ORIGINAL INVESTIGATION

Prospective Study of Leukocyte Count as a Predictor

of Incident Breast, Colorectal, Endometrial, and Lung
Cancer and Mortality in Postmenopausal Women
Karen L. Margolis, MD, MPH; Rebecca J. Rodabough, MS; Cynthia A. Thomson, PhD, RD;
Ana Maria Lopez, MD; Anne McTiernan, MD, PhD; for the Womens Health Initiative Research Group

Background: The immune system and inflammation are
implicated in the pathogenesis of cancer. Prospective stud-
ies linking biomarkers of inflammation with cancer in-
cidence and mortality have been inconclusive.
Methods: To determine whether there is an indepen-
dent association of white blood cell (WBC) count with
incident cancer in postmenopausal women, a prospec-
tive cohort study was performed at 40 US clinical cen-
ters involving 143 748 postmenopausal women aged 50
to 79 years who were free of cancer at baseline and were
enrolled in the Womens Health Initiative. The main out-
come measures were incident invasive breast, colorec-
tal, endometrial, and lung cancer.
Results: In multivariate models, there was a graded as-
sociation of WBC count with incidence of all 4 types of
cancer. Compared with the lowest quartile of WBC count
(2.50-4.79109 cells/L), women with a WBC count
in the upper quartile (6.80-15.00109 cells/L) had a
statistically significantly higher risk of invasive breast can-
cer (hazard ratio [HR], 1.15; 95% confidence interval [CI],
1.04-1.26), colorectal cancer (HR, 1.19; 95% CI, 1.00-
1.41), endometrial cancer (HR, 1.42; 95% CI, 1.12-
1.79), and lung cancer (HR, 1.63; 95% CI, 1.35-1.97).
The findings were similar when cancers that occurred dur-
ing the first 2 years of follow-up were excluded. Statis-
tically significant associations remained for invasive breast
cancer and endometrial cancer when the analyses were
limited to nonsmokers. The WBC count was also statis-
tically significantly associated with breast cancer, lung
cancer, and overall cancer mortality.
Conclusion: Postmenopausal women with higher WBC
counts have a higher risk of incident invasive breast, co-
lorectal, endometrial, and lung cancer, as well as a higher
risk of breast, lung, and overall cancer mortality.
Arch Intern Med. 2007;167(17):1837-1844

Author Affiliations:
HealthPartners Research
Foundation, Minneapolis,
Minnesota (Dr Margolis);
Fred Hutchinson Cancer
Research Center, Seattle,
Washington (Ms Rodabough
and Dr McTiernan); and
Department of Nutritional
Sciences (Dr Thomson) and
the Arizona Cancer Center
(Dr Lopez), University of
Arizona, Tuscon.
Group Information: A full list
of the members of the Womens
Health Initiative Research
Group was published in
Arch Intern Med
(2007;167[9]:901).
A
CAUSAL LINK BETWEEN IN-
flammation and cancer
was first hypothesized in
1863 by Virchow, who ob-
served leukocytes in neo-
plastic tissues.1 Well-known associations
between cancer and certain infections (eg,
chronic hepatitis B and hepatocellular car-
cinoma) and inflammatory conditions (eg,
Crohn disease and colorectal carcinoma)
have supported the notion that cancer
For editorial comment
see page 1822
arises at sites of chronic inflammation.1 The
apparent protection from certain types of
cancer by aspirin and nonsteroidal anti-
inflammatory drugs provides an addi-
tional line of evidence of a causal rela-
tion.2 Researchers have begun to elucidate
the molecular mechanisms by which in-
fectious agents, inflammatory cells, and in-
flammatory mediators may initiate and
promote cancer.3-5
Several prospective studies 6-8 have
found that the white blood cell (WBC)
count is a predictor of cancer mortality,
although a study9 among Korean men and
women found no association, and an-
other study10 found the association to be
specific to smoking-related cancers. The
WBC count and C-reactive protein level
have been shown to be associated with an
increased risk of colorectal cancer in 4
studies,11-14 but the C-reactive protein level
was unassociated with colorectal cancer in
another study15 that enrolled only women.
A meta-analysis16 of fibrinogen levels has
also shown an association with increased
risk of colorectal cancer mortality.
CME course available online
www.archinternmed.com
The Womens Health Initiative (WHI)
is a multicenter prospective study of
161 808 postmenopausal women com-
posed of diverse racial/ethnic and socio-
economic groups. At baseline, partici-
pants in the WHI underwent a WBC count,

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 in addition to an extensive medical history and a physi-
cal examination. Because of its large size and broad rep-
resentation of women from across the United States, this
cohort provides an opportunity to determine whether
there is an association of WBC count with specific types
of cancer that are common in postmenopausal women,
as well as to examine the independence of any associa-
tion from other known risk factors. In this article, we de-
scribe the relation between the baseline WBC count and
newly diagnosed cancers with an annualized incidence
of 0.1% or higher in women enrolled in the WHI. These
outcomes included invasive breast, colorectal, endome-
trial, and lung cancer.
METHODS
STUDY POPULATION
The WHI is an ongoing ethnically and geographically diverse
multicenter clinical trial and observational study designed to
address the leading causes of morbidity and mortality in post-
menopausal women.17 Briefly, 161 808 women aged 50 to 79
years were recruited at 40 clinical centers throughout the United
States. Recruitment began on September 1, 1993, and ended
on December 31, 1998. The WHI clinical trials (N=68 132) in-
clude the following 3 overlapping components: the hormone
trial, dietary modification trial, and calcium/vitamin D supple-
mentation trial. In the hormone trial, women who had under-
gone hysterectomy were assigned to the estrogen-alone trial
(0.625 mg/d of conjugated equine estrogens vs placebo); the
remaining women with a uterus were assigned to the estrogen
plus progesterone trial (0.625 mg/d of conjugated equine es-
trogens plus 2.5 mg/d of medroxyprogesterone acetate vs pla-
cebo). In the diet modification trial, a low-fat eating pattern was
compared with a usual diet. In the calcium/vitamin D supple-
mentation trial, 1000 mg of elemental calcium plus 400 IU of
vitamin D3 daily was compared with placebo.
Participants in the observational study (n = 93 676) were
women who were screened for the clinical trial but proved to
be ineligible or unwilling to participate or were recruited through
a direct invitation for screening into the observational study.
Details of the scientific rationale, eligibility requirements, and
baseline characteristics of the participants in the WHI have been
published elsewhere.17-22 All participants provided informed con-
sent using materials approved by institutional review boards
at each center.
The following participants were excluded from the origi-
nal cohort of 161 808 for these analyses: 15 849 with any his-
tory of cancer except nonmelanoma skin cancer at baseline, 1681
with a missing baseline WBC count, 1401 with missing data
regarding cancer history at baseline, 316 with a WBC count
greater than 15.0109 cells/L, and 191 with a WBC count less
than 2.5109 cells/L. Some women had more than 1 exclu-
sion criterion, yielding a final analytic sample of 143 748. This
included 79 227 participants (55.1%) in the observational study
and 64 521 participants (44.9%) in the clinical trials. Analyses
of endometrial cancer were limited to women who had not un-
dergone hysterectomy at baseline (n=85 621).
DATA COLLECTION
Participants underwent initial screening visits during which per-
sonal information, medical history, family history, and health-
related habits were assessed using standardized question-
naires. Medication and supplement use were assessed using a
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medication inventory. Certified staff performed physical mea-
surements and obtained blood samples at the baseline clinic
visit. The blood collection took place in the morning after a
12-hour tobacco-free fast. The hemogram sample was col-
lected in a tube containing the anticoagulant edetic acid. These
samples were analyzed for WBC count at local laboratories at
each of the 40 WHI clinical centers using standardized quality
assurance procedures.
FOLLOW-UP AND ASCERTAINMENT OF CASES
The WHI follow-up was conducted by semiannual (clinical trials)
or annual (observational study) mailed self-administered ques-
tionnaires. As of March 31, 2005, response rates for years 1
through 8 medical history updates in the observational study
ranged from 93% to 96%, with only 1.9% of the participants lost
to follow-up. An additional 2.2% had discontinued their partici-
pation in the study, and 6.1% had died. In the clinical trials, an-
nual follow-up visits were required; 1.2% were lost to follow-
up, 3.2% had discontinued participation, and 5.3% had died.
At each semiannual or annual contact, participants were
asked if they had been told by a physician for the first time that
they had a new cancer or malignant tumor. For all new can-
cers except nonmelanoma skin cancers, trained study physi-
cian adjudicators and cancer coders, blinded to exposure sta-
tus, reviewed pathology reports, discharge summaries, operative
reports, radiology reports, and death certificates for all biop-
sies, surgical procedures, and deaths to verify any cancer out-
come. Pathology reports were available and were reviewed for
98% of invasive breast cancers, 95% of colorectal cancers, 97%
of endometrial cancers, and 87% of lung cancers.
STATISTICAL ANALYSIS
To describe participant characteristics across levels of WBC
count, WBC counts were categorized using quartile divisions.
Cross-tabulations were examined.
Hazard ratios (HRs) and nominal 95% confidence intervals
(CIs) from Cox proportional hazards regression models are re-
ported for the outcomes of invasive breast cancer, colorectal can-
cer, endometrial cancer, lung cancer, and cancer mortality. The
initial models were stratified on enrollment in the observa-
tional study, on study component (assignment to active hor-
mone or placebo) in the 2 hormone trials (estrogen plus pro-
gestin and estrogen alone), or on assignment to intervention or
control in the dietary modification trial and were adjusted for
age and exclude an additional 651 participants without follow-
up. Additional potential confounders and effect modifiers (height,
parity, smoking, race/ethnicity, alcohol intake, waist to hip ra-
tio, physical activity, menstrual history, body mass index, hor-
mone therapy use, history of breastfeeding, bilateral oophorec-
tomy, family history of cancer, previous hormone therapy, history
of diabetes mellitus, history of benign breast disease, and use of
aspirin or nonsteroidal anti-inflammatory drugs) were in-
cluded in at least 1 of the multivariate models. Participants with-
out complete case data for all covariates in a given multivariate
model were excluded from that analysis. Follow-up time for each
woman was accrued from enrollment to the date of cancer di-
agnosis, death, loss to follow-up, or administrative censoring date
(March 31, 2005). The mean length of follow-up for the cohort
was 7.8 years (range, 0-11.2 years).
The assumption of proportionality was tested by including
indicators for the upper 3 WBC quartiles, product terms be-
tween these indicators, and follow-up time and by using a like-
lihood ratio procedure to test for zero coefficients for the 3 prod-
uct terms. The assumption was met for all of the outcomes
included in the analysis. Trends across WBC quartiles were as-
WWW.ARCHINTERNMED.COM
 sessed by including a variable that equaled the median of the
WBC values within the pertinent quartile. Corresponding P val-
ues are reported.
Stratified fully adjusted Cox proportional hazards regres-
sion models were examined for interactions of WBC count with
potential confounding variables. Interactions of WBC count with
age, aspirin use, hormone therapy, current and past smoking,
history of cardiovascular disease, and nonsteroidal anti-
inflammatory drug use were tested separately for each cancer
using likelihood ratio tests and comparing fully adjusted Cox
proportional hazards regression models with and without the
interaction terms.
In secondary analyses by cancer location, we separately ex-
amined the WBC count as a continuous outcome and omitted
current smokers and cancers diagnosed within the first 2 years
of follow-up. Women who participated in the clinical trials were
required to have a negative mammogram (or a negative report
of a mammogram verified by WHI staff ) within 12 months be-
fore entering the study. We examined the association of WBC
count with invasive breast cancer in this subgroup who had un-
dergone previous breast cancer screening with well-
documented negative results. We also examined the associa-
tion of the WBC count with colorectal cancer in the subgroup
of women who self-reported having been screened using fecal
occult blood testing, sigmoidoscopy, or colonoscopy within the
previous 5 years. All analyses were performed using commer-
cially available statistical software (SAS for Windows, version
9.1.3; SAS Institute Inc, Cary, North Carolina).
RESULTS
The mean age of the participants at baseline was 63 years,
7% were current smokers, 18% were of a minority race/
ethnicity, and 20% regularly used aspirin. Approxi-
mately two-thirds of the participants were overweight or
obese. Other baseline characteristics of the WHI partici-
pants are given by WBC quartile in Table 1. Higher WBC
counts were associated with older age, aspirin use, higher
parity, hypertension, diabetes mellitus, bilateral oopho-
rectomy, current hormone use, greater body mass in-
dex, greater waist and hip circumferences, early age of
menarche and menopause, and current smoking and 20
or more pack-years of smoking. Lower WBC counts were
associated with physical activity, months of breastfeed-
ing, increased alcohol consumption, and black or Asian/
Pacific Islander race/ethnicity. There was little or no as-
sociation of WBC count with past smoking, benign breast
disease, or family history of cancer.
In age-adjusted models (Table 2), there was a graded
association of WBC count with incident invasive breast
cancer (4639 cases), colorectal cancer (1341 cases), en-
dometrial cancer (766 cases), and lung cancer (1237 cases).
In situ breast cancer (1070 cases) was not associated with
WBC count (HR for upper vs lower quartile of WBC count,
1.01; 95% CI, 0.85-1.21; P=.98 for trend [data not shown]).
In multivariate models further adjusted for potential con-
founders, the strength of the associations was somewhat
attenuated, but significant trends with increasing WBC
quartile remained. Compared with women in the lowest
quartile of WBC count (2.50-4.79109 cells/L), women
in the highest quartile of WBC count (6.80-15.00
109 cells/L) had a 15% higher risk of invasive breast can-
cer, 19% higher risk of colorectal cancer (with similar
results for colon and rectal cancers), 42% higher risk of
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endometrial cancer, and 63% higher risk of lung cancer.
In multivariate models with WBC count modeled as a lin-
ear variable per 109 cells/L, there was also a statistically
significant association between increasing WBC count and
higher risk of invasive breast cancer (HR, 1.03; 95% CI,
1.01-1.05), colorectal cancer (HR, 1.08; 95% CI, 1.04-
1.12), endometrial cancer (HR, 1.07; 95% CI, 1.02-
1.12), and lung cancer (HR, 1.11; 95% CI, 1.08-1.15).
To examine whether subclinical cancer could have
caused inflammation and raised the WBC count, we looked
at models excluding 1044 invasive breast cancers, 320 co-
lorectal cancers, 185 endometrial cancers, and 260 lung
cancers that occurred during the first 2 years of follow-
up. The point estimates of the HRs, CIs, and P values were
almost identical, and trends across quartiles were statis-
tically significant, despite the reduced power.
After excluding current smokers from the multivari-
ate analyses, there were almost identical associations be-
tween WBC count and invasive breast cancer (upper quar-
tile HR, 1.14; 95% CI, 1.03-1.26; P =.01 for trend) and
endometrial cancer (upper quartile HR, 1.45; 95% CI,
1.14-1.84; P =.001) but a slightly weaker and statisti-
cally nonsignificant association with colorectal cancer (up-
per quartile HR, 1.16; 95% CI, 0.97-1.39; P =.07). For
breast, colorectal, or endometrial cancer, there were no
statistically significant interactions between WBC count
and smoking status (current smoker vs past smoker vs
never smoker). There were only 198 lung cancers that
occurred in never smokers, and there was no associa-
tion of WBC count with lung cancer in this subgroup.
There was a statistically significantly increased risk of lung
cancer in women with a WBC count in the upper quar-
tile among past smokers (HR, 1.65; 95% CI, 1.30-2.10)
and current smokers (HR, 1.96; 95% CI, 1.15-3.32). How-
ever, in the lung cancer models, a formal test of interac-
tion between the WBC count and pack-years of past and
current smoking was statistically nonsignificant (P=.33).
No significant interactions with the WBC count were ob-
served for the following variables: age, aspirin use, hor-
mone therapy, history of cardiovascular disease, and non-
steroidal anti-inflammatory drug use.
Among women with complete covariate information
who had a documented negative breast cancer screening
test at baseline in the clinical trials, 1553 invasive breast
cancers occurred during the follow-up period. Com-
pared with the overall results in women in the highest WBC
quartile, women in the clinical trials in the highest WBC
quartile had a similar risk for invasive breast cancer, but
the results were no longer statistically significant (HR, 1.12;
95% CI, 0.96-1.30; P=.18). Among women who at enroll-
ment reported having undergone colorectal cancer screen-
ing within the previous 5 years, 647 colorectal cancers oc-
curred during follow-up. Compared with the overall results,
women in this subgroup with WBC counts in the highest
WBC quartile had a somewhat lower risk for colorectal can-
cer, and there was no statistically significant association
of WBC count with incident colorectal cancer (HR, 1.13;
95% CI, 0.89-1.42; P=.23).
Cause-specific cancer mortality is given in Table 3.
Invasive breast cancer mortality remained more than 2-fold
elevated in the highest WBC quartile, with little differ-
ence between age-adjusted and multivariate-adjusted
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 Table 1. Baseline Characteristics of the Womens Health Initiative Clinical Trials and Observational Study Participants
by Quartile of White Blood Cell (WBC) Count

Quartile of WBC Count, 109 Cells/L, No. (%)

Characteristic a 2.50-4.79 4.80-5.69 5.70-6.79 6.80-15.00 Total P Value b

Age at screening, y .001
50-59 13 244 (38.5) 12 363 (34.1) 11 706 (32.0) 11 348 (31.1) 48 661 (33.9)
60-69 14 982 (43.6) 16 398 (45.2) 16 655 (45.5) 16 645 (45.6) 64 680 (45.0)
70-79 6162 (17.9) 7505 (20.7) 8212 (22.5) 8528 (23.4) 30 407 (21.2)
Race/ethnicity .001
White 26 927 (78.3) 30 148 (83.1) 30 678 (83.9) 30 583 (83.7) 118 336 (82.3)
Black 4557 (13.3) 2979 (8.2) 2654 (7.3) 2844 (7.8) 13 034 (9.1)
Hispanic 1097 (3.2) 1516 (4.2) 1626 (4.4) 1673 (4.6) 5912 (4.1)
American Indian 114 (0.3) 154 (0.4) 168 (0.5) 186 (0.5) 622 (0.4)
Asian/Pacific Islander 1225 (3.6) 1025 (2.8) 930 (2.5) 678 (1.9) 3858 (2.7)
Unknown 468 (1.4) 444 (1.2) 517 (1.4) 557 (1.5) 1986 (1.4)
Smoking .001
Never smoked 19 236 (56.5) 19 393 (54.1) 18 382 (50.9) 15 905 (44.1) 72 916 (51.3)
Past smoker 13 926 (40.9) 15 106 (42.1) 15 424 (42.7) 14 817 (41.1) 59 273 (41.7)
Current smoker 877 (2.6) 1373 (3.8) 2299 (6.4) 5333 (14.8) 9882 (7.0)
Pack-years of smoking .001
Never smoked 19 236 (57.9) 19 393 (55.3) 18 382 (52.0) 15 905 (45.1) 72 916 (52.5)
5 5271 (15.9) 5339 (15.2) 5067 (14.3) 4426 (12.6) 20 103 (14.5)
5 to 20 4623 (13.9) 4924 (14.0) 5180 (14.7) 5226 (14.8) 19 953 (14.4)
20 4076 (12.3) 5412 (15.4) 6690 (18.9) 9679 (27.5) 25 857 (18.6)
Alcohol use .001
Nondrinker 3889 (11.4) 3980 (11.0) 3925 (10.8) 3981 (11.0) 15 775 (11.0)
Past drinker 5701 (16.7) 6115 (17.0) 6721 (18.5) 7907 (21.8) 26 444 (18.5)
1 Drink/mo 3642 (10.7) 4365 (12.1) 4616 (12.7) 5234 (14.4) 17 857 (12.5)
1 Drink/wk 6747 (19.7) 7415 (20.6) 7648 (21.0) 7567 (20.9) 29 377 (20.6)
1 to 7 Drinks/wk 9705 (28.4) 9684 (26.9) 9360 (25.8) 8067 (22.2) 36 816 (25.8)
7 Drinks/wk 4486 (13.1) 4482 (12.4) 4068 (11.2) 3526 (9.7) 16 562 (11.6)
Physical activity, METs/wk .001
0 4209 (12.8) 4945 (14.3) 5649 (16.2) 7017 (20.2) 21 820 (15.9)
0.5-6.75 8280 (25.2) 9587 (27.7) 9994 (28.7) 10 916 (31.5) 38 777 (28.3)
6.76-16.63 9214 (28.0) 9726 (28.1) 9665 (27.8) 8959 (25.8) 37 564 (27.4)
16.63 11 197 (34.0) 10 348 (29.9) 9518 (27.3) 7816 (22.5) 38 879 (28.4)
Aspirin use 6132 (17.8) 7079 (19.5) 7466 (20.4) 7970 (21.8) 28 647 (19.9) .001
Prescription NSAID use 1731 (5.0) 1988 (5.5) 2122 (5.8) 2490 (6.8) 8331 (5.8) .001
Prior hormone use .001
Never 15 553 (45.3) 16 107 (44.5) 15 605 (42.7) 15 225 (41.8) 62 490 (43.5)
Past 5234 (15.2) 5638 (15.6) 5672 (15.5) 5588 (15.3) 22 132 (15.4)
Current estrogen alone 7398 (21.5) 7833 (21.6) 8411 (23.0) 8815 (24.2) 32 457 (22.6)
Current estrogen plus progesterone 6163 (17.9) 6636 (18.3) 6840 (18.7) 6825 (18.7) 26 464 (18.4)
Body mass index c .001
25 15 687 (46.0) 13 195 (36.7) 11 347 (31.3) 9536 (26.3) 49 765 (34.9)
25 to 30 11 495 (33.7) 13 072 (36.4) 12 981 (35.8) 12 057 (33.3) 49 605 (34.8)
30 6899 (20.2) 9691 (27.0) 11 931 (32.9) 14 614 (40.4) 43 135 (30.3)
Waist circumference, cm .001
80 17 387 (50.8) 14 576 (40.3) 12 037 (33.0) 9572 (26.3) 53 572 (37.4)
80 to 88 7767 (22.7) 8670 (24.0) 8591 (23.6) 7749 (21.3) 32 777 (22.9)
88 9103 (26.6) 12 888 (35.7) 15 811 (43.4) 19 088 (52.4) 56 890 (39.7)
Hip circumference, cm .001
100 12 999 (38.0) 11 650 (32.3) 10 226 (28.1) 9326 (25.6) 44 201 (30.9)
100 to 110 12 904 (37.7) 13 481 (37.3) 13 275 (36.4) 12 196 (33.5) 51 856 (36.2)
110 8345 (24.4) 10 977 (30.4) 12 931 (35.5) 14 853 (40.8) 47 106 (32.9)
Waist to hip ratio .001
0.758 12 287 (35.9) 9821 (27.2) 7909 (21.7) 5912 (16.3) 35 929 (25.1)
0.758 to 0.8043 9385 (27.4) 9520 (26.4) 9001 (24.7) 7728 (21.3) 35 634 (24.9)
0.8043 to 0.8572 7344 (21.5) 9048 (25.1) 9743 (26.8) 10 041 (27.6) 36 176 (25.3)
0.8572 5210 (15.2) 7704 (21.3) 9760 (26.8) 12 682 (34.9) 35 356 (24.7)
Height, cm .001
157.5 7444 (21.8) 8907 (24.7) 9473 (26.1) 10 359 (28.5) 36 183 (25.3)
157.6-161.9 8126 (23.8) 8940 (24.8) 9382 (25.8) 9300 (25.6) 35 748 (25.0)
162.0-166.0 8885 (26.0) 9116 (25.3) 8980 (24.7) 8900 (24.5) 35 881 (25.1)
166.0 9718 (28.4) 9092 (25.2) 8526 (23.4) 7750 (21.3) 35 086 (24.6)

(continued )

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 Table 1. Baseline Characteristics of the Womens Health Initiative Clinical Trials and Observational Study Participants
by Quartile of White Blood Cell (WBC) Count (cont)

Quartile of WBC Count, 109 Cells/L, No. (%)

Characteristic a 2.50-4.79 4.80-5.69 5.70-6.79 6.80-15.00 Total P Value b

Age at menarche, y .001
11 7073 (20.6) 7675 (21.2) 8058 (22.1) 8532 (23.4) 31 338 (21.9)
12 8894 (25.9) 9348 (25.8) 9568 (26.2) 9500 (26.1) 37 310 (26.0)
13 10 267 (29.9) 10 650 (29.4) 10 518 (28.8) 10 163 (27.9) 41 598 (29.0)
14 8070 (23.5) 8506 (23.5) 8337 (22.9) 8217 (22.6) 33 130 (23.1)
Age at menopause, y .001
45 6243 (19.2) 7273 (21.3) 7776 (22.6) 8688 (25.3) 29 980 (22.1)
45-49 8673 (26.7) 8721 (25.5) 8853 (25.7) 9051 (26.4) 35 298 (26.1)
50-52 9875 (30.4) 10 224 (29.9) 9969 (29.0) 9224 (26.9) 39 292 (29.0)
53-60 7700 (23.7) 8006 (23.4) 7807 (22.7) 7360 (21.4) 30 873 (22.8)
No. of term pregnancies .001
Never pregnant 3320 (9.7) 3294 (9.1) 3214 (8.8) 3121 (8.6) 12 949 (9.1)
Never had term pregnancy 1040 (3.0) 863 (2.4) 936 (2.6) 924 (2.5) 3763 (2.6)
1 3061 (8.9) 3069 (8.5) 3091 (8.5) 3202 (8.8) 12 423 (8.7)
2 8713 (25.5) 9097 (25.2) 9002 (24.7) 8971 (24.7) 35 783 (25.0)
3 8253 (24.1) 8673 (24.0) 8915 (24.5) 8830 (24.3) 34 671 (24.2)
4 4935 (14.4) 5631 (15.6) 5772 (15.8) 5638 (15.5) 21 976 (15.4)
5 4893 (14.3) 5469 (15.2) 5489 (15.1) 5671 (15.6) 21 522 (15.0)
No. of months breastfed child .001
0 16 143 (47.6) 17 074 (47.7) 17 703 (49.0) 18 103 (50.2) 69 023 (48.6)
1-6 8467 (25.0) 9306 (26.0) 9505 (26.3) 9509 (26.4) 36 787 (25.9)
7-12 4087 (12.0) 4146 (11.6) 3903 (10.8) 3728 (10.3) 15 864 (11.2)
13-23 3150 (9.3) 3257 (9.1) 3058 (8.5) 2868 (8.0) 12 333 (8.7)
24 2088 (6.2) 2035 (5.7) 1971 (5.5) 1854 (5.1) 7948 (5.6)
Bilateral oophorectomy 5827 (17.3) 6377 (18.0) 6837 (19.1) 7303 (20.5) 26 344 (18.7) .001
Benign breast disease .01
No 25 566 (78.1) 27 047 (78.7) 27 242 (78.6) 27 293 (79.0) 107 148 (78.6)
Yes, 1 biopsy 5045 (15.4) 5160 (15.0) 5167 (14.9) 5210 (15.1) 20 582 (15.1)
Yes, 2 biopsies 2106 (6.4) 2172 (6.3) 2233 (6.4) 2031 (5.9) 8542 (6.3)
Diabetes mellitus 1017 (3.0) 1570 (4.3) 2095 (5.7) 3650 (10.0) 8332 (5.8) .001
Hypertension .001
Never 24 268 (74.1) 23 933 (69.6) 22 447 (64.8) 19 694 (57.2) 90 342 (66.3)
Untreated 2382 (7.3) 2745 (8.0) 2881 (8.3) 2963 (8.6) 10 971 (8.1)
Treated 6080 (18.6) 7731 (22.5) 9292 (26.8) 11 802 (34.2) 34 905 (25.6)
Family history of cancer
Any cancer 21 811 (66.2) 23 068 (66.4) 23 006 (65.8) 22 835 (65.6) 90 720 (66.0) .11
Female breast cancer 6009 (18.5) 6391 (18.5) 6211 (17.9) 6137 (17.8) 24 748 (18.2) .03
Colorectal cancer 5202 (16.5) 5534 (16.6) 5497 (16.4) 5314 (16.0) 21 547 (16.4) .22
Endometrial cancer 1850 (5.8) 1946 (5.7) 1933 (5.7) 2038 (6.0) 7767 (5.8) .22

Abbreviations: METs, metabolic equivalent tasks; NSAID, nonsteroidal anti-inflammatory drug.

a Because of missing data, the total number of participants varies among the characteristics.
b From 2 tests.
c Calculated as weight in kilograms divided by height in meters squared.

models. Colorectal cancer mortality had a borderline as- COMMENT

sociation with WBC quartile, which was also not altered
substantially by multivariate adjustment. Compared with
other cancers, there were few cases of endometrial can-
cer mortality (n=48), and the statistically significant trend
in mortality with WBC quartile in the age-adjusted model
was not seen after multivariate adjustment. Age-
adjusted lung cancer mortality was more than 3-fold el-
evated among women in the highest WBC quartile. After
adjustment for smoking, there was marked attenuation
of the association, but there was still a statistically sig-
nificant 65% increase in lung cancer mortality in the high-
est WBC quartile. Nonlung cancer and total cancer mor-
tality also showed statistically significant associations with
WBC quartile.
These findings demonstrate for the first time (to our knowl-
edge) that WBC count is associated with incident inva-
sive breast, colorectal, endometrial, and lung cancer among
postmenopausal women, providing further support for the
hypothesis of a causal link between inflammation and the
initiation, promotion, and progression of these types of
tumors. The strongest associations were observed for en-
dometrial and lung cancer incidence. We also found a
strong association of WBC count with invasive breast and
lung cancer mortality, as well as overall cancer mortality,
supporting previous studies6-8 that found a positive asso-
ciation between WBC count and cancer mortality.

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 Table 2. Cancer Incidence (per 100 Person-Years) and Age- and Multivariate-Adjusted HRs
According to Quartile of Baseline White Blood Cell Count

Age-Adjusted Risk Multivariate-Adjusted Risk

Cancer Type Incidence per 100
and Quartile No. Person-Years HR (95% CI) P Value for Trend HR (95% CI) P Value for Trend
Invasive breast a
Q1 993 0.37 1 [Reference] 1 [Reference]
Q2 1172 0.41 1.10 (1.02-1.19) 1.08 (0.99-1.19)
.001 .01
Q3 1209 0.43 1.11 (1.03-1.20) 1.08 (0.98-1.19)
Q4 1265 0.45 1.18 (1.09-1.27) 1.15 (1.04-1.26)
Total 4639 1.66
Colorectal b
Q1 281 0.10 1 [Reference] 1 [Reference]
Q2 313 0.11 1.01 (0.86-1.19) 0.98 (0.82-1.17)
.001 .02
Q3 348 0.12 1.09 (0.94-1.28) 1.04 (0.88-1.24)
Q4 399 0.14 1.27 (1.09-1.48) 1.19 (1.00-1.41)
Total 1341 0.48
Endometrial c
Q1 154 0.09 1 [Reference] 1 [Reference]
Q2 179 0.10 1.12 (0.90-1.39) 1.08 (0.85-1.37)
.001 .001
Q3 212 0.13 1.34 (1.09-1.65) 1.24 (0.99-1.57)
Q4 221 0.14 1.50 (1.22-1.84) 1.42 (1.12-1.79)
Total 766 0.46
Lung d
Q1 158 0.06 1 [Reference] 1 [Reference]
Q2 225 0.08 1.30 (1.06-1.59) 1.12 (0.91-1.38)
.001 .001
Q3 302 0.11 1.70 (1.40-2.06) 1.24 (1.02-1.51)
Q4 552 0.20 3.15 (2.64-3.77) 1.63 (1.35-1.97)
Total 1237 0.44

Abbreviations: CI, confidence interval; HR, hazard ratio (computed from Cox proportional hazards models stratified by participation in the Womens Health
Initiative clinical trials or observational study); Q, quartile (Q1, 2.50-4.79 109 cells/L; Q2, 4.80-5.69 109 cells/L; Q3, 5.70-6.79 109 cells/L; and
Q4, 6.80-15.00 109 cells/L).
a Multivariate model is adjusted for age, race/ethnicity, smoking, alcohol intake, physical activity, use of aspirin or nonsteroidal anti-inflammatory drugs,
hormone therapy use, body mass index, height, age at menarche and menopause, parity, months of breastfeeding, bilateral oophorectomy, history of benign
breast disease, and family history of breast cancer.
b Multivariate model is adjusted for age, race/ethnicity, smoking, alcohol intake, physical activity, use of aspirin or nonsteroidal anti-inflammatory drugs,
hormone therapy use, body mass index, history of diabetes mellitus, and family history of colorectal cancer.
c Analyses limited to women with a uterus. Multivariate model is adjusted for age, race/ethnicity, smoking, physical activity, use of aspirin or nonsteroidal
anti-inflammatory drugs, hormone therapy use, body mass index, height, age at menarche and menopause, parity, and family history of endometrial cancer.
d Multivariate model is adjusted for age, race/ethnicity, pack-years of smoking, and current and past smoking.

Adjustment of multivariate models for known risk fac-
tors, exclusion of incident cases early in the follow-up
period, and limitation of the analyses to nonsmokers di-
minish the chance that our findings are a result of con-
founding or reverse causality, especially for breast and
endometrial cancer. We also tested models limited to
women who had previously undergone breast cancer
screening (verified mammography reports) and colorec-
tal cancer screening (self-report only). Because these
analyses included only one-third to one-half as many can-
cer cases, power was much diminished, and there were
no statistically significant associations of WBC count with
these cancers in this analysis. Because we did not dem-
onstrate that an elevated WBC count is present before
breast and colorectal cancer is detectable by screening,
definitive evidence of a causal relation is not present.
The weaker and statistically nonsignificant relation of
WBC count with colorectal cancer in nonsmokers could
be because of chance or because the overall association
is caused by elevated WBC counts in smokers. Smoking
is a risk factor for colorectal adenomas,23 and our data
show that current smoking is also strongly related to WBC
count. Similarly, confounding of the relation of WBC
count and lung cancer by smoking is a possibility, al-
though we adjusted for current smoking, past smoking,
and pack-years of smoking in the multivariate analysis.
In addition to the epidemiological evidence, exten-
sive basic research supports a role of the immune sys-
tem and inflammation in the pathogenesis of cancer. Most
tumors are heavily infiltrated by inflammatory cells, which
in turn produce cytokines and chemokines that regu-
late the growth, migration, and differentiation of tumor
and stromal cells.1,2,24,25 Several genetic polymorphisms
in cytokine genes have been associated with an in-
creased risk for colorectal adenomas, a precursor of co-
lorectal cancer.26 Neutrophils, eosinophils, and mono-
nuclear cells produce reactive oxygen and nitrogen species
that further damage cellular DNA, RNA, lipids, and pro-
teins.27 Proteases, matrix metalloproteinases, angio-
genic factors, and other soluble mediators produced by
leukocytes affect cell survival and tissue remodeling.28
Of the cytokines, tumor necrosis factor may play a cen-
tral role as a tumor promoter, as well as in the interac-
tion between tumor and inflammatory cells, in part
through induction of nuclear factor Bsignaling path-
ways.29 Cancer cells may use the same adhesion mol-

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 Table 3. Cause-Specific Cancer Mortality (per 100 Person-Years) and Age- and Multivariate-Adjusted HRs
According to Quartile of Baseline White Blood Cell Count

Age-Adjusted Risk Multivariate-Adjusted Risk

Cancer Type Mortality per 100
and Quartile No. Person-Years HR (95% CI) P Value for Trend HR (95% CI) P Value for Trend
Invasive breast a
Q1 32 0.01 1 [Reference] 1 [Reference]
Q2 46 0.02 1.35 (0.86-2.12) 1.17 (0.69-1.98)
.001 .001
Q3 56 0.02 1.64 (1.06-2.54) 1.46 (0.88-2.42)
Q4 78 0.03 2.35 (1.56-3.55) 2.16 (1.33-3.50)
Total 212 0.08
Colorectal b
Q1 63 0.02 1 [Reference] 1 [Reference]
Q2 63 0.02 0.90 (0.63-1.27) 0.80 (0.55-1.17)
.04 .07
Q3 67 0.02 0.93 (0.66-1.31) 0.85 (0.58-1.23)
Q4 94 0.03 1.31 (0.95-1.80) 1.27 (0.89-1.81)
Total 287 0.10
Endometrial c
Q1 9 0.01 1 [Reference] 1 [Reference]
Q2 7 0.01 0.73 (0.27-1.95) 0.59 (0.21-1.66)
.04 .35
Q3 15 0.01 1.55 (0.68-3.56) 1.23 (0.52-2.91)
Q4 17 0.01 1.89 (0.84-4.24) 1.22 (0.51-2.95)
Total 48 0.03
Lung d
Q1 90 0.03 1 [Reference] 1 [Reference]
Q2 128 0.05 1.28 (0.98-1.68) 1.13 (0.86-1.49)
.001 .001
Q3 179 0.06 1.75 (1.36-2.26) 1.28 (0.98-1.66)
Q4 327 0.12 3.25 (2.57-4.10) 1.65 (1.29-2.12)
Total 724 0.26
Nonlung e
Q1 473 0.18 1 [Reference] 1 [Reference]
Q2 524 0.18 1.00 (0.88-1.13) 0.94 (0.82-1.09)
.001 .001
Q3 575 0.20 1.07 (0.95-1.21) 0.92 (0.79-1.06)
Q4 766 0.28 1.45 (1.29-1.62) 1.25 (1.09-1.44)
Total 2338 0.84
Total cancer e
Q1 563 0.21 1 [Reference] 1 [Reference]
Q2 652 0.23 1.05 (0.94-1.17) 0.95 (0.83-1.09)
.001 .001
Q3 754 0.27 1.18 (1.06-1.32) 0.98 (0.86-1.12)
Q4 1093 0.39 1.74 (1.57-1.92) 1.33 (1.17-1.51)
Total 3062 1.10

Abbreviations: CI, confidence interval; HR, hazard ratio (computed from Cox proportional hazards models stratified by participation in the Womens Health
Initiative clinical trials or observational study); Q, quartile (Q1, 2.50-4.79 109 cells/L; Q2, 4.80-5.69 109 cells/L; Q3, 5.70-6.79 109 cells/L; and
Q4, 6.80-15.00 109 cells/L).
a Multivariate model is adjusted for age, race/ethnicity, smoking, alcohol intake, physical activity, use of aspirin or nonsteroidal anti-inflammatory drugs,
hormone therapy use, body mass index, height, age at menarche and menopause, parity, months of breastfeeding, bilateral oophorectomy, history of benign
breast disease, and family history of breast cancer.
b Multivariate model is adjusted for age, race/ethnicity, smoking, alcohol intake, physical activity, use of aspirin or nonsteroidal anti-inflammatory drugs,
hormone therapy use, body mass index, history of diabetes mellitus, and family history of colorectal cancer.
c Analyses limited to women with a uterus. Multivariate model is adjusted for age, race/ethnicity, smoking, physical activity, use of aspirin or nonsteroidal
anti-inflammatory drugs, hormone therapy use, body mass index, height, age at menarche and menopause, parity, and family history of endometrial cancer.
d Multivariate model is adjusted for age, race/ethnicity, pack-years of smoking, and current and past smoking.
e Multivariate model is adjusted for age; race/ethnicity; smoking; alcohol intake; physical activity; use of aspirin or nonsteroidal anti-inflammatory drugs;
hormone therapy use; body mass index; height; waist to hip ratio; age at menarche and menopause; parity; bilateral oophorectomy; family history of breast,
colorectal, ovarian, and endometrial cancer; and history of diabetes mellitus, hypertension, and benign breast disease.

ecules and trophic factors made by inflammatory cells
in homing during metastasis.2,3 Therefore, inflamma-
tion seems to play a key role in all stages of cancer from
initiation to distant spread.
Several limitations of this analysis must be consid-
ered. Differential cell counts were not performed for the
WHI, so we do not have information about what types
of leukocytes were more prone to be elevated in women
who subsequently developed cancer. Only 1 measure-
ment of WBC count was performed, and the analyses were
performed in 40 local laboratories on automated counters.
Multiple measurements in a central laboratory would have
reduced measurement error and increased the precision
of our results; therefore, our present results are likely to
be underestimates of the true associations due to non-
differential misclassification. The participants in the WHI
were generally healthy, well-educated, postmenopausal
women; therefore, our results may not apply to the gen-
eral population or to men, despite the broad geographic
representation of the 40 clinical centers.

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 In summary, we demonstrated that postmenopausal
women with higher WBC counts have a higher risk of
incident invasive breast, colorectal, endometrial, and lung
cancer, as well as a higher risk of breast, lung, and over-
all cancer mortality. Before these findings can be ap-
plied clinically, they should be replicated in other popu-
lations, preferably with 2 measurements of WBC count,
and expanded to include other biomarkers of inflamma-
tion that may be more specifically linked to underlying
causal mechanisms of neoplasia.
Accepted for Publication: March 23, 2007.
Correspondence: Karen L. Margolis, MD, MPH, Health-
Partners Research Foundation, PO Box 1524, Mail Stop
21111R, Minneapolis, MN 55440-1524 (Karen.L.Margolis
@HealthPartners.com).
Author Contributions: Dr Margolis had full access to all
the data in the study and takes responsibility for the in-
tegrity of the data and the accuracy of the data analysis.
Study concept and design: Margolis and Thomson. Acqui-
sition of data: Margolis, Thomson, and McTiernan. Analy-
sis and interpretation of data: Margolis, Rodabough, Thom-
son, and McTiernan. Drafting of the manuscript: Margolis
and Thomson. Critical revision of the manuscript for im-
portant intellectual content: Rodabough, Lopez, and
McTiernan. Statistical analysis: Rodabough. Obtained fund-
ing: Margolis. Administrative, technical, and material sup-
port: Thomson and McTiernan. Study supervision: Thom-
son and McTiernan.
Financial Disclosure: None reported.
Funding/Support: The WHI program is funded by the
National Heart, Lung, and Blood Institute, US Depart-
ment of Health and Human Services (Dr Margolis).
Role of the Sponsor: The funding source participated in
the design and conduct of the study and approved the
final manuscript but was not involved in the analysis or
interpretation of the data.
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