Modern mammography screening and breast cancer mortality: population study
BMJ
2014;
- Harald Weedon-Fekjær, researcher123,
- Pål R Romundstad, professor of epidemiology1,
- Lars J Vatten, professor of epidemiology14
- Correspondence to: H Weedon-Fekjær harald.weedon-fekjar@medisin.uio.no
- Accepted 19 May 2014
Abstract
Objective To evaluate the
effectiveness of contemporary mammography screening using individual
information about screening history and breast cancer mortality from
public screening programmes.
Design Prospective cohort study of
Norwegian women who were followed between 1986 and 2009. Within that
period (1995-2005), a national mammography screening programme was
gradually implemented, with biennial invitations sent to women aged
50-69 years.
Participants All Norwegian women aged 50-79 between 1986 and 2009.
Main outcome measures Multiple
Poisson regression analysis was used to estimate breast cancer mortality
rate ratios comparing women who were invited to screening (intention to
screen) with women who were not invited, with a clear distinction
between cases of breast cancer diagnosed before (without potential for
screening effect) and after (with potential for screening effect) the
first invitation for screening. We took competing causes of death into
account by censoring women from further follow-up who died from other
causes. Based on the observed mortality reduction combined with the all
cause and breast cancer specific mortality in Norway in 2009, we used
the CISNET (Cancer Intervention and Surveillance Modeling Network)
Stanford simulation model to estimate how many women would need to be
invited to biennial mammography screening in the age group 50-69 years
to prevent one breast cancer death during their lifetime.
Results During 15 193 034 person
years of observation (1986-2009), deaths from breast cancer occurred in
1175 women with a diagnosis after being invited to screening and 8996
women who had not been invited before diagnosis. After adjustment for
age, birth cohort, county of residence, and national trends in deaths
from breast cancer, the mortality rate ratio associated with being
invited to mammography screening was 0.72 (95% confidence interval 0.64
to 0.79). To prevent one death from breast cancer, 368 (95% confidence
interval 266 to 508) women would need to be invited to screening.
Conclusion Invitation to modern mammography screening may reduce deaths from breast cancer by about 28%.
Introduction
The efficacy of mammography screening was tested in randomised trials in the 1970s and 1980s.1
More than 10 years ago, an overview by the World Health Organization
indicated that mammography screening may reduce mortality from breast
cancer by 25%.2
However, the methods used by some of the original trials have been
criticised, and a report from the Cochrane Collaboration considered the
estimates of mortality benefit from many of those trials to be invalid.3 4 Recent advances in modern chemotherapy and adjuvant treatment have improved the survival of women with breast cancer,5 6
and progress in treatment has led some investigators to question the
need for early detection of breast cancer by mammography screening.7
Updated studies are clearly needed, but new
randomised trials are not realistic and evaluations of modern screening
require accurate information about screening history compared with the
timing of breast cancer diagnosis, as well as precise and long term
follow-up of mortality. Many observational studies have assessed breast
cancer mortality associated with mammography screening, but results have
been inconsistent, ranging from no effect to improved mortality
benefits than those obtained in the original screening trials.8 9 10 11 12 13 14 15 16 Norway provides an ideal setting to study the effects of mammography screening,17 18
but in two previous Norwegian studies that used an incidence based
mortality approach, only fractions of the available and potentially
important data were included in the analyses.8 11
We analysed data from all women in Norway who were
aged 50 to 79 during 1986 to 2009, the period during which the Norwegian
mammography screening programme was gradually implemented (1995-2005).
We compared the rates of deaths from breast cancer among those who were
invited to screening (with a potential for screening effect) with those
who had not been invited to screening before breast cancer was diagnosed
(without a potential screening effect).
Methods
The Norwegian breast cancer screening programme
The Norwegian breast cancer screening programme was
initiated by the Norwegian government in 1995 and introduced in four
counties in November of that year. The programme was gradually
implemented in the remaining 15 counties, with complete national
coverage achieved in 2005. The screening programme is administered by
the Norwegian Cancer Registry, and all women aged 50-69 are invited to
screening every two years. Two view screening mammograms are taken in
breast diagnostic centres exclusively dedicated to the diagnosis and
treatment of breast diseases. Two readers independently evaluate the
mammograms, and women whose mammograms require further consideration are
referred for diagnostic mammography, and, if necessary, for additional
clinical evaluation. Attendance for screening has been relatively
stable, at approximately 76%.
The reporting of cancer to the Norwegian cancer
registry is mandatory, and diagnostic information is obtained separately
from clinicians, pathologists, and death certificates, with 0.2% of all
cancers ascertained only from death certificates.18
The unique 11 digit personal identification number of each citizen
allows follow-up for cause specific mortality, which is provided by
Statistics Norway. We used data used on individual dates of screening
invitations, dates of breast cancer diagnoses, and dates of breast
cancer deaths.
Study participants
We included all Norwegian women aged 50 to 79 years
between 1986 and 2009. The dynamic nature of inclusions and exclusions
to the cohort by age means that women contributed person years of
observation from the age when they were eligible to be observed until
they were censored from further observation, either because of death
(from breast cancer or other causes), they had reached 80 years of age,
or they had reached the end of follow-up (31 December 2009). The actual
number of participating women in dynamic cohorts will vary for each
given year, but in 2000 a total of 638 238 women were under observation,
and the study included 15 193 034 person years of observation.
The first invitation to take part in the Norwegian
mammography screening programme depended on the woman’s county of
residence and her birth cohort, but from 1995 to 2005 all women in the
country aged between 50 and 69 were gradually invited to participate.
The supplementary figure shows the mortality rate of breast cancer in
Norway (1986-2009) among women aged 50-79 and the period during which
the mammography screening programme was implemented in Norwegian
counties (1995-2005).
Statistical analysis
In the analysis, we regarded women with a diagnosis
of breast cancer after the invitation date to mammography screening as
being exposed to screening, and women with a diagnosis of breast cancer
before the invitation date as being unexposed to screening. To assess
the effect of invitation to screening we compared incidence based breast
cancer mortality among women invited to screening (intention to screen)
with those not invited, under the counterfactual assumption that if
invited women had not been invited, their risk of death from breast
cancer would be similar to that of women who had not (yet) been invited.
To account for differences in age and effects of
birth cohort and calendar time, we used a multivariable Poisson
regression model. To achieve optimal flexibility in the statistical
adjustments, we used natural splines to allow for non-linear variations
in age, period, and cohort effects (see R code in supplementary appendix
d). In sensitivity analyses, we also tested the statistical models
without smoothing of period and cohort effects, and we used age and
period models without the birth cohort variable to limit the potential
for colinearity. In addition because the rates for breast cancer
mortality differed slightly between counties, we adjusted for county of
residence. In the Poisson regression analysis we took competing causes
of death into account by censoring from further follow-up those women
who died from causes other than breast cancer.
The time interval from diagnosis until death from
breast cancer varies from a few months to many years, and therefore we
carefully separated breast cancers diagnosed in women before invitation
to first screening from those diagnosed after invitation to first
screening to avoid misclassification of breast cancer deaths according
to exposure status (invited or not invited before diagnosis). At the
beginning of the implementation period in each county almost all deaths
from breast cancer occurred among women with a diagnosis before
screening invitations started. Over time a gradually higher proportion
of breast cancer deaths could be attributed to breast cancers diagnosed
after women had been invited to screening. We accounted for this dynamic
change by estimating the proportion of the observed breast cancer
mortality that was expected to be due to cancers diagnosed after the
first screening invitation, assuming that invitations to screening had
no effect on breast cancer mortality. In the estimation we used the
interval from diagnosis until death from breast cancer among women (in
10 year age groups) who had not yet been invited. Thus we avoided the
lead time bias that would have occurred if we had used the interval from
diagnosis until breast cancer death among invited women. As an offset
in the statistical modelling we added to the model the estimated
proportion of breast cancer deaths that was attributed to breast cancers
diagnosed after screening invitation, thus adjusting the expected
breast cancer mortality for each group according to invitation status
(see supplementary appendix for formulas and implementation).
The individual data were precisely split according
to exposure status, with separation of invited and not yet invited women
within each age-period-county combination during the implementation
period of mammography screening in each county. Thus the analysis
compares two groups, using detailed information, with adjustment for
differences by age, period, cohort, and county. Using this dynamic
modelling approach we could utilise all the available individual data in
the analysis, without the limitation of selected comparison groups, as
in previous studies using data from Norway.8 11
To account for all random statistical uncertainty,
we used bootstrap replications and calculated 95% confidence intervals
for the estimated effects associated with invitation to mammography
screening. To test the robustness of the results, we repeated the
analyses under a broad range of statistical assumptions, including a
pure age-period-county model, different smoothing of age and period
effects, different choice of reference period and reference age groups,
and varying the effect of screening invitation by calendar year.
Since screening effects are likely to vary by age
and time since screening, these variables may not be balanced between
comparison groups. In a separate sensitivity analysis we therefore
weighted the screening variable based on the simulated screening effects
by age and time since screening provided by the CISNET (Cancer
Intervention and Surveillance Modeling Network) Stanford simulation
model.19 20 21
We also calculated the number of women who need to
be invited to screening to prevent one death from breast cancer. The
number relates to Norwegian women in the age group 50-69 years in 2009.
Firstly, we assumed an effect of screening invitations corresponding to
the reduction in breast cancer mortality that we observed in our data.
Secondly, we used the observed breast cancer mortality in Norway in 2009
and adjusted for the observed reduction in mortality associated with
invitation to mammography screening. Thus we could estimate the likely
breast cancer mortality in the absence of screening. Thirdly, we used
the observed all cause mortality in Norway in 2009 and calculated the
probability that women who were first invited at 50 years of age were
alive at a given age (51, 52, 53, and so on up to 79 years of age).
Effects of screening are likely to vary by age and by time since
screening, but these effects are difficult to estimate empirically owing
to a limited number of observations. Therefore we applied the CISNET
Stanford model scaled to the observed Norwegian breast cancer mortality
reduction to estimate the likely screening effects by age and time since
screening. In the CISNET Stanford model, smaller tumour size and lower
clinical stage at diagnosis resulting from an earlier diagnosis is
assumed to explain potential reductions in breast cancer mortality. By
combining the breast cancer mortality rates in Norway in 2009, the
estimated reduction in breast cancer mortality, and the CISNET Stanford
simulation model, we calculated the absolute reduction in breast cancer
mortality that could be attributed to screening within each age group.
After combining the estimated reduction in breast cancer mortality with
the probability of reaching a certain age, given the observed all cause
mortality in 2009, we could summarise the data and estimate the
probability that one death from breast cancer could be avoided by being
invited to mammography screening. Thus the inverse of that probability
yielded the number of women aged 50-69 who need to be invited to
screening to prevent one death from breast cancer during their lifetime.
(See the spreadsheet in the supplementary appendix for further
details.)
All statistical analyses were conducted using the R statistical package22 (see the supplementary appendix for details of the calculation).
Results
During 15 193 034 person years of observation, breast
cancer deaths occurred in 1175 of the women invited to mammography
screening and in 8996 of the women who were not invited. After
adjustment for age, birth cohort, county of residence, and underlying
national trends in breast cancer mortality, the mortality rate ratio
associated with being invited to screening was 0.72 (95% confidence
interval 0.64 to 0.79), indicating a 28% lower risk of death from breast
cancer in women who were invited for screening compared with women who
were not invited (table 1⇓).
Mortality rate ratio of
breast cancer among women aged 50-79 who were invited or not invited
(reference) to the Norwegian mammography screening programme, 1986-2009
After the invitations to screening had ended (at 70
years of age), we found that the benefit for breast cancer mortality
persisted (table 2⇓),
but with a possible gradual decline by time since screening (P for
trend 0.35). Thus, between five and 10 years after the invitations to
screening had ended, the adjusted mortality rate ratio was 0.79 (95%
confidence interval 0.57 to 1.01).
Breast cancer mortality rate
ratios associated with invitations to mammography screening programme
in relation to screening period
To test the robustness of the findings we repeated
the analyses under different statistical assumptions (sensitivity
analyses), including leaving out the cohort effect, using non-smoothed
period effects, and weighting the screening effect by age and time since
screening (table 3⇓).
However, these additional procedures did not substantially influence
the estimated effect and yielded mortality rate ratios ranging from 0.71
to 0.75. By introducing a period dependent screening effect, the
results suggested a possible increasing reduction in breast cancer
mortality by calendar year, but that analysis had limited statistical
power (P=0.29).
Breast cancer mortality rate
ratios associated with invitations to mammography screening programme
in alternative (sensitivity) analyses under different statistical
assumptions
We also estimated how many women between 50 and 69
years of age would need to be invited to mammography screening to
prevent one death from breast cancer, based on the estimated effect on
breast cancer mortality that we found in this study and the observed all
cause and breast cancer specific mortality in Norway in 2009. Overall,
368 (95% confidence interval 266 to 508) women in the age group 50-69
years would need to be invited to biennial mammography screening to
prevent one death from breast cancer during their lifetime (see
supplementary appendix table for calculation).
Based on the estimated effect of screening
invitations (table 1), we also estimated the effect of mammography
screening among women who actually attended (approximately 76% of
invited women). Thus attendance may be associated with a 37% reduction
in breast cancer mortality (0.28/0.76=0.37), and 280 women would need to
attend screening to prevent one death from breast cancer
(368×0.76=280).
Discussion
In this study, based on more than 15 million person
years of observation, we estimated that invitation to mammography
screening was associated with a 28% reduced risk of death from breast
cancer compared with not being invited to screening, and that 368 women
need to be invited to screening to prevent one death from breast cancer.
The screening effect persisted but seemed to be gradually reduced after
invitations to screening had ended. The large population and long
follow-up of mortality provided precise estimates and suggests that
chance is unlikely to explain the main findings of the study.
Strengths and limitations of this study
Modern treatment has reduced the number of deaths from breast cancer,5 6 20
and in the analysis we took into account the effect of changes in
nationwide treatment by adjusting for trends in national breast cancer
mortality. To improve and standardise breast cancer treatment across
Norway, clinical guidelines were implemented before mammography
screening became established. Although some differences in treatment may
remain, such differences are unlikely to be systematically related to
mammography screening status (invited or not invited). However, breast
diagnostic centres were established in parallel with the Norwegian
mammography screening programme and resulted in centralisation of care
for women with breast cancer. We cannot exclude the possibility that
organisational aspects of care related to these centres may have
contributed to some of the decrease in breast cancer mortality that we
observed after invitations to screening.
Before the national screening programme,
mammography screening was available at private radiology institutions,
and many women had mammograms for clinical or screening purposes.23
Assuming that screening activity was highly frequent, an increase in
breast cancer incidence and some increase in ductal carcinoma in situ
would be expected to precede the implementation of the screening
programme. However, in contrast with this expectation, no clear increase
in incidence was observed before the national mammography screening
programme was established.24 25
Therefore it seems unlikely that screening activity before the national
programme could have substantially influenced and attenuated the
results of the present study.
Comparison with other studies
In some studies, women who attended for mammography
screening were compared with women who did not attend. In a review of
studies that compared breast cancer mortality in women who did and did
not attend for screening programmes in Europe, attendance was estimated
to be associated with a breast cancer mortality benefit of 31%.12 In a recent Norwegian study, attendance was associated with a mortality benefit of 43%.26
Attendance does, however, imply an active choice, and women who choose
to attend may differ from those who choose not to attend in ways that
may lead to biased estimates of the screening effect.27
To prevent such a bias we analysed the data according to whether women
were invited or not invited to screening (intention to screen).
Two previous prospective studies in Norway also
used incidence based mortality to assess the potential benefits of
mammography screening.8 11
In contrast with the present study, those studies restricted the
analyses to selected comparison groups (birth cohorts or counties) and
reported moderate mortality benefits (10% and 11%, respectively) with
low precision (wide confidence intervals). In the study by Kalager and
colleagues,8
the low precision was due to a short follow-up of mortality, which
ended in 2005. Another limitation was that instead of using detailed
information about the actual age of the women and date of screening
invitations in each county, the investigators used broad categories that
probably resulted in some misclassification of exposure (screening or
not, in relation to diagnosis). Also, the investigators included breast
cancer deaths based on time of diagnosis and not on the actual time of
death. Therefore, women with an earlier diagnosis as a result of
screening were more likely to be included as invited cases (deaths) than
were unscreened women, whose diagnosis was not forwarded by the
screening facility. As a consequence, the association of screening
invitation with breast cancer mortality is likely to be diluted in that
study. In a separate analysis, we limited our data to more closely match
that of Kalager and colleagues’,8
and found a reduction in breast cancer mortality of 14% associated with
an invitation to screening, which is slightly stronger than the effect
reported by the investigators using even fewer detailed data. In the
study by Olsen and colleagues,11
effects of mammography screening were only assessed for selected birth
cohorts and only in the four counties where the screening programme was
first introduced. Therefore the investigators missed any effect in the
remaining birth cohorts, as well as in the other 15 Norwegian counties.
In a recent comprehensive review of European studies,13 two (from Denmark and Finland) that used incidence based mortality were identified as particularly reliable.9 28
According to those studies, the mammography screening programme in
Copenhagen was associated with a 25% reduction in breast cancer
mortality,8
and in Finland, a reduction of 24% was attributed to the recently
established mammography screening programme. The Finnish study, however,
was associated with substantial statistical uncertainty.28
It has been questioned whether the evidence from
the original screening trials is still relevant within the context of
modern treatment for breast cancer,5 6
and with generally greater awareness of the disease among women. Our
findings, as well as the results from the Danish and Finnish studies,9 28
suggest that the relative effectiveness of mammography screening is
comparable to the efficacy reported from some of the randomised
screening trials.2 29
In our study the estimated benefit for breast
cancer mortality (28%) associated with invitation to mammography
screening indicates a substantial effect, but evolving improvements in
treatment will probably lead to a gradual reduction in the absolute
benefit of screening.5 20 30
Based on breast cancer mortality data from 1980, the Euroscreen Working
Group estimated that 111 to 143 women would need to be screened to
prevent one death from breast cancer.31
Using breast cancer mortality data from 2009, we estimated that 368
women in the age group 50-69 years would need to be invited to screening
to prevent one death from breast cancer during their lifetime. Our
higher number is partly attributable to different assumptions about the
duration of the effect of screening and partly attributable to lower
breast cancer mortality in the absence of screening. The secular decline
in breast cancer mortality caused by progress in treatment is
substantial, and one consequence of further improvements in treatment is
that increasingly more women will need to be invited to mammography
screening to prevent one death from breast cancer.
Instead of using individual screening information
(incidence based analysis), other researchers have related the timing of
introducing mammography screening to time trends in breast cancer
mortality.10 12
In these studies, breast cancers that were diagnosed before screening
cannot be reliably distinguished from screening detected cancers. In a
separate analysis of our data, we disregarded individual information
about the time of diagnosis, and similar to studies using mortality
trend analysis, we also found no association of the time that
mammography screening was implemented with breast cancer mortality (data
not shown). This illustrates how important it is to properly separate
breast cancers according to screening status at diagnosis, otherwise any
effect of screening will be diluted and cannot be attributed to
screening.32
Therefore, incidence based mortality and detailed screening status are
necessary requirements for an appropriate assessment of the
effectiveness of mammography screening.32
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