Breast Cancer Incidence, 1980–2006: Combined Roles of Menopausal Hormone Therapy, Screening Mammography, and Estrogen Receptor Status
Breast Cancer Incidence, 1980-2006: Combined Roles of Menopausal Hormone Therapy, Screening Mammography, and Estrogen Receptor Status
Andrew G. Glass ) 0
James V. Lacey Jr 0
J. Daniel Carreon 0
Robert N. Hoover 0
0 Affiliations of authors: Oncology Research, Center for Health Research, Kaiser Permanente Northwest, Portland, OR (AGG); Division of Cancer Epidemiology and Genetics, National Cancer Institute , Rockville, MD (JVL, JDC , RNH). Health Research, Kaiser Permanente Northwest , 3800 N Interstate Ave, Portland, OR 97227 (
Breast cancer incidence has been rising since at least 1935-1939, but recent US data reveal a statistically significant decline in breast cancer incidence in 2003 that persisted through 2004. Identifying the specific contributions of the potential causes of this long-term increase and the recent decrease in incidence has been challenging. Marked changes in rates of mammography screening and use of menopausal hormone therapy since 1980 have added further complexity. We examined the potential association between menopausal hormone therapy use and recent changes in breast cancer incidence. Using tumor registry, clinical, pathology, and pharmacy data from Kaiser Permanente Northwest, a large prepaid US health plan, we compared age-specific and age-adjusted breast cancer incidence rates (2-year moving averages) with use of screening mammography and dispensed menopausal hormone therapy prescriptions between 1980 and 2006. Temporal changes in incidence rates were assessed via joinpoint regression. A total of 7386 incident invasive breast cancers were diagnosed in plan members from 1980 through 2006. Overall age-adjusted breast cancer incidence rates per 100 000 women rose 25% from the early 1980s (105.6) to 1992-1993 (131.7) and an additional 15% through 2000-2001 (151.3), then dropped by 18% to 2003-2004 (123.6) and edged up slightly in 2005-2006 (126.2). These patterns were largely restricted to women aged 45 years or older and to estrogen receptor-positive (ER+) breast cancers. Incidence rates of ER-negative tumors experienced neither of the rises seen for ER+ tumors but also fell precipitously from 2003 through 2006. Rates of mammography screening sharply increased from 1980 to 1993 but then leveled off, and 75%-79% of women aged 45 years or older received a mammogram at least once every 2 years from 1993 through 2006. Menopausal hormone therapy dispensings, particularly of estrogen-plusprogestin formulations, increased from 1988 to 2002 but then dropped by approximately 75% after 2002. From 1980 through 2006, quantitative and qualitative trends in breast cancer incidence rates, particularly for ER+ tumors, parallel major changes in patterns of mammography screening and use of menopausal hormone therapy.
Breast cancer incidence rates have risen since at least 1935–1939
). In 1990, we reported (
) that breast cancer incidence had
increased among women aged 60 years or older at diagnosis and
for estrogen receptor–positive (ER+) breast cancers between 1960
and 1985 in the Kaiser Permanente Northwest (KPNW) prepaid
health plan. We discussed various possible explanations, including
changes in reproductive risk factor profiles over time, the
introduction of screening mammography, and growing use of
menopausal hormone therapy. It was unclear whether these were
sufficient to explain the patterns observed.
After 1985, rates of screening mammography in the United
States continued to increase (
), and breast cancer incidence rates
began to reflect the effects of widespread screening. During the
same period, the types of menopausal hormone therapy prescribed
expanded from unopposed estrogen to estrogen plus progestin, the
numbers of dispensed menopausal hormone therapy prescriptions
increased dramatically, and menopausal hormone therapy use
expanded from primarily treatment for menopausal symptoms to
more widespread use for potential chronic disease prevention (
At the same time, epidemiologic studies continued to document
strong, statistically significant increased risks of breast cancer in
women who used menopausal hormone therapy compared with
women who never used it (
In July 2002, the Women’s Health Initiative (WHI)
estrogenplus-progestin trial, a randomized, double-blinded,
placebocontrolled clinical trial of estrogen-plus-progestin use among
postmenopausal women for primary prevention of chronic disease
was stopped early because risks exceeded benefits (
). Increased risks
of breast cancer among the women assigned to take estrogen plus
progestin contributed specifically to the conclusion that overall
health risks exceeded benefits of use of estrogen plus progestin in the
WHI. After the release of these WHI findings, menopausal hormone
therapy use by American women substantially declined in 2003 (
Recently released data from the National Cancer Institute’s (NCI’s)
Surveillance, Epidemiology, and End Results (SEER) program
showed a marked, statistically significant decline in breast cancer
incidence in 2003 and 2004, after showing smaller and non–statistically
significant declines starting in 1999 (
). This finding sparked
speculation that the widespread cessation of menopausal hormone therapy
use after the WHI was responsible for the drop in breast cancer
incidence because fewer women taking menopausal hormone therapy
would mean fewer women exposed to the increased breast cancer risk
that accompanies use of estrogen plus progestin (
Between 2000 and 2005, nationwide use of screening
mammography fell by 4% overall among women aged 40 years or older
and by almost 7% among women aged 50–64 years (
strong circumstantial evidence for a link between recent changes in
menopausal hormone therapy use and lower nationwide breast
cancer incidence, the recent changes in mammography use and the
absence of data from single, defined populations in which one
could directly evaluate all three factors—breast cancer incidence,
menopausal hormone therapy use, and mammography—have
raised questions about the determinants of the recent decline in
US breast cancer incidence rates. To address these questions, we
assessed data on breast cancer incidence, dispensed menopausal
hormone therapy prescriptions, and screening mammography at
KPNW, a large, prepaid health plan. Incorporating data through
December 31, 2006, also permits an assessment of more recent
patterns than are available in the NCI SEER program.
Subjects and Methods
Our study population comprised female KPNW members who
participated in the plan from January 1, 1980, to December 31,
2006. Members receive essentially all preventive and therapeutic
care from KPNW physicians at KPNW-owned hospitals or at
leased beds in local facilities. Virtually all cancer care occurs within
these KPNW facilities under the direction of KPNW physicians.
The racial/ethnic distribution of KPNW members (approximately
82% white, 3% African American, 5% Asian American, 5%
Hispanic, and 5% other) (
) reflects that of the surrounding
Portland, OR, metropolitan area and has not substantially changed
during the study period. Since 1982, KPNW has included
Medicare enrollees. Medicare members account for 13%–15% of
the KPNW population, are fully integrated into the health plan,
and receive care that is identical to that received by non-Medicare
members of KPNW.
C O N T E X T A N D C A V E A T S
The incidence of breast cancer in the United States has risen
steadily in recent decades through 2003, when incidence began to
decline. Rates of menopausal hormone therapy use and screening
mammography have also changed over time, and the relative
contributions of these factors to the incidence of breast cancer is
Analysis of time trends in breast cancer incidence, dispensed
menopausal hormone therapy prescriptions, and screening
mammography use among women enrolled in a large health plan from
1980 through 2006.
In women aged 45 years and older, age-adjusted incidence of
breast cancer (mainly estrogen receptor–positive) rose from the
early 1980s through 2001, then dropped by 18% from 2003 through
2006. Menopausal hormone therapy dispensings increased from
1988 to 2002 and then dropped by 75%. Rates of mammography
screening increased from 1980 through 1993 and then remained
largely stable through 2006.
The rise in breast cancer incidence rates through the late 1990s is
consistent with the effects of mammography screening and
increasing use of menopausal hormone therapy, and the recent
decline in incidence is consistent with the drop in hormone use.
This descriptive, population-level study examined aggregate data,
so changes in other unmeasured risk factors could theoretically
explain the observed incidence patterns.
The inclusion of Medicare patients has increased the
percentage of older women in KPNW. Since 1986, women aged 45–59
years old and women aged 60 years or older have constituted 25%
and 20%, respectively, of the KPNW female population, which
reached 255 171 on June 30, 2006. Approximately 15% of
members leave the KPNW plan each year, but the actual number of
plan members has increased every year for nearly 60 years. Almost
all non-Medicare KPNW members receive employer-based health
The KPNW system includes computerized administrative,
clinical, mammography, and pharmacy databases that allow
linkage of several sources of data for all members of the plan. KPNW
also maintains a tumor registry that has been fully integrated into
these data systems since 1970. Repeated audits in conjunction with
continuing accreditation surveys every 3 years by the Commission
on Cancer of the American College of Surgeons have verified
95%–98% ascertainment of all newly diagnosed cancers among
Using the KPNW tumor registry files, we identified all
incident primary invasive breast cancers that were diagnosed among
KPNW plan members between January 1, 1980, and December
31, 2006. All cases are routinely coded from the pathology reports
according to the current edition of the International Classification
of Diseases for Oncology (ICD-O).
This study was reviewed and approved, under a waiver of
written informed consent, by the KPNW Center for Health
Research’s Research Subjects Protection Office.
The KPNW Department of Pathology reviews pathology
specimens from all newly diagnosed cancers, including those from the
approximately 15% of KPNW members who are initially
diagnosed at community hospitals. The Department works largely in a
single central location with frequent consultations, collaborative
quality reviews, and requisite quality assurance activities.
Hormone Receptor Status
Tumor specimens from KPNW patients have been analyzed for
estrogen receptor (ER) status since the mid-1970s. Assays were
performed at the Oregon Health and Science University from 1980
through 1990, at Nichols Laboratory from 1991 through 1997, and
at the KPNW Laboratory since 1998. All laboratories passed
quality reviews of the NCI-sponsored clinical cooperative groups for
accuracy and quality of receptor measurement. The reagents for,
methods of staining of, and analysis and definitions of positive and
negative reporting of immunohistochemistry-based ER status by
KPNW pathologists have not changed since 1998. The percent of
tumors analyzed for ER status increased from 67% in 1980 to 81%
in 1989, 89% in 1994, and 99% in 2006.
The computerized Radiology Information Management system
(RIM) at KPNW records every radiologic procedure among
KPNW members. Mammograms at KPNW are coded as either
“screening” or “diagnostic.” During the entire study period (1980–
2006), KPNW general radiology benefits have covered all
mammograms at KPNW facilities. Mammograms at other facilities are
neither covered nor reimbursed, so RIM captures essentially all
mammograms received by KPNW members. We used population
figures from KPNW administrative files to calculate annual
percentages of female KPNW members who received screening
mammography between 1980 and 2006. We calculated annual
agespecific proportions (for women aged 45–59 years and ≥60 years)
of KPNW members who received screening mammography by
dividing the total number of screening mammograms performed at
KPNW each year by the total number of women in that age group
in KPNW. For 1992–2006, we also obtained KPNW-computed
rates for the percent of women receiving a mammogram at least
once every 2 years; such data are required of health plans reporting
in the Health Plan Employer Data and Information Set.
Kaiser Permanente operates a large in- and outpatient pharmacy
system that serves KPNW members throughout the region. More
than 70% of KPNW members had pharmacy benefits after 1987,
and 93%–97% of members had them after 1993. Members who fill
prescriptions at non-KPNW pharmacies must pay full price for
medications, which means that essentially all prescriptions were
filled at KPNW.
Since 1987, The Outpatient Pharmacy System (TOPS) at
KPNW has tracked all medications obtained by KPNW members
by recording each drug and dose dispensed. We queried TOPS for
the numbers of prescriptions dispensed by KPNW pharmacies
between 1988 and 2006. We used the number of oral estrogen or
oral estrogen-plus-progestin prescriptions dispensed by KPNW
pharmacies to calculate annual age-specific proportions of KPNW
members who received at least one estrogen or
estrogen-plusprogestin prescription. Members who filled multiple
prescriptions for these medications during the year were counted only
once for each particular medication.
Until 2005, almost all estrogens dispensed at KPNW
pharmacies were oral conjugated equine estrogens, with only a small
percentage of women receiving prescriptions for oral micronized
estradiol. Starting in 2005, estradiol replaced conjugated equine
estrogens as the predominant oral estrogen dispensed at KPNW
pharmacies. Estrogen plus progestin was prescribed as two
separate prescriptions, one for these oral estrogens and one for oral
medroxyprogesterone acetate (MPA). KPNW physicians have
only rarely prescribed unopposed MPA or the single tablet that
contains both estrogen and MPA. Therefore, the number of
dispensed oral “progestins” accurately estimates the number of
dispensed estrogen-plus-progestin prescriptions. We estimated the
number of dispensed prescriptions for unopposed estrogen by
subtracting the number of dispensed progestins from the number
of dispensed estrogens.
Health plan membership counts provided the population figures
for calculating incidence rates. Both age-specific and age-adjusted
incidence rates of invasive breast cancer were calculated, with the
adjusted rates standardized by the direct method to the US 2000
standard population (
). Rates are expressed per 100 000 women
per year and presented as 2-year moving averages to reduce random
variation. All figures are displayed according to the
recommendations of Devesa et al. (14).
We assessed temporal changes in incidence rates via joinpoint
), a method of weighted least squares log-linear
regression analysis that uses joined straight-line segments to
identify time points at which statistically significant changes in
incidence rates occur (16). For trends in breast cancer incidence rates
by age group and ER status, we fit joinpoint regression models
with up to three joinpoints (i.e., up to four straight-line segments)
and chose the best-fitting model based on permutation tests that
were adjusted for multiple comparisons to maintain an overall
twosided P value of less than .05. After the number of joinpoints was
identified, each joined line segment was expressed as an annual
percentage change (APC) with a corresponding 95% confidence
interval (CI). We used the 2-year moving average incidence rates
to identify the best-fitting model (i.e., to identify the time points at
which statistically significant changes in breast cancer incidence
occurred) and to calculate the APCs.
Breast Cancer Incidence at Kaiser Permanente Northwest
A total of 7386 female KPNW members were diagnosed with
invasive breast cancer from 1980 through 2006. Of these 7386
breast cancers, 5742 (78%) were classified as infiltrating ductal
carcinoma and 570 (7.7%) as invasive lobular carcinoma (Table 1).
The percentage of pure lobular carcinoma was relatively constant
over time, whereas the percentage of infiltrating ductal carcinoma
declined from 85% in 1986 to 72% in 2000–2006. The declining
percentage of infiltrating ductal carcinoma seems likely due to the
introduction of new codes, which allowed combination diagnoses
of infiltrating ductal carcinoma with other histologies, in the
Second and Third Editions of the ICD-O. These categories did
not exist in the 1980s but accounted for 10.9% of the breast cancer
diagnoses in 2000–2006.
The overall incidence of breast cancer was relatively constant
in the early 1980s (age-adjusted annual rate of 105.6 per 100 000
women), rose dramatically from 1982–1983 through 1986–1987,
dropped slightly from 1987–1988 through 1989–1990, and then
resumed its rise to a peak in 1990–1991 (132.3 per 100 000; Fig. 1).
After another short decline, rates then rose steadily through
2000–2001 (151.3 per 100 000). There was a small decline to
2001–2002 and an abrupt decline from 2001–2002 to 2003–2004,
after which rates stabilized through 2005–2006. The average rise
in the annual rate from the early 1980s to 1992–1993 (2.7 cases
per 100 000 women) was similar to the rise from 1992–1993 to
2000–2001 (2.4 cases per 100 000). However, because of the
steadily rising incidence rates, the proportional increase was
greater from 1982–1983 to 1992–1993 (28%) than from 1992–
1993 to 2000–2001 (15%). The 2-year moving average incidence
rates of invasive breast cancer in 2003–2004 (123.6 per 100 000),
2004–2005 (128.4), and 2005–2006 (126.2) were comparable to
rates last seen in 1984–1985 (124.1).
The joinpoint regression analysis confirmed these patterns and
identified three years at which statistically significant changes in
breast cancer incidence rate trends occurred: 1983, 1986, and 2001.
When expressed as APCs, incidence rates fell 1.8% per year (95%
Fig. 1. Age-adjusted annual incidence rates for invasive breast cancer at
Kaiser Permanente Northwest (KPNW), 1980–2006, for all ages and for
age groups. Data points reflect 2-year moving averages, based on the
KPNW tumor registry and KPNW administrative files of female health
plan members, with the individual-year data reflecting the 2-year moving
average of that year plus the previous year (e.g., 1990 data point reflects
2-year moving average from 1989 through 1990). Joinpoint regression
and annual percentage changes in incidence are superimposed on
incidence plots. Open symbols represent statistically significant changes in
incidence (i.e., joinpoints), based on joinpoint regression; dashed lines
represent straight-line segments between joinpoints. Adjacent numbers
represent annual percentage changes for those segments.
CI = –8.6% to 5.6%) from 1980 to 1983, increased 10.6% per year
(95% CI = 4.2% to 27.9%) from 1983 to 1986, increased 0.7% per
year (95% CI = 0.01% to 1.4%) from 1986 to 2001, and then declined
4.3% per year (95% CI = –7.2% to –1.1%) from 2001 to 2006.
Age-Specific Incidence Rates
For women younger than 45 years of age, there was essentially no
change in incidence rates of invasive breast cancer over the 27-year
period (Fig. 1). Incidence rates increased both among women aged
45–59 years and women aged 60 years and older. From the early
1980s to 1992–1993, incidence rates increased more rapidly among
1980 1982 1984 1986 1988 990 992 994 9961 9981 0002 0022 0042 0062
1 1 1
Year of diagnosis
women aged 60 years and older (39%) than among women aged
45–59 years (19%). From 1992–1993 to 2002–2003, incidence rates
increased more rapidly among women aged 45–59 years (19%) than
among women aged 60 years and older (12%).
Joinpoint regression analyses also confirmed these patterns.
There were no statistically significant changes in incidence rate
trends for women younger than 45 years of age, one statistically
significant change for women aged 45–59 years (at 2000), and two
statistically significant changes for women aged 60 years or older
(at 1987 and 2001). Expressed as APCs, these changes reflected a
2.0% (95% CI = 1.1% to 2.8%) increase per year between 1980
and 2000 and a 4.9% (95% CI = –9.7% to 0.1%) decrease per year
between 2000 and 2006 for women aged 45–59 years. For women
aged 60 years or older, the best-fitting model showed a 7.0% (95%
CI = 4.4% to 9.7%) increase per year between 1980 and 1987, a
0.6% (95% CI = –0.3% to 1.6%) increase per year from 1987 to
2001, and a 4.1% (95% CI = –7.9% to –0.03%) decrease per year
from 2001 to 2006.
Stage-Specific Incidence Rates
Increasing rates of cancers diagnosed at localized stages—
essentially node-negative cancers confined to the breast—accounted
for almost all the overall rate increase from 1980 through
1998–1999 (Fig. 2). Rates of regional-stage tumors (either locally
invasive beyond the breast or with spread to axillary nodes)
remained nearly constant through 2001–2002. Rates of both
localized tumors and regional-stage tumors fell in the 2000s. The rates
of distant-stage tumors steadily declined between 1980 and 2006.
Estrogen Receptor Status
There were dramatic differences in the incidence rate trends by
ER status (Fig. 3). ER+ tumors closely followed the pattern found
for all breast cancers, including the recent decline from 1999–
2000 through 2005–2006. Similar overall patterns were noted for
ER+ ductal cancers and ER+ lobular cancers, with larger relative
increases seen for lobular tumors (data not shown).
The three joinpoints (1983, 1986, and 2001) for statistically
significant changes in ER+ incidence rate trends were the same as
those for overall breast cancer incidence rate trends. Expressed as
APCs, these four trends reflected a 5.0% (95% CI = 3.7% to
14.4%) annual increase from 1980 to 1983, a 18.9% (95% CI =
0.1% to 41.2%) annual increase from 1983 to 1986, a 2.1% (95%
CI = 1.2% to 2.9%) annual increase from 1986 to 2001, and a 2.7%
(95% CI = –6.4% to 1.1%) annual decrease from 2001 to 2006.
In contrast to the incidence rates trends for the ER+ tumors,
those for ER-negative (ER−) tumors, which were based on fewer
cases and were somewhat more variable, showed no evidence of an
increase over the entire 27-year period. Instead, incidence rates
fluctuated but declined overall throughout the 1980s and then
remained level throughout much of the 1990s until an abrupt
decline after 1999. This latter decline showed no evidence of
abating, dropping steadily from 24.0 per 100 000 women in 2002–2003
to 15.9 per 100 000 in 2004–2005 and 16.6 per 100 000 in 2005–
2006. The APCs for ER– incidence rates were –2.1% (95% CI =
–3.2% to –1.0%) from 1980 to 1995, 3.7% (95% CI = –9.0% to
18.1%) from 1995 to 1999, and –9.8% (95% CI = –12.8% to
–6.6%) from 1999 to 2006.
Screening mammography was not common at KPNW before 1982;
less than 5% of women aged 45 years or older underwent the
procedure each year (Fig. 4). Beginning in 1983, the proportion of
women receiving annual mammography rose rapidly to
approximately 25% in 1986. After a brief plateau in 1986–1987, the
proportion rose to 48.1% (95% CI = 47.6% to 48.7%) in 1991 among
women aged 45–59 years and 46.0% (95% CI = 45.5% to 46.5%) in
1998 among women aged 60 years or older. These proportions then
stabilized until 2000, fell to 44%–45% in both age groups between
2001 and 2004 but then rose to 46.6% (95% CI = 46.2% to 47.0%)
among women aged 45–59 years and 48.0% (95% CI = 47.6% to
48.5%) among women aged 60 years or older in 2006. For each year
ERFig. 3. Age-adjusted annual incidence rates for invasive breast cancer at
Kaiser Permanente Northwest (KPNW), 1980–2006, by estrogen
receptor (ER) status. Data points reflect 2-year moving averages, based on
the KPNW Tumor Registry and KPNW administrative files of female
health plan members, with the individual-year data reflecting the 2-year
moving average of that year plus the previous year (e.g., 1990 data
point reflects 2-year moving average from 1989 to1990). Joinpoint
regression and annual percentage changes (APCs) in incidence are
superimposed on incidence plots. Not shown are incidence rates for
invasive breast cancers with unknown ER status, which made up 33%
of all breast cancers in 1980, 19% of all breast cancers in 1989, 11% of
all breast cancers in 1994, and less than 1% of all breast cancers in 2006,
when ER status was unknown for only one breast cancer diagnosed at
KPNW. Open symbols represent statistically significant changes in
incidence (i.e., joinpoints), based on joinpoint regression. Dashed lines
represent straight-line segments between joinpoints. Adjacent
numbers represent APCs for those segments.
between 1993 and 2006, 75%–79% of women older than 45 years
of age had a screening mammogram within the past 2 years.
Menopausal Hormone Therapy
In 1988, shortly after TOPS began, 13.9% (95% CI = 13.5% to
14.4%) of women aged 45–59 years and 14.5% (95% CI = 14.1%
to 14.9%) of women aged 60 years or older were dispensed
unopposed estrogens. The respective percentages for MPA were 14.1%
(95% CI = 13.7% to 14.5%) and 4.7% (95% CI = 4.5% to 5.0%),
respectively. The percentage of women aged 45–59 years
dispensed an estrogen or progestin prescription steadily rose for 8
years until 1995 and then leveled off through 2001 (Fig. 5). The
percentage of women aged 45–59 years dispensed unopposed
1980 1982 1984 986 988 990 992 994 996 998 0002 0022 0042 0062
1 1 1 1 1 1 1
Calendar year of examination
Fig. 4. Percentage of female Kaiser Permanente Northwest (KPNW)
members aged 45 years or older who received at least one screening
mammography examination per year, 1980–2006, by age group (45–59
years versus 60 years or older). Data are from KPNW Radiology
Information Management system, which records all radiologic
procedures among KPNW members. Screening mammograms do not
include diagnostic mammograms.
estrogen prescriptions peaked at 21.1% (95% CI = 20.7% to
21.6%) in 1994, a level 64% higher than the 1988 level. Over the
same period, MPA dispensings rose approximately 80% overall.
For women aged 60 years or older, unopposed estrogen
dispensings rose 90% and MPA dispensings rose 270% through 1999,
when both leveled off. Unopposed estrogen dispensings continued
to rise among older women after plateauing among younger
women, such that in 2000, dispensings among older women
surpassed dispensings among younger women. Although MPA
dispensings also rose sharply among older women during the 1990s,
dispensings remained appreciably higher in younger women.
Compared with 1999, when 21.7% (95% CI = 21.5% to 22.0%) of
Unopposed estrogens 45-59 years
Unopposed estrogens 60+ years
Estrogen plus progestin 45-59 years
Estrogen plus progestin 60+ years
988 990 992 994 996 998 000 002 0042 0062
1 1 1 1 1 1 2 2
Calendar year of dispensing
women aged 45 years or older were dispensed prescriptions for
unopposed estrogens, unopposed estrogen dispensings were 5%
lower in 2001, 11% lower in 2002, 29% lower in 2003, and 69%
lower in 2006. Estrogen-plus-progestin dispensings among women
aged 45 years or older peaked in 1999 at 21.8 (95% CI = 21.5% to
22.1%) but were 6% lower in 2001, 15% lower in 2002, 59%
lower in 2003, and 79% lower in 2006.
Neither tamoxifen nor raloxifene was widely dispensed at KPNW
during the study period. In women aged 45–59 years, tamoxifen
dispensings increased from 0.1% in 1988 to 0.9% in 1994 and then
remained stable at 0.8%–1.1% through 2006. In women aged 60
years or older, dispensing rose from 0.5% in 1988 to 1.9% in 1992
and then remained stable (1.8%–2.3%) through 2006. Between 1998
and 2006, raloxifene was dispensed to 0.06%–0.21% of women aged
45–59 years and 0.09%–0.41% of women aged 60 years or older.
We previously described (
) a steady rise in breast cancer incidence
rates among older women enrolled in KPNW from the early
1960s to early 1980s, which seemed, at least in the later years, to
be restricted to ER+ tumors (
). In our update and expansion of
these data, we observed three major patterns. First, breast cancer
incidence rates rose markedly—by 28% overall—from 1982–1983
(when rates were 103.2 per 100 000) to 1992–1993 (131.7). Second,
after slightly declining, the rates then rose steadily but more
slowly—by 15% overall—through 2000–2001 (151.3). Finally, the
rates dropped dramatically—by 18%—through 2004 and then
leveled off through 2006 (126.2). Rates as low as these were last
observed in the mid-1980s.
The rise in incidence rates throughout the 1980s and early
1990s is qualitatively and quantitatively consistent with the
simultaneous adoption of screening mammography at KPNW. The
proportion of women regularly screened progressively rose from a
few percent in 1980 to 75% after 1993. In general, populations
into which screening mammography is introduced demonstrate
increased breast cancer incidence rates from three sources.
Initially, women undergoing their first screen experience a major
increase in rate due to the detection of prevalent, small,
slowgrowing tumors that have accumulated over several years. This
“prevalence” rate, in the first year of screening, is generally 50%–
100% higher than that seen in unscreened populations (
The incidence rates in screened populations decline following
the initial screening but plateau at rates higher than those in
unscreened populations because of two other sources of increase.
First, as a result of the lead time introduced by screening, age at
diagnosis declines, on average, by 2–4 years. Second, some tumors
that might never have come to clinical recognition without
mammography—particularly small, slower-growing tumors—are
detected (i.e., “overdiagnosis” or length–time bias). Although the
presence of these two sources of increased breast cancer incidence
in screened populations is generally accepted, their quantitative
effect on breast cancer incidence rates is controversial; estimates
range from a 10% to a 50% excess compared with incidence in
unscreened populations (
We believe that the rapid rise in breast cancer rates up to the
early 1990s seen in the KPNW reflects these three sources of
increase, with the slight decline at that point marking the
exhaustion of large numbers of previously unscreened women
undergoing prevalence examinations. The new baseline rate, which is
approximately 30% higher than the baseline rate seen before
screening began in the early 1980s, is consistent with, albeit at the
higher end of, the estimates for the excess expected due to lead
time and overdiagnosis in screened women (i.e., a 30% overall
increase translates to a 40% increase in the 75% of the population
Not only is the total rise in incidence rates that we observed
in KPNW women through the early 1990s consistent with
screening effects, but the characteristics of the rise are as well.
Rapidly rising rates from the early 1980s (103.2 in 1982–1983)
through 1987 (146.3 in 1986–1987) closely correspond to the
concurrent sharp initial increase in mammography screening.
The subsequent temporary plateauing of screening rates occurred
at the same time as the pause in increase in annual mammography
screening, and the subsequent rise in cancer rates, albeit at a
lower pace than the initial rise, mimicked the final twofold rise in
mammography. The greater rise in breast cancer incidence rates
among women aged 60 years or older than women aged 45–59
years is also consistent with screening effects: older women have
had more years to both accumulate prevalent tumors and
have detected tumors that, in the absence of screening, would
have been undetected before they died of other causes. Other
factors, such as increasing menopausal hormone therapy use, may
have contributed to the rise in rates during the 1980s, particularly
because the total increase is at the upper end of what might be
expected from mammography alone. However, the substantial
influence of screening complicates attempts to quantify effects of
By the early 1990s, the percentage of the population receiving
screening mammograms leveled off, which essentially rules out
mammography as an explanation for the second rise in incidence
(from 132.3 in 1989–1990 to 155.3 in 1998–1999) or the steep drop
in incidence from 2001–2002 (150.5) through 2005–2006 (126.2).
Instead, these trends parallel increased use of menopausal hormone
therapy, particularly estrogen plus progestin, at KPNW
throughout the 1990s, until menopausal hormone therapy use slightly
declined in 2000–2002 and dramatically dropped in 2003. Similar
usage patterns have been observed in other populations (
and are likely related to reports from two clinical trials [the Heart
and Estrogen/progestin Replacement Study in 2000 (
) and WHI
estrogen-plus-progestin results in 2002 (
)] that documented harm
associated with use of menopausal hormone therapy for chronic
disease prevention. Increased cessation of estrogen-plus-progestin
use would be expected to produce immediate effects on breast
cancer incidence because the increased breast cancer risk associated
with estrogen plus progestin is a late-stage effect: breast cancer risk
is higher in current users but rapidly declines after cessation of use
) and returns to the level in nonusers within 5 years. The larger
rate increase in the 1990s in the younger versus older women is
also consistent with the more frequent use of estrogen plus
progestin by younger women and with the higher risks associated with
this formulation versus unopposed estrogen (
Our incidence data for 2002–2004, (age-adjusted annual
incidence rates of 137.0 per 100 000 for 2002–2003 and 123.6 per
100 000 for 2003–2004) are nearly identical to the observed
nationwide decline reported by the recent Annual Report to the
Nation on the Status of Cancer, 1975–2003, in which breast cancer
incidence peaked in 2001 at an age-adjusted rate of 137.3 and then
fell to 133.8 in 2002 and 124.2 in 2003 (
). The –4.3% APC in
KPNW data from 2000 to 2006 is identical to the –4.3% APC in
SEER data from 2000 to 2003 (
The incidence trends by receptor status are provocative. The
patterns for ER+ cancers will resemble those for total breast cancer
because ER+ cancers currently make up more than 80% of breast
cancers diagnosed in women older than 45 years of age. It is also
consistent with the likelihood that they contribute
disproportionately to the slow-growing tumors that are detected with the
introduction of mammography, and their stronger association with
menopausal hormone therapy use in studies that find a difference
by receptor status (
). The incidence rates of ER+ cancer fell
sharply from 122.6 per 100 000 women in 1999–2000 to 99.9 in
2003–2004, rose to 108.1 in 2004–2005, and then fell again to
106.4 in 2005–2006. Although these rate swings might represent
chance variation, they warrant continued monitoring. It is possible
that some ER+ tumors in menopausal hormone therapy users were
undetected yet invasive, such that cessation of menopausal
hormone therapy may have simply retarded their growth and
postponed their diagnosis by 1 or 2 years. Alternatively, as noted, the
KPNW pharmacy shifted estrogen prescriptions from primarily
conjugated equine estrogen to estradiol formulations in 2005.
Elevated breast cancer risk has been found with both types of
estrogens, but potential risk differences have been the source of
) speculation (
The patterns for ER– tumors are more enigmatic. Their rate
did not rise during the period of rapid increase in mammography
screening, and indeed substantially declined between 1999 and
2006. We anticipated that screening effects would be more
apparent for ER+ tumors, which make up a higher percentage of
screening-detected cancers than of interval cancers (
). However, we
also expected to see some screening effects on ER− incidence rates.
The lack of any rise in incidence of ER− tumors during the 1990s
(when menopausal hormone therapy use substantially increased),
followed by a decline in incidence over 2003–2006 that was even
more precipitous than the decline seen for ER+ tumors, is
particularly difficult to interpret. ER− cancers are far less common than
ER+ cancers at KPNW, and thus, instability in the rate estimates
could have obscured patterns. There were no identifiable changes
in laboratory procedures at KPNW that would have alone
accounted for the increased incidence of ER+ tumors and decreased
incidence of ER− tumors, but temporal changes in other unknown
risk factors for ER− tumors (29) would limit our ability to evaluate
the potential association between mammography screening,
menopausal hormone therapy use, and incidence of ER− tumors.
Simple shifts from ER-unknown to ER+ or ER− cannot explain
the increased incidence of ER+ tumors; between 2000 and 2006, as
incidence of both ER+ tumors and ER− tumors declined, the
percentage of breast cancers with unknown ER status fell from
4% to less than 1%.
Our study has limitations. Similar to other investigations of
the impact of mammography and menopausal hormone therapy
on breast cancer incidence rates (
), ours is a descriptive study
evaluating whether population-based rates, rather than
individuallevel data, were associated with aggregate measures of
mammography screening and menopausal hormone therapy prescribing
patterns. Thus, it is possible that changes in other, unmeasured
causes could have produced the incidence patterns that we
observed. However, credible evidence of dramatic changes in
other breast cancer risk factors after 2000 has not been
documented. We also analyzed data on dispensed hormone therapy
prescriptions. To the extent that women did not comply with the
prescriptions, we will have underestimated actual usage. On the
other hand, by relying on pharmacy dispensing records, we
eliminated errors associated with patient recall and reporting. In the
aggregate, potential biases due to misclassified hormone therapy
use or mammography screening are likely to be small and
nondifferential. Other publications hypothesized that lower breast
cancer incidence rates nationwide in 2003 and 2004 were
correlated with decreased menopausal hormone therapy use in other
populations after 2002 (
). Our data from the KPNW health
plan, where breast cancer incidence rates are almost identical to
incidence rates in NCI SEER, show that, in a single, large, study
population, the statistically significant decline in breast cancer
incidence rates continued through December 31, 2006. Using
hormone therapy dispensing data and mammography screening
statistics in the KPNW health plan, we showed that breast cancer
incidence rates and hormone therapy prescriptions followed
parallel tracks of decline from 1999–2000 through 2006, while
mammography screening fell slightly in 1999–2000, stabilized through
2003, and then increased from 2004 through 2006.
In summary, since 1980, time trends in breast cancer
incidence, particularly for ER+ tumors, seem consistent with the
impact of major changes in patterns of mammography screening
and use of menopausal hormone therapy. While incidence rates
for women under age 45 years remained stable, the rates for
women aged 45–59 years and women aged 60 years or older both
rose about 50% from the early 1980s to 2001. This rise seemed
to occur in two phases, the first during the 1980s, coinciding with
the progressive adoption of screening mammography by 75%–
79% of eligible women in the plan, and the second
corresponding to increases in menopausal hormone therapy use, particularly
combined therapy, throughout the 1990s. The incidence rates
for both older age groups dropped dramatically in 2003–2006 in
conjunction with a profound decline in menopausal hormone
therapy prescriptions. Whereas ER− tumor incidence showed
the recent dramatic decline, it did not show the two earlier
National Cancer Institute (5 UO1 CA 062938) to A. G. Glass; Intramural
Research Program, National Cancer Institute, National Institutes of Health.
The funding source played no role in the design, execution, or reporting of
A. G. Glass had full access to the data and had final responsibility for the
decision for publication. A. G. Glass, J. V. Lacey, and R. N. Hoover all
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None of the authors have any conflict of interest to declare. Several KPNW employees generously supplied administrative data that made this study possible. In particular, we wish to thank Beverly Battaglia and Vicki Shindler of the Tumor Registry, Mariesa Domby and Stephanie Schoap of Clinical Practice Support, Michael Nash and Neil Frederickson of Market Analysis and Planning, and Steven N. Piscoran of Pharmacy Administration . Manuscript received September 11 , 2006 ; revised May 11, 2007 ; accepted June 11, 2007 .