Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 76–82
12227
Longitudinal trends in utilization of endocrine therapies for breast cancer: an
international comparison
E. Kelly* PharmB, C. Y. Lu† PhD, S. Albertini* MS and A. Vitry* PhD
*Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide,
SA, Australia and †Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA
Received 4 June 2014, Accepted 6 October 2014
Keywords: aromatase inhibitors, breast cancer, drug utilization, tamoxifen
SUMMARY
What is known and objective: Endocrine therapy is an effective
treatment for post-menopausal women with ‘oestrogen receptor-
positive’ invasive breast cancers. There are two main types of
endocrine therapies: selective oestrogen receptor modulators
(tamoxifen) and aromatase inhibitors (anastrozole, letrozole and
exemestane). The aim of this study was to compare the patterns of
use of endocrine therapies for breast cancer in women between
nine developed countries.
Methods: A longitudinal, cross-national drugutilization studywas
conducted. The endocrine therapies included were tamoxifen and
the aromatase inhibitors: anastrozole, letrozole and exemestane.
Annual drug utilization data were collected from Australia,
Denmark, England, Finland, France, Iceland, the Netherlands,
Norway and Sweden over the period 2001–2012. Utilization was
measured in DDD/1000 inhabitants/day and was also adjusted for
breast cancer incidence and female population statistics.
Results and discussion: Total use of endocrine therapies either
increased or remained steady in all countries. Total endocrine
therapy usage was consistently highest in England and France.
Norway showed the lowest usage of endocrine therapies overall,
using only 1
80 DDD/1000 inhabitants/day in 2012. Downward
trends in tamoxifen use and upward trends in aromatase
inhibitors were seen across all countries over the study period.
By 2012, aromatase inhibitors represented over half of total
endocrine therapy use in all countries, and as high as 74% and
80% in France and Denmark, respectively.
What is new and conclusion: Our analysis found a shift in use of
endocrine therapy from tamoxifen to aromatase inhibitors. This
trend is consistent with major clinical guidelines endorsing
preferential use of aromatase inhibitors in post-menopausal
women. Stabilization or small increase in tamoxifen use in the
recent years may reflect the recognition of tamoxifen as still an
appropriate first-line treatment. The similarity in utilization
patterns may be due to the relatively comparable healthcare
systems in the countries, namely universal health insurance and
pharmaceutical coverage. Differences in utilization observed
could be due to differences in breast cancer incidence, prescribing
behaviours, interpretation of new trial evidence, and timing of
drug marketing approval and reimbursement between countries.
Correspondence: Dr A. Vitry, Quality Use of Medicines and Pharmacy
Research Centre, Sansom Institute, School of Pharmacy and Medical
Sciences, University of South Australia, GPO Box 2471, Adelaide SA
5001, Australia. Tel.: +61 8 8302 2392; fax: +61 8 8302 1087; e-mail:
agnes.vitry@unisa.edu.au
© 2014 John Wiley & Sons Ltd
doi: 10.1111/jcpt.
INTRODUCTION
Breast cancer is the leading cause of cancer deaths in women
around the world, with approximately 522 000 women dying of
the disease in 2012.1 Breast cancer is also the most commonly
occurring cancer in women, with around 1
7 million new cases
diagnosed worldwide in 2012.1 Breast cancer incidence is partic-
ularly high in developed countries such as Australia, where more
than 14 710 new cases were recorded in 2012.1 This equates to an
age-standardized incidence of 86
0 per 100 000 in Australian
women, 2-fold higher than the global age-standardized incidence
of 43
3 per 100 000 in 2012.1
Endocrine therapy is a valuable treatment option for post-
menopausal women with ‘oestrogen receptor-positive’ (ER+)
invasive breast cancers. These account for around two-thirds of
all breast cancer cases.2, 3 There are two main types of endocrine
therapies: selective oestrogen receptor modulators such as tamox-
ifen, and aromatase inhibitors (AIs). The three AIs currently
available are anastrozole, letrozole and exemestane.
Traditionally, a 5-year course of tamoxifen therapy has been the
standard adjuvant treatment for ER+ breast cancers following
surgery.4 This treatment has been shown to reduce both breast
cancer recurrence and mortality, corresponding to an overall
reduction in the risk of death of 9
2% over 15 years.5 More
recently, the AIs have gained popularity as adjuvant therapy for
ER+ breast cancers. The AIs have been studied in three main
regimens: as upfront therapy instead of tamoxifen, as a replace-
ment therapy after 2–3 years of tamoxifen or as extended therapy
following the standard 5 years of tamoxifen treatment.6, 7 A meta-
analysis of the early AI trials showed they were associated with
lower breast cancer recurrence compared with tamoxifen, either
used as upfront or used as replacement therapy.8 The AIs also
showed lower all-cause mortality compared with tamoxifen,
although only for those patients who took them after 2–3 years
of tamoxifen treatment.8
Although AIs have been available for the treatment of advanced
breast cancer since the late 1990s, they were only marketed and
subsidized for treatment of early breast cancer from the 2000s. In
all countries, anastrozole was the first AI indicated for the
treatment of early breast cancer under the European mutual
recognition process in 2004 and then was subsidized shortly after
(e.g. October 2004 for France). In Australia, anastrozole was
subsidised with restrictions (when tamoxifen was contraindicated
or not tolerated) in July 2004 and without these restrictions in July
2005. Generic products were ultimately marketed when AIs lost
their patents in 2010–2011. Few studies have reported longitudinal
trends in use of endocrine therapies at the national level. Notably,
76
Enocrine breast cancer
our previous study in Australia found a switch in use from
tamoxifen to AIs in Australia over the period 1996–2008.9
Published studies largely provided snapshots of use of endocrine
therapies without examining or comparing longitudinal trends. A
study in Sweden showed that the use of endocrine therapy in
women with operable breast cancer increased over time and, in
2005, was 60–80% in women aged between 40 and 59.10 Although
a review of breast cancer care in 18 countries included a snapshot
of endocrine therapy use in 2008, it did not compare longitudinal
trends in use and did not provide details on sampling strategies
and the national representativeness of the IMS health data.11 The
aim of this study was to compare the utilization patterns of
endocrine therapy in nine countries of the Organisation for
Economic Co-operation and Development (OECD) over the last
decade.
METHODS
A longitudinal, cross-national drug utilization study was con-
ducted between 2001 and 2012 in nine OECD countries, namely
Australia, Denmark, England, Finland, France, Iceland, the Neth-
erlands, Norway and Sweden. Endocrine medicines were identi-
fied by their Anatomical Therapeutic Chemical codes and included
tamoxifen (L02BA01) and the three AIs: anastrozole (L02BG03),
letrozole (L02BG04) and exemestane (L02BG06). We first measured
annual drug utilization in defined daily doses (DDDs)/1000
inhabitants/day, which is the standard unit recommended by
the World Health Organisation.12 This measure enables compar-
isons of usage independent of the country’s population, the pack
size and dosage of the medication dispensed. Table 1 summarizes
sources of drug utilization and population data used in this
analysis. For Australia and England, aggregate prescription
volume data were obtained from their national public databases
13, 14
and population data were obtained from the Australian and
UK national statistics bodies.15,16 For France, dispensing data
provided by the French main insurance scheme that covers
approximately 68% of the French population were extrapolated
to the whole population. For other countries, the drug utilization
data were already available in DDDs/1000 inhabitants/day or
available in total DDDs and we used the Eurostat demographics
database to adjust for the country’s population.17
We also adjusted for the female population and breast cancer
incidence in each country to express use of endocrine therapies in
DDDs/1000 new breast cancer cases/day. Age-standardized
breast cancer incidence data for the year 2008 were retrieved from
the GLOBOCAN cancer database developed by the International
Agency for Research on Cancer.18
RESULTS
Total endocrine therapy utilization
For all countries, usage of endocrine therapies either remained
steady or increased over the study period (Fig. 1). The total usage
of endocrine therapies was consistently highest in France and
England and lowest in Norway. In 2012, overall usage in France
was 3
21 DDDs/1000 inhabitants/day compared with 1
80 in
Norway, a 1
7-fold difference. Comparing Australia, England,
France, Denmark and Sweden, where data were available for the
entire study period, Denmark showed the largest growth in total
endocrine therapy use. From 2001 to 2012, endocrine therapy
usage in Denmark increased by 76%, from 1
70 to 3
00 DDDs/1000
© 2014 John Wiley & Sons Ltd
77
E. Kelly et al.
inhabitants/day. Sweden also displayed a substantial growth of
47% from 1
94 to 2
84 DDDs/1000 inhabitants/day. Growth in
England and France was more modest as usage was already high
in 2001: a 3% increase from 2
96 to 3
05 DDDs/1000 inhabitants/
day in England and a 14% increase from 2
81 to 3
21 DDDs/1000
inhabitants/day in France.
Countries’ utilization levels of endocrine therapies somewhat
followed their breast cancer incidence. After adjusting for female
population and breast cancer incidence (Fig. 2), England and
France were still highest in utilization of all endocrine therapies
and Norway still displayed one of the lowest uses. The difference
between France and Norway was 1
4-fold, slightly smaller than the
difference based on unadjusted utilizations. In contrast, the
Netherlands whose breast cancer incidence was the second highest
(96
8 per 100 000 people) had overall the lowest use adjusting for
its breast cancer incidence and female population (Fig. 2). Between
2005 and 2012, the largest increase (57%) was observed in Finland
from 4447 to 6292 DDDs/1000 new breast cancer cases/day.
Individual endocrine therapy usage
Utilization of the different endocrine therapies varied between
countries both quantitatively and in their trends over time. A
similar pattern was observed in Australia, Denmark, England,
France, Norway and Sweden, showing a gradual decline in
tamoxifen usage with a corresponding increase in utilization of AIs
(Figs 3 and 4). In Finland, use of tamoxifen was almost stable over
time with a gradual uptake of the AIs. After the initial drop in use,
a slight increase in tamoxifen use was observed in the more recent
years in the Netherlands (since 2009), in Sweden (since 2011) and
in Australia (since 2012). The greatest and earliest uptake of AI was
observed in France with total AI usage increasing from 0
43
DDDs/1000 inhabitants/day in 2001 to 2
40 in 2008 representing a
458% increase.
By 2012, the AIs represented over half of all endocrine therapy
use in all countries, with the highest relative usage observed in
France (74%) and Denmark (80%) (Fig. 5). From 2001 to 2008,
anastrozole was the most used AI in all countries except Iceland,
where letrozole use was highest. In 2012, anastrozole was still the
most used AI in Australia, England, the Netherlands and Sweden.
In Norway, Denmark and Finland, there was a sharp increase in
letrozole use and decrease in anastrozole use from the years 2008–
2009 (Fig. 6). In all countries, exemestane was the least utilized of
all AIs, ranging from around 4% of all AIs in Denmark to 18% in
France.
DISCUSSION
This longitudinal study showed similar trends in total endocrine
therapy usage between 2001 and 2012 across nine OECD countries,
with some differences in the use of individual agents. Our findings
are similar to a 2008 report that showed a high use of endocrine
therapies in the UK, with use in the Netherlands around 70%
lower than UK, and use in Denmark, Finland, France, Norway and
Sweden somewhere in between.11 Based on the published litera-
ture and consultation with national experts, there are several
possible reasons for the trends observed.
Differences in breast cancer incidence, mortality and survival
may account for some of the differences in endocrine therapy use
across countries. For example, although France appeared to utilize
endocrine therapies at a high rate, its age-standardized breast
cancer incidence was higher than other countries. After adjusting
Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 76–82
Enocrine breast cancer E. Kelly et al.

Table 1. Sources of drug use, population and breast cancer incidence data

2008
GLOBOCAN
Standardized
Breast Cancer
Format (i.e. Incidence per
Source of drug units) of drug Population Calculating DDDs/ Calculating DDDs/1000 new 100 000
Country use data use data data source 1000 inhabitants/day breast cancer cases/day population

Australia ‘PBS Statistics’, Raw Australian 84
8

Medicare prescription Bureau of
N  M  Q  1000 TotalDDDs  1000
Australia 13 dataa Statistics DDD  P  D BD
(midyear)15
Denmark ‘Medstat.dk’, Dispensed ‘Eurostat’ Data already supplied 89
1
Danish volume (1000 databaseb 17 as DDD/1000
TotalDDDs  1000
Medicines DDD) or inhabitants/day BD
Agency34 DDDs/1000
inhabitants/
day
England ‘Prescription Raw UK Office for 87
9
Cost Analysis’ prescription National
N  M  Q  1000 TotalDDDs  1000
documents data1 – Statistics DDD  P  D BD
from the separate (midyear) 16
National documents for
Health Service each year
14

Finland ‘Finnish DDDs/1000 ‘Eurostat’ Data already supplied Total DDDs calculated 86
6
17
Statistics on inhabitants/ database as DDDs/1000
Medicines’, day inhabitants/day DDD=1000 inhabitants/d  P  D
Finnish 1000
National
Agency for then used in
Medicines 35
TotalDDDs  1000
BD

France French general Raw ‘Eurostat’ Total DDDs calculated 98
7

health prescription database 17
from raw prescription TotalDDDs  1000
insurance data data extrapolated to BD
scheme 36 representing the whole population
68% of the
population
Iceland ‘Statistics’, Total DDDs or ‘Eurostat’ Data already supplied 86
2
Icelandic DDDs/1000 database 17
as DDDs/1000
TotalDDDs  1000
Medicines inhabitants/ inhabitants/day BD
Agency 37 day
The ‘GIP Database’, Total DDDs ‘Eurostat’ Calculated from total 96
8
Netherlands Dutch database 17
DDDs and total
TotalDDDs  1000
Healthcare population BD
Insurance
Board 38 TotalDDDs  1000
PD

Norway ‘The Total DDDs ‘Eurostat’ Calculated from total 76
2

Norwegian database 17
DDDs and total
TotalDDDs  1000
Prescription population BD
Database’
from the TotalDDDs  1000
Norwegian PD
Institute for
Public Health
39

(continued)

© 2014 John Wiley & Sons Ltd Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 76–82
78
Enocrine breast cancer E. Kelly et al.

Table 1 (continued)

2008
GLOBOCAN
Standardized
Breast Cancer
Format (i.e. Incidence per
Source of drug units) of drug Population Calculating DDDs/ Calculating DDDs/1000 new 100 000
Country use data use data data source 1000 inhabitants/day breast cancer cases/day population

Sweden Swedish DDDs/1000 ‘Eurostat’ Data already supplied Total DDDs calculated 82
7
17
pharmacy inhabitants/ database as DDD/1000
sales supplied day inhabitants/day DDD=1000 inhabitants=d  P  D
by B. 1000
Wettermark
then used in

TotalDDDs  1000
BD

DDD, defined daily dose; N, number of prescriptions dispensed in the year; M, mass of each dose; Q, average dispensed quantity per prescription; P, total
population of the country for the year of data collection; D, number of days in the year; B, annual number of new breast cancer cases, which was equal to the
2008 age-Standardized incidence rate per 100 000 provided in the 2008 GLOBOCAN cancer database 18 multiplied by the country’s female population.
a
Raw prescription data were number of prescriptions dispensed by formulation (i.e. strength and quantity).
b
As of January 1st each year.

3·50 7000
3·30
6500
3·10
DDD/1000 inhabitants/day

DDD/1000 new breast cancer cases/day

2.90
6000
2·70
2·50 5500
2·30
5000
2·10
1·90
4500
1·70
1·50 4000

3500
Year
Australia Denmark England
3000
Finland France Iceland 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
Netherlands Norway Sweden Year
Australia Denmark England
Fig. 1. Trends in total endocrine therapy utilization by country. Finland France Iceland
Netherlands Norway Sweden
for incidence, French utilization was lower than it first appeared.
However, incidence did not fully explain the differences in use Fig. 2. Trends in total endocrine therapy utilization by country,
across countries. For instance, total endocrine therapy usage in adjusting for breast cancer incidence and female population.
DDD/1000 inhabitants/day in the Netherlands was similar to
Australia and Norway. However, its utilization was in fact the and the 2006 UK’s National Institute for Health and Care
lowest after accounting for its high breast cancer incidence. Excellence guidance all endorsed use of aromatase inhibitors in
Moreover, breast cancer detection rate and incidence are likely to the adjuvant setting for post-menopausal women with hormonally
be linked with the availability and recommendations for breast sensitive early breast cancer.7, 21 However, our results showed that
cancer screening in each country over time.19, 20 after an initial decline, use of tamoxifen plateaued in the most
The utilization of AI increased whereas that of tamoxifen recent years and even increased slightly in Australia, Sweden and
decreased in all countries between 2003 and 2012. This is consistent the Netherlands. This may reflect growing knowledge of the
with clinical guidelines that recommended a preferential use of AI toxicity profile of AI and the recognition of tamoxifen as an
over tamoxifen on the basis of their better efficacy.8 The 2004 and appropriate first-line treatment as it has been recommended in the
2010 American Society of Clinical Oncology (ASCO) guidelines most recent 2014 ASCO guidelines.22

© 2014 John Wiley & Sons Ltd Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 76–82
79
Enocrine breast cancer E. Kelly et al.

3 2012
100%

2·5 90%

80%
DDD/1000 inhabitants/day

2
70%

1·5 60%

50%
1
40%

0·5 30%

20%
0
10%

Year 0%
Australia Denmark England
Finland France Iceland
Netherlands Norway Sweden
Exemestane Anastrozole

Fig. 3. Trends in tamoxifen utilization by country. Letrozole Tamoxifen

Fig. 5. Market shares of individual endocrine therapy within each

country in 2012.
3·00

2·50
100%
DDD/1000 inhabitants/day

2·00
90%

1·50
80%

1·00 70%

0·50 60%

0·00 50%

Year 40%
Australia Denmark England Finland France
Iceland Netherlands Norway Sweden 30%

Fig. 4. Trends in aromatase inhibitor utilization by country. 20%

The countries included in our study all have universal health 10%
coverage, including pharmaceutical reimbursement systems. Vari-
ations in uptake of individual endocrine therapy may be explained
0%
by differences in the timing and extent of the approval and
funding of the medicines. In Australia, reimbursement decisions
have been shown to have a major influence on medication use and
prescribing, including endocrine therapies.9, 23 Notably, anastroz-
ole use in Australia increased by more than 80% from 2004 to 2005, Exemestane Letrozole Anastrozole
following its extended listing for early breast cancer on the
national drug formulary in July 2004. In contrast, use of individual Fig. 6. Relative uses of aromatase inhibitors in 2008 and 2012
AIs increased earlier and more gradually in England than in within each country.

© 2014 John Wiley & Sons Ltd Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 76–82
80
Enocrine breast cancer E. Kelly et al.

Australia. This could be explained by the ‘negative list’ system for
prescription drugs under the UK’s National Health Service, where
drugs will be subsidized (depending on the resources of local
healthcare regions) as soon as they are marketed unless specified
otherwise.24 In 2011, the Danish Council for the use of expensive
hospital medicines issued a guidance that recommended letrozole
to be the drug of first choice as the end of patent for letrozole led to
cheaper prizes in tenders.25 This may explain the shift in use from
anastrozole to letrozole in recent years in this country. New trial
data on the extended use of letrozole as adjuvant endocrine
therapy after 5 years of tamoxifen 26 may have also contributed to
the preferential use of letrozole over anastrozole from the years
2008–2009 in Norway, Denmark and Finland compared to the
other countries where anastrozole remained the most used AI in
2012.
Interestingly, in the United States that has a very different
healthcare environment to the countries we examined, studies
showed a link between endocrine therapy usage and the initial
presentation of the Anastrozole, Tamoxifen Alone or in Combina-
tion (ATAC) trial results at a cancer conference in 2001.27, 28 The
double-blind ATAC trial compared 5 years of adjuvant tamoxifen
treatment with 5 years of upfront anastrozole therapy in over 9000
patients with early-stage breast cancer and showed a significantly
lower breast cancer recurrence rate in the anastrozole group.29
There were no abrupt changes in anastrozole use in the nine
countries of this study after the 2005 publication of the ATAC trial
results (data not shown).
Differences between countries may also be explained by
variations in adherence and discontinuation rates of oral hormonal
therapies which have been shown to range from 45% to 96% and
12–73%, respectively, in a recent review of the literature.10
Furthermore, the optimal total duration of endocrine therapy is
still debated with recent data supporting the extended use of
tamoxifen or AI after 5 years of treatment with endocrine
therapy.26, 30 Therefore, different usage differences between coun-
tries may reflect different interpretations of the scientific evidence.
Patterns of endocrine therapy use may reflect the general trends
in medication use in particular countries. For example, France has
often been shown to have high use of prescription medications
overall.31–33 In contrast, the Netherlands has low prescription
medication use, partly due to patients’ general attitudes towards
drug therapies.32, 33 Prescriber preferences for faster adoption of
newer drugs may also explain high uptake rates of the newer
endocrine therapies, for example, in France.
This study has several limitations. Firstly, drug utilization
studies using prescription or wholesale data cannot account for
actual patient consumption of the medication. The aggregated data
used did not provide information on the indication (e.g. early or
advanced breast cancer) or treatment regimen (e.g. upfront AI
therapy or switch scenario). Furthermore, DDDs/1000 inhabit-
ants/day do not reflect actual clinical doses; however, the DDDs
generally correspond to the clinical treatment doses in the case of
endocrine therapies. Prevalence of use of endocrine therapy has
also been shown to vary with age.10 Without individual consump-
tion data, we were not able to adjust for potential differences in
adherence to endocrine therapy, duration of use and age.
Secondly, the different durations of data availability between
countries made comparisons of the longitudinal trends difficult.
Data were only available from 2004 in the Netherlands and
Norway, 2005 in Finland and 2007 in Iceland. As the AIs had been
introduced into Europe well before this time (anastrozole in 1995,
letrozole in 1996 and exemestane in 1999), we could not examine
uptake trends immediately following the drugs’ market entry.
Finally, we used the 2008 GLOBOCAN breast cancer incidence
estimates. There may be some differences between the GLOBO-
CAN data set and national data mainly due to the fact that
GLOBOCAN uses the world population age distribution for age
standardization (relatively young), whereas national sources may
use national age distributions which may be older. However, using
the GLOBOCAN data improves the comparability across coun-
tries. We have used the 2008 GLOBOCAN data for adjusting the
usage data over the whole study period 2001–2012. Therefore,
changes in breast cancer incidence over time may remain unac-
counted for in our study.
CONCLUSIONS
This study found that total endocrine therapy usage remained
largely stable between 2001 and 2012 in nine OECD countries. All
countries demonstrated a shift in use from tamoxifen to AIs,
predominantly anastrozole, although this was overtaken by
letrozole in the more recent years in some countries. This trend
is consistent with earlier clinical guidelines endorsing preferential
use of AI in post-menopausal women. Differences in utilization
observed could be due to differences in breast cancer incidence
and screening programmes, prescribing behaviours, and timing of
drug marketing approval and reimbursement between countries.
ACKNOWLEDGEMENTS
We thank Dr Bj€
orn Wettermark, Karolinska Institutet, Sweden for
supplying the Swedish data for this project as well as valuable
feedback and advice.
SOURCES OF FUNDING
Dr C. Lu was supported by an Australian National Health and
Medical Research Council Public Health Training Fellowship.
CONFLICT OF INTERESTS
The authors have no conflict of interest to declare.

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