMST, by the inclusion of a scenario with long MST and small STS as an alternative to ourbase-case model, which had short MST and high STS.
The MST for screen-detectable NPIS was the longest among pre-cancer states, suggestingthat more NPIS are detected in the prevalent screen than in incident screens. Forscreen-detectable PIS, the MST was very short, roughly three to ten weeks. Being muchshorter than the yearly screening interval, this implies that few progressive lesionsare detected in the in situ stage. However, the pool of progressive lesionswill renew itself at each screen, implying that the rate of progressive lesions detectedat each screen is constant proportionally to the background incidence of invasive breastcancer. According to our estimates, the combined MST of PIS and PIBC was under one yearin 66% of cases. This would support annual screening for women aged 40 to 49. Biennialor triennial screening would result in many women developing both pre-cancer and havinga clinical diagnosis during the screening interval.
To our knowledge, only one study used a six-state Markov model to estimate the detectionrates of NPIS in screening, but did not estimate STS [
11]. Using UK data for women aged 50 and over, authors predicted that 39% and 21%of screen-detected
in situ cancers were non-progressive at prevalent andincident screens, respectively. The model had a lack of fit for UK data, overestimatingcancers detected at prevalent and underestimating cancers detected at incident screens.In this study, we predicted a higher proportion of NPIS, possibly due to a higherrelative background incidence of
in situ to invasive cancer in women aged 40 to49 compared to women aged 50 to 69 [
14]. In previous studies, the MST of PIBC in women aged 40 to 49 ranged from 1.05to 2.46 years [
6‐
8,
13,
20], which is longer than our estimate of 0.95 years. However, this study is thefirst to report MST estimates for women aged 40 to 49 in the UK, and for older women,previous estimates show a shorter MST in British women compared to other Europeancountries [
11].
Our estimate of overdiagnosis for annual screening in women aged 40 to 49 in the UK wasin line with those reported in other studies. Hellquist
et al. [
21] estimated that 1% (-6 to 8) of all breast cancers were overdiagnosed in ascreening programme for women aged 40 to 49 screened every 18 months in Sweden. In asystematic review, the range of overdiagnosis for women aged 40 to 49 years was -4% to7.1% [
22]. Despite large credible intervals in our estimates of STS and MST, the rangeof overdiagnosis from this study was small, 0.3% to 2.2% of breast cancers diagnosedwithin ages 40 to 49 years. Thus, although precise estimates of STS and MST are hard toobtain, the estimate of overdiagnosis is relatively unaected. Our sensitivity analysisincluded a large range of STS and MST values, and our results should be generalisable toother countries with similar breast cancer incidence rates as the UK. However, it is notclear to what extent our results are extendable to programmes with longer screeningintervals: the impact of screening frequency on overdiagnosis in women aged 40 to 49years would require further studies.
Conclusions
The most important implication of this study is that, in women aged 40 to 49 in the UK,a small proportion of breast cancers were overdiagnosed due to screening, between 0.3%to 2.2% of all breast cancers diagnosed within ages 40 to 49 years. Since women aged 40to 49 have shorter MST, lower STS, and lower mortality rates than women aged 50 andover, less overdiagnosis would normally be expected which may explain why estimates ofoverdiagnosis from this study are smaller than those reported for women aged 50 onwards [
2,
3,
23,
24]. Second, although a high proportion of
in situ cancers detected atscreening were estimated to be non-progressive, the great majority of these would havepresented clinically in the absence of screening, implying they would not beoverdiagnosed. Finally, the mean sojourn time of preclinical invasive breast cancer,including its
in situ precursor, was just under one year, suggesting thatannual screening would be most appropriate for women aged 40 to 49.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
NBG participated in the conception and design of the study, the development of themethodology and the interpretation of results, performed the analyses, and drafted themanuscript. MGC participated in the conception of the study, the interpretation ofresults and reviewed the manuscript. SMM participated in the conception and design ofthe study, the acquisition of data, the development of the methodology and theinterpretation of results, revised and reviewed the manuscript, and supervised thestudy. All authors read and approved the final manuscript.