VOLUME 27 䡠 NUMBER
JOURNAL OF CLINICAL ONCOLOGY
From the Department of Clinical
Biochemistry, Herlev Hospital, and The
Copenhagen City Heart Study, Bispeb-
jerg Hospital, Copenhagen University
Hospital; and Faculty of Health
Sciences, University of Copenhagen,
Copenhagen, Denmark.
Submitted August 26, 2008; accepted
January 21, 2009; published online
ahead of print at www.jco.org on
March 16, 2009.
Supported by the Danish Heart Founda-
tion, the Danish Medical Research
Council, and the Research Council at
Herlev Hospital, Copenhagen University
Hospital.
The funding sources are public or
nonprofit organizations and had no role
in the design or conduct of the study,
analyzing or interpreting the data, or
approving the submitted manuscript.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Corresponding author: Børge G.
Nordestgaard, MD, DMSc, Department
of Clinical Biochemistry, Herlev Hospi-
tal, Copenhagen University Hospital,
Herlev Ringvej 75, DK-2730 Herlev,
Denmark; e-mail: brno@heh.regionh.dk.
The Appendix is included in the
full-text version of this article,
available online at www.jco.org.
It is not included in the PDF version
(via Adobe® Reader®).
© 2009 by American Society of Clinical
Oncology
0732-183X/09/2713-2217/$20.00
DOI: 10.1200/JCO.2008.19.8440
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13 䡠 MAY 1 2009
O R I G I N A L R E P O R T
Baseline C-Reactive Protein Is Associated With Incident
Cancer and Survival in Patients With Cancer
Kristine H. Allin, Stig E. Bojesen, and Børge G. Nordestgaard
A B S T R A C T
Purpose
We tested the hypothesis that baseline plasma levels of C-reactive protein (CRP) are associated
with risk of incident cancer in the general population and early death in patients with cancer.
Patients and Methods
A total of 10,408 individuals from the Danish general population who had CRP measured at
baseline were observed for up to 16 years; 1,624 developed cancer, and of these, 998 patients
died during follow-up. Follow-up was 100% complete. We excluded individuals with a cancer
diagnosis at baseline.
Results
Baseline CRP levels more than 3 versus less than 1 mg/L were associated with multifactorially
adjusted hazard ratios of 1.3 (95% CI, 1.0 to 1.6) for cancer of any type, 2.2 (95% CI, 1.0 to 4.6)
for lung cancer, 1.9 (95% CI, 0.8 to 4.6) for colorectal cancer, and 0.7 (95% CI, 0.4 to 1.4) for breast
cancer. Corresponding hazard ratios for the highest versus the lowest quintile of baseline CRP
levels were 1.3 (95% CI, 1.0 to 1.6), 2.1 (95% CI, 1.2 to 3.8), 1.7 (95% CI, 0.8 to 3.2), and 0.9 (95%
CI, 0.5 to 1.7), respectively. Multifactorially adjusted hazard ratios for early death in patients with
cancer were 1.8 (95% CI, 1.2 to 2.7) for CRP more than 3 versus less than 1 mg/L and 1.4 (95%
CI, 1.1 to 1.7) for the highest versus the lowest quintile. Elevated CRP levels were associated with
early death in patients with cancer having localized disease, but not in those with metastases
(interaction; P ⫽ .03).
Conclusion
Elevated levels of CRP in cancer-free individuals are associated with increased risk of cancer of any
type, of lung cancer, and possibly of colorectal cancer. Moreover, elevated levels of baseline
CRP associate with early death after a diagnosis of any cancer, particularly in patients
without metastases.
J Clin Oncol 27:2217-2224. © 2009 by American Society of Clinical Oncology
is also associated with incident cancer.4-16 A limita-
INTRODUCTION
tion of the prospective studies is the use of a single
C-reactive protein (CRP) is an acute-phase reactant CRP measurement at baseline, because lack of
that is elevated during bacterial infection, inflamma- additional measurements precludes adjustment
tory disease, trauma, myocardial infarction, surgery, for regression dilution bias17 and thereby tends
and cancer1; CRP is produced in the liver in response to underestimate any association. Elevated levels
to elevated cytokine levels after an inflammatory of plasma CRP have also been associated with
stimulus.2 Two hypotheses have been proposed to poor survival in patients with cancer7,18-22; how-
explain the relationship between elevated CRP levels ever, in only two of these studies including few
and cancer.3 The first hypothesis states that elevated participants were CRP measured with a high-
CRP levels are a result of an underlying cancer or a sensitivity assay,7,19 allowing examination of asso-
premalignant state, whereas the second hypothesis ciations in the high-normal interval just greater
states that chronic inflammation and elevated CRP than 1 mg/L. Thus it is still unclear whether, and
might have a causal role in carcinogenesis. to which extent, CRP levels are associated with
Case-control studies have reported higher lev- incident cancer as well as early death in patients
els of CRP in patients with cancer compared with with cancer.
controls,3 whereas results from prospective studies We tested the hypothesis that baseline plasma
are conflicting, with some studies suggesting that levels of CRP in the general population are associ-
CRP is not merely a marker of prevalent cancer, but ated with risk of incident cancer, including the three
© 2009 by American Society of Clinical Oncology 2217
Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
 Allin, Bojesen, and Nordestgaard

most common cancers (ie, lung, colorectal, and breast cancer), and we
corrected for regression dilution bias. In addition, we tested the hy-
pothesis that baseline plasma levels of CRP are associated with early
death in patients with cancer with any type of cancer.
PATIENTS AND METHODS
Study Design
The Copenhagen City Heart Study is a prospective cohort study of the
Danish general population, in which participants 20 years of age or older were
drawn randomly from the Copenhagen Central Person Register.23,24 It was
initiated in 1976 to 1978, with follow-up examinations in 1981 to 1983, 1991 to
1994, and 2001 to 2003. Participants in the present study are from the 1991 to
1994 and/or 2001 to 2003 examination (additional information on patients
and methods is described in the Appendix, online only).
For the analysis of plasma CRP levels and incident cancer, we in-
cluded 10,520 individuals who had plasma CRP measured at the 1991 to
1994 and/or 2001 to 2003 examination. We excluded participants with
liver cirrhosis diagnosed before or during the study period from analysis
(n ⫽ 112) because their ability to produce CRP must be expected to be
impaired, and 233 participants were excluded because of incomplete in-
formation about covariates. Furthermore, we excluded participants with a
diagnosis of any cancer (n ⫽ 772), lung cancer (n ⫽ 54), colorectal cancer
(n ⫽ 93), female breast cancer (n ⫽ 164), or other cancer (n ⫽ 581) before
study entry, from the analysis of the respective cancer subtypes. Follow-up
time for each participant began at entry into the study (1991 to 1994 or
2001 to 2003) and ended at occurrence of cancer, death, emigration, or July
2007, whichever came first. During the study period, we had 100% follow-
up. The median and maximum follow-up periods were 13 and 16 years,
respectively (Appendix Fig A1, online only).
Diagnoses of invasive cancer from 1947 until July 2007 were obtained
from the Danish Cancer Registry,25,26 which identifies 97.8% of all cancers in
Denmark,27 as well as from the national Danish Patient Registry (Appendix
Table A1, online only).
Individuals with a diagnosis of cancer during the period of follow-up
(n ⫽ 1624) were observed from their date of diagnosis until death, emigration,
or July 2007, whichever came first. The median and maximum follow-up
periods were 2 and 15 years, respectively. Information about mortality was
obtained from the national Danish Civil Registration System, which is
100% complete.
Ethics
The ethical committee of Copenhagen and Frederiksberg, Denmark,
approved the study (KF100.2039/91 and KF01-144/01). All participants gave
written informed consent.

Table 1. Baseline Characteristics of Participants in the Copenhagen City Heart Study 1991 to 1994 and/or 2001 to 2003 Examination
According to Plasma Levels of CRP at Study Entry
Plasma Levels of CRP, mg/L

⬍1 1-3 ⬎3
(n ⫽1,348) (n ⫽5,852) (n ⫽2,405)

Characteristic No. % No. % No. % P

Sex, women 720 53.4 3,271 55.9 1,378 57.3 .07
Age at entry, years ⬍ .001
Median 44 58 63
Interquartile range 30-58 44-69 53-71
No. of cigarettes smoked per day ⬍ .001
Median 0 0 3
Interquartile range 0-9 0-15 0-18
Smoking ⬍ .001
Never 424 31.7 1,491 25.5 542 22.6
Former 442 33.0 1,675 28.7 618 25.8
Current 473 35.4 2,682 45.9 1,241 51.7
Alcohol consumption, g/wk .02
ⱕ 168/252ⴱ 1,184 87.8 5,004 85.5 2,027 84.3
⬎ 168/252ⴱ 167 12.4 848 14.5 378 15.7
Body mass index, kg/m2 ⬍ .001
⬍ 18.5 53 3.9 115 2.0 26 1.1
18.5-24.9 902 67.3 2,969 51.6 850 36.6
25-29.9 327 24.4 2,031 35.3 873 37.6
ⱖ 30.0 58 4.4 643 11.2 574 24.7
Current oral contraceptive
therapy among
premenopausal women 67 15.4 270 27.2 132 48.5 ⬍ .001
Postmenopausal status among
women 477 66.3 2,244 68.6 952 69.1 .39
Current hormone replacement
therapy among
postmenopausal women 55 19.3 456 20.0 268 24.2 .01

NOTE. All covariates (except number of women and age) are adjusted for age. P values were calculated using ␹ tests for categorical variables and Kruskal-Wallis
2

one-way analysis of variance tests for continuous variables.

Abbreviation: CRP, C-reactive protein.
ⴱ
Total of 168 g/wk for women and 252 g/wk for men; these cut-off values are from the recommendation concerning alcohol consumption from the Danish National
Board of Health.

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 C-Reactive Protein, Cancer Risk, and Prognosis

Measurement of CRP
Plasma levels of CRP were determined with a high-sensitivity assay on
8,778 participants from the 1991 to 1994 examination on plasma stored for 12
to 15 years and on 5,931 participants from the 2001 to 2003 examination on
fresh plasma samples using turbidimetry or nephelometry (Dako, Glostrup,
Denmark, or Dade Behring, Deerfield, IL).
Statistical Analysis
We analyzed data using the statistical software package STATA version
10.0 (StataCorp, College Station, TX). A two-sided P value less than .05 was
considered statistically significant. A priori, we divided baseline CRP levels into
quintiles as well as into three categories: low (⬍ 1.0 mg/L), average (1.0 to 3.0
mg/L), or high (⬎ 3.0 mg/L). The CRP groups were coded 1, 2, 3, 4, and 5
corresponding to the quintiles and 1, 2, and 3 corresponding to the categories
for trend tests in log-rank and Cox statistics.
We plotted survival against follow-up time using the Kaplan-Meier
method and tested differences between categories of CRP using log-rank
trend tests. To estimate hazard ratios with 95% CIs for incident cancer, we
used Cox proportional hazards regression. We used age as time scale, thus
analyzing age at event using left truncation (ie, delayed entry). Hereby, age
differences are automatically adjusted for. We used a multifactorial Cox
regression model including sex and time-dependent covariates from the
1991 to 1994 and 2001 to 2003 examinations: smoking (never, former, cur-
rent), smoking dose (cigarettes per day), alcohol consumption (women, ⱕ 168
or ⬎ 168 g per week; men, ⱕ 252 or ⬎ 252 g per week), body mass index
(⬍ 18.5, 18.5 to 24.9, 25 to 29.9, or ⱖ 30.0 kg/m2), and, for women, also use of
oral contraceptive therapy, postmenopausal status, and use of hormone re-
placement therapy.
To estimate hazard ratios with 95% CIs for early death of cancer, we
used Cox proportional hazards regression analyzing time to event. We
used a Cox regression model including age at diagnosis, sex, cancer type
(lung, colorectal, breast, or other cancer), cancer stage (localized, regional
metastases, or distant metastases), cancer histology (adenocarcinoma,

P-CRP (mg/L) Participants Events Adjusted multifactorially Cancer cases that occurred
within 2 years excluded
Any cancer

<1 1,331 / 1,311 105 / 85 P = .0 6 P = .5 7

1 to 3 5,754 / 5,615 1,029 / 890

>3 2,318 / 2,222 458 / 362

Lung cancer

<1 1,385 /1,365 11 / 9 P = .008 P = .06

1 to 3 6,194 /6,055 151 /135

>3 2,542 /2,446 93 / 75

Fig 1. Hazard ratios for cancer inci-

Colorectal cancer dence by plasma levels of C-reactive
protein (P-CRP) in categories. Multifacto-
<1 1,379 / 1,359 9/9 P = .10 P = .72 rial adjustment was for age, sex, smoking,
alcohol consumption, body mass index,
1 to 3 6,176 / 6,037 122 / 108 and, for women, also oral contraceptive
therapy, menopausal status, and hormone
>3 2,527 / 2,431 60 / 45 replacement therapy. P values for trend
tests examine whether increasing levels
of CRP are associated with increasing
hazard ratios.
Breast cancer

<1 733 / 724 20 / 18 P = .4 0 P = .2 2

1 to 3 3,418 / 3,343 135 / 120

>3 1,410 / 1,364 52 / 43

Other cancer

<1 1,348 / 1,328 73 / 55 P = .52 P = .95

1 to 3 5,864 / 5,725 699 / 595

>3 2,382 / 2,286 288 / 227

1 3 5 1 3 5
Hazard Ratio (95% confidence interval)

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 Allin, Bojesen, and Nordestgaard

P-CRP (mg/L) Participants Events Adjusted multifactorially Cancer cases that occurred
within 2 years excluded
Quintiles

Any cancer
1. (< 1.10) 1,877 / 1,829 168 / 134 P = .0 2 P = .2 1

2. (1.10 to 1.41) 1,884 / 1,830 311 / 266

3. (1.42 to 1.98) 1,881 / 1,830 361 / 311
4. (1.99 to 3.56) 1,881 / 1,830 389 / 337
5. (≥ 3.57) 1,880 / 1,829 363 / 289
Lung cancer
1. (< 1.11) 2,024 / 1,974 20 / 16 P = .00 1 P = .0 1

2. (1.11 to 1.43) 2,024 / 1,972 36 / 34

3. (1.44 to 2.00) 2,024 / 1,974 57 / 47
4. (2.01 to 3.64) 2,025 / 1,973 66 / 62
5. (≥ 3.65) 2,024 / 1,973 76 / 60
Fig 2. Hazard ratios for cancer inci-
Colorectal cancer
dence by plasma levels of C-reactive
1. (< 1.11) 2,019 / 1,964 17 / 13 P = .33 P = .8 7 protein (P-CRP) in quintiles. Multifactorial
adjustment was for age, sex, smoking,
2. (1.11 to 1.43) 2,014 / 1,971 41 / 39
alcohol consumption, body mass index,
3. (1.44 to 2.00) 2,016 / 1,961 44 / 41 and, for women, also oral contraceptive
therapy, menopausal status, and hormone
4. (2.01 to 3.62) 2,017 / 1,966 44 / 36
replacement therapy. P values for trend
5. (≥ 3.63) 2,016 / 1,965 45 / 33 tests examine whether increasing levels
Breast cancer of CRP are associated with increasing
hazard ratios.
1. (< 1.12) 1,112 / 1,086 30 / 27 P = .7 9 P = .6 7
2. (1.12 to 1.43) 1,110 / 1,086 44 / 37
3. (1.44 to 2.00) 1,115 / 1,087 47 / 42
4. (2.01 to 3.67) 1,111 / 1,086 46 / 40
5. (≥ 3.68) 1,113 / 1,086 40 / 35
Other cancer
1. (< 1.10) 1,919 / 1,867 119 / 91 P = .51 P = .8 7
2. (1.10 to 1.42) 1,920 / 1,868 221 / 184
3. (1.43 to 1.99) 1,917 / 1,869 234 / 202
4. (2.00 to 3.59) 1,918 / 1,867 264 / 225
5. (≥ 3.60) 1,920 / 1,868 222 / 175

1 3 5 1 3 5

Hazard ratio (95% confidence interval)

squamous carcinoma, other carcinoma, or other histology), and time from
blood sampling to diagnosis.
Because approximately 41% of the participants had CRP measured at
both the 1991 to 1994 and 2001 to 2003 examination, we were able to correct
hazard ratios for regression dilution bias with a nonparametric method.17
Spearman’s rank correlation coefficient between the two CRP measurements
was 0.5.
RESULTS
Baseline characteristics of the participants by plasma levels of CRP at
study entry are listed in Table 1. Levels of CRP were correlated with
several of these characteristics. Median values of CRP were 1.7 mg/L
among all participants, and 1.9, 2.3, 1.8, and 1.7 mg/L among individ-
uals who developed any cancer, lung cancer, colorectal cancer, or
breast cancer, respectively, during the period of follow-up.
Any Cancer
Increasing levels of CRP by quintiles were associated with in-
creasing risk of incident cancer, whereas a similar trend was seen for
CRP by categories: P for trend ⫽ .02 and .06 (Figs 1 and 2). Multifac-
torially adjusted hazard ratios were 1.3 (95% CI, 1.0 to 1.6) for CRP
more than 3 versus less than 1 mg/L and 1.3 (95% CI, 1.0 to 1.6) for the
highest versus the lowest quintile.
Lung Cancer
Increasing levels of CRP, by categories or quintiles, were associ-
ated with increasing risk of incident lung cancer: P for trend ⫽ .008
and .001, respectively (Figs 1 and 2). Multifactorially adjusted hazard
ratios were 2.2 (95% CI, 1.0 to 4.6) for CRP more than 3 versus less
than 1 mg/L and 2.1 (95% CI, 1.2 to 3.8) for the highest versus the
lowest quintile.

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 C-Reactive Protein, Cancer Risk, and Prognosis

Colorectal Cancer
Levels of CRP, by categories or quintiles, were not associated
statistically significant with risk of incident colorectal cancer: P for
trend ⫽ .10 and .33, respectively (Figs 1 and 2). Multifactorially
adjusted hazard ratios were 1.9 (95% CI, 0.8 to 4.6) for CRP
more than 3 versus less than 1 mg/L and 1.7 (95% CI, 0.8 to 3.2)
for the highest versus the lowest quintile. For CRP more than 3
versus less than 1 mg/L and for the highest versus the lowest
quintile, we had 90% statistical power to exclude a hazard ratio of
ⱖ 2.3 and ⱖ 2.1, respectively.
Breast Cancer
Levels of CRP, by categories or quintiles, were not associated with
risk of incident breast cancer: P for trend ⫽ .40 and .79, respectively
(Figs 1 and 2). Multifactorially adjusted hazard ratios were 0.7 (95%
CI, 0.4 to 1.4) for CRP more than 3 versus less than 1 mg/L and 0.9
(95% CI, 0.5 to 1.7) for the highest versus the lowest quintile. For CRP
more than 3 versus less than 1 mg/L and for the highest versus the
lowest quintile, we had 90% statistical power to exclude a hazard
ratio of ⱖ 1.9 and ⱖ 1.9, respectively.
Sensitivity Analyses
After exclusion of individuals with CRP more than 10 mg/L, as an
indication of overt inflammation at baseline, the results were similar to
those in Figures 1 and 2. To eliminate an effect of occult cancer on CRP
levels, we also conducted additional analyses excluding incident cases
of cancer diagnosed within 2 years after blood sampling, and hazard
ratios were attenuated (Figs 1 and 2). Mean time from blood sampling

P-CRP Participants Events Localized Metastases

(mg/L)

Any cancer

<1 1,269 / 1,246 43 / 20 P = .4 7 P = .0 0 3

1 to 3 5,149 / 5,004 424 / 279

>3 2,028 / 2,009 168 / 149

Lung cancer

<1 1,371 / 1,377 4/3 P = .63 P = .04

1 to 3 5,961 / 6,121 30 / 78

>3 2,028 / 2,493 19 / 44

Fig 3. Hazard ratios for cancer inci-

Colorectal cancer dence by plasma levels of C-reactive
protein (P-CRP) stratified for cancer stage.
<1 1,368 / 1,371 6/1 P = .83 P = .02 Multifactorial adjustment was for age,
70 sex, smoking, alcohol consumption, body
1 to 3 5,970 / 6,094 48 / 40 mass index, and, for women, also oral
118 contraceptive therapy, menopausal status
>3 2,426 / 2,489 20 / 22 and hormone replacement therapy. P val-
ues for trend tests examine whether in-
creasing levels of CRP are associated with
increasing hazard ratios.
Breast cancer

<1 717 / 717 6/4 P = .7 9 P = .9 6

1 to 3 3,303 / 3,314 68 / 31

>3 1,357 / 1,374 21 / 16

Other cancer

<1 1,305 / 1,288 32 / 13 P = .55 P = .14

1 to 3 5,425 / 5,322 310 / 157

>3 2,186 / 2,171 123 / 77

1 3 1 3 6 9 15

Hazard ratio (95% confidence interval)

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 Allin, Bojesen, and Nordestgaard

to a diagnosis of cancer was 6.3 years for all participants and 5.8 years
for individuals with CRP more than 3 mg/L.
To examine whether CRP is associated with cancer of different
stages at diagnosis, we stratified for localized cancer and metastases
(Fig 3). Increasing levels of CRP, by categories, were associated with
increasing risk of incident any, lung, and colorectal cancer with me-
tastases: P for trend ⫽ .003, .04, and .02, respectively. Corresponding
multifactorially adjusted hazard ratios were 2.3 (95% CI, 1.3 to 4.0),
4.4 (95% CI, 1.1 to 18), and 10.4 (95% CI, 0.9 to 118), respectively, for
CRP more than 3 versus less than 1 mg/L.
Appendix Table A1 (online only) shows the specific distribution
(including International Classification of Diseases codes) of the full
spectrum of malignancies that occurred within the cohort. CRP levels
were not associated with nonmelanoma skin cancer (n ⫽ 297), pros-
tate cancer (n ⫽ 106), cancer of the bladder and excretory urinary tract
(n ⫽ 100), melanoma (n ⫽ 60), pancreas cancer (n ⫽ 55), or cancer of
the ovary and female genital organs (n ⫽ 54). Cancer types with fewer
than 50 incident cases were not examined as a result of limited statis-
tical power.
Survival After a Diagnosis of Cancer
Survival after a diagnosis of cancer, unadjusted for potential
confounders, decreased with increasing levels of plasma CRP at study
entry: log-rank trend test P ⬍ .001 (Fig 4). Multifactorially adjusted
hazard ratios were 1.8 (95% CI, 1.2 to 2.7) for CRP more than 3 versus
less than 1 mg/L and 1.4 (95% CI, 1.1 to 1.7) for the highest versus the
lowest quintile: P for trend ⫽ .002 and .002.
When we stratified for cancer type, stage, and histology, and for
time from blood sampling to diagnosis, elevated levels of CRP were
associated with early death separately in patients with other cancer,
100 Log-rank trend, P < .001
80
Overall Survival (%)
localized cancer, squamous carcinoma, and less than 2 years as well as
more than 8 years from blood sampling to diagnosis, but not in the
other stratified groups (Table 2). However, tests of interaction were
all nonsignificant, except for cancer stage (P ⫽ .03.), suggesting
that elevated CRP levels are associated with early death irrespective
of cancer type and histology and time from blood sampling to
diagnosis, but that elevated CRP levels are associated with early
death in patients with cancer having localized disease, but not in
those with metastases.
DISCUSSION
In this prospective cohort study that included approximately 10,000
individuals observed for up to 16 years, we found that increasing levels
of CRP were associated with increasing risk of incident cancer of any
type, of lung cancer, and possibly of colorectal cancer, but CRP levels
were not associated with breast cancer. Furthermore, we found that
elevated levels of CRP were associated with early death after a
diagnosis of cancer.
What is the biologic underlying mechanism of the association
between levels of CRP and risk of cancer? Several findings support the
hypothesis that elevated levels of CRP are a marker of occult cancer.
First, tumor growth can cause tissue inflammation around the tumor
and thus increase plasma levels of CRP.3 Second, tumor cells are
known to produce various cytokines and chemokines that attract
leukocytes, and some cancerous cells have been shown to express CRP
and secrete interleukin-6 and interleukin-8, which stimulate CRP
production in the liver.3,28 Finally, it is possible that CRP is a part of a
host immune response to the tumor.3 However, there is increasing
evidence that chronic inflammation, of which CRP is a marker, is a
causal factor in several malignancies.28,29 It is evident that inflam-
matory cells act as tumor promoters, producing an attractive envi-
ronment for tumor growth, inducing DNA damage, promoting
angiogenesis, and favoring neoplastic spread and metastasis.28 In the
present association study, we cannot distinguish between elevated

CRP being a marker of occult cancer or inflammation and elevated

CRP being causative in carcinogenesis. However, mean time from
60
CRP, mg/L blood sampling to diagnosis of cancer was 5.8 years in the CRP cate-
<1 gory more than 3 mg/L, suggesting that elevated levels of CRP might
40 be more than just a marker of occult cancer. Conversely, when we
1 to 3 excluded incident cancer cases diagnosed within 2 years of blood
>3 sampling, the association between CRP levels and incident any cancer
20 was attenuated. Also in support of CRP being a marker of occult
cancer, we found that elevated CRP levels were associated with any,
lung, and colorectal cancer with metastases at diagnosis, but not with
0 2 4 6 8 10 localized cancer only.
Thus far, seven prospective nested case-control studies and five
Time Since Diagnosis (years) prospective cohort studies have been published, but the results are
No. at risk
hsCRP, mg/L
<1 106 71 49 28 17 9 inconsistent.4-13,15,16 A recent meta-analysis found an odds ratio of
1 to 3 1,050 565 417 288 193 119 1.10 (95% CI, 1.02 to 1.18) for any cancer and of 1.32 (95% CI, 1.08 to
>3 468 218 162 107 69 41
1.61) for lung cancer for a log unit increase in CRP level.6 Despite the
Fig 4. Survival after a diagnosis of cancer by levels of C-reactive protein (CRP). considerable heterogeneity in the meta-analysis (I2 ⬎ 70%), these
P value for log-rank trend test examines whether increasing levels of CRP are findings are in support of our findings of baseline CRP levels being
associated with decreasing survival. Results are unadjusted. Multifactorially
adjusted hazard ratios for early death in patients with cancer by levels of CRP are associated with risk of any cancer and lung cancer. In support of our
presented in Table 2. hs, high-sensitivity assay. finding of an increasing risk of lung cancer with increasing levels of

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 C-Reactive Protein, Cancer Risk, and Prognosis

Table 2. Risk of Early Death in Patients With Cancer From the Copenhagen City Heart Study 1991 to 1994 and/or 2001 to 2003 Examination According
to Plasma Levels of CRP at Study Entry
Plasma Levels of CRP, mg/L

⬍1 1-3 ⬎3

Stratification No. of Patients No. of Events P, Interaction HR HR 95% CI HR 95% CI P, Trend

None, all cancer 1,624 998 1.0 1.5 1.0 to 2.2 1.8 1.2 to 2.7 .002
Cancer type
Lung cancer 230 209 .83 1.0 1.9 0.7 to 4.9 2.1 0.8 to 5.4 .26
Colorectal cancer 173 114 1.0 1.3 0.3 to 5.3 1.2 0.3 to 5.1 .92
Breast cancer 202 65 1.0 0.6 0.1 to 3.5 1.1 0.2 to 6.7 .17
Other cancer 1,019 610 1.0 1.4 0.9 to 2.3 1.8 1.1 to 2.9 .006
Cancer stage
Localized cancer 647 317 .03 1.0 2.2 1.1 to 4.5 2.5 1.2 to 5.3 .03
Metastases 455 400 1.0 0.7 0.4 to 1.3 0.8 0.4 to 1.4 .95
Cancer histology
Adenocarcinoma 513 352 .77 1.0 1.2 0.6 to 2.3 1.4 0.7 to 2.8 .15
Squamous carcinomaⴱ 327 150 1.0 2.3 0.8 to 6.8 3.5 1.1 to 10.8 .009
Other carcinoma 192 151 1.0 1.3 0.3 to 5.6 1.6 0.4 to 6.8 .33
Other histology 129 92 1.0 1.0 0.4 to 2.9 1.3 0.4 to 3.8 .49
Time from blood sampling to
diagnosis, years
⬍2 262 202 .61 1.0 2.1 0.9 to 4.9 2.6 1.1 to 6.2 .04
2-8 785 499 1.0 1.2 0.7 to 2.1 1.5 0.8 to 2.7 .06
⬎8 577 297 1.0 1.9 0.9 to 4.1 2.4 1.1 to 5.3 .02

NOTE. Participants with a diagnosis of any cancer before study entry were excluded from the analyses. During follow-up, 1,624 participants developed cancer, and
of these, 998 died. All hazard ratios are multifactorially adjusted for age at diagnosis, sex, cancer type, cancer stage, cancer histology, and time from blood sampling
to diagnosis. P values for trend tests examine whether increasing levels of CRP are associated with decreasing survival. P values for interaction tests examine
whether an interaction exists between the covariate stratified for and levels of CRP in categories. Information about stage and histology was available for 1,102 and
1,161, respectively, of the 1,624 patients with cancer. In the multifactorial Cox regression model, a category including unknown stage and a category including
unknown histology were included.
Abbreviations: CRP, C-reactive protein; HR, hazard ratio.
ⴱ
Exclusion of 29 patients with lung cancer of 327 patients with squamous carcinoma resulted in multifactorially adjusted hazard ratios of 2.1 (95% CI, 0.7 to 6.3)
for CRP 1 to 3 versus ⬍ 1 mg/L and 3.5 (95% CI, 1.1 to 11.2) for CRP ⬎ 3 versus ⬍ 1 mg/L (P for trend ⫽ .007).

CRP, studies have suggested an increased risk of lung cancer in indi-
viduals with asthma as well as in individuals with tuberculosis or other
infectious inflammation of the lung.30
An increased risk of colorectal cancer has been observed in pa-
tients with inflammatory bowel diseases,15,28 suggesting that chronic
inflammation and elevated CRP levels could be associated with risk of
colorectal cancer. Although we did not find a statistically significant
association between elevated levels of CRP and incident colorectal
cancer, the hazard ratios for colorectal cancer were of a magnitude
comparable to that for any cancer and lung cancer; the number of
cases was just smaller for colorectal cancer. Furthermore, we found an
association between elevated levels of CRP and risk of colorectal can-
cer with metastases. A recent meta-analysis found an odds ratio of 1.09
(95% CI, 0.98 to 1.21) for a log unit increase in CRP level, whereas
another recent meta-analysis found that levels of CRP were weakly
associated with an increased risk of colorectal cancer (odds ratio, 1.12;
95% CI, 1.01 to 1.25) for a log unit increase in CRP level.6,14 In support
of our finding of no association of CRP levels with risk of breast cancer,
a recent meta-analysis found an odds ratio for breast cancer of 1.10
(95% CI, 0.97 to 1.26) for a log unit increase in CRP level.6 One could
suspect that many of the breast cancer cases in the present study were
screening detected (early stage) and that CRP could be associated with
late stage at breast cancer diagnosis. However, we did not find an
association between elevated levels of CRP and incident breast cancer
with metastases.
Several studies have reported that CRP can be used as a prognos-
tic marker in patients with cancer, but so far only two studies with few
participants have measured CRP with a high-sensitivity assay.7,19
Il’yasova et al7 found a hazard ratio of 1.4 (95% CI, 1.1 to 1.8) for early
death of patients with cancer for a log unit increase in CRP level, and
Heikkilä et al19 reported similar estimates. The results of our study,
which included far more participants, support these findings and
consequently the value of CRP as a prognostic marker in patients with
cancer. Interestingly, our results do not seem to suggest any differen-
tial effect on the association between elevated levels of CRP and early
death according to different cancer types or histology, or according to
time from blood sampling to diagnosis. However, our results suggest
that the prognostic value of CRP as a marker of early death is present
primarily in patients with localized cancer without known metastases
at time of diagnosis. Consequently, CRP does not merely seem to be a
surrogate for known metastases at diagnosis, and CRP might provide
prognostic information beyond that provided by cancer type, stage,
and histology.
We studied the value of elevated CRP levels as a risk factor for
cancer and as a prognostic marker in patients with cancer in a large
prospective cohort study with up to 16 years of follow-up and had no
losses to follow-up. In addition, we were able to adjust for regression
dilution bias, because CRP was measured twice in approximately 41%
of the participants. Potential limitations of our study include con-
founding and selection bias. However, we included several important

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 Allin, Bojesen, and Nordestgaard

potential confounders associated with CRP levels in the Cox regres-

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
sion model. Despite this, we naturally cannot exclude all possible OF INTEREST
confounders and the possibility that CRP may act as a surrogate for
imperfectly measured risk factors for cancer as a result of not measur-
The author(s) indicated no potential conflicts of interest.
ing exposure during the etiologically relevant time or misspecification
of exposure, like body mass index as a surrogate for body fat. Selection
bias of healthy individuals would draw the results in a direction toward
AUTHOR CONTRIBUTIONS
the null hypothesis and therefore cannot explain our positive results.
Despite adjustment for age at diagnosis, sex, cancer type, cancer stage,
Conception and design: Kristine H. Allin, Stig E. Bojesen,
cancer histology, and time from blood sampling to diagnosis, the
Børge G. Nordestgaard
interpretation of the positive association found between elevated levels Financial support: Børge G. Nordestgaard
of CRP and early death after a cancer diagnosis is diminished by the Provision of study materials or patients: Stig E. Bojesen,
heterogeneity of the cancer diagnoses and lack of information Børge G. Nordestgaard
about treatment. Collection and assembly of data: Kristine H. Allin, Stig E. Bojesen,
In conclusion, we have demonstrated that elevated levels of CRP Børge G. Nordestgaard
in apparently cancer-free individuals are associated with increased risk Data analysis and interpretation: Kristine H. Allin, Stig E. Bojesen,
Børge G. Nordestgaard
of incident cancer of any type, lung cancer, and possibly colorectal Manuscript writing: Kristine H. Allin, Stig E. Bojesen,
cancer. Moreover, we have demonstrated that elevated levels of CRP at Børge G. Nordestgaard
baseline are associated with early death after a diagnosis of cancer, Final approval of manuscript: Kristine H. Allin, Stig E. Bojesen,
particularly in patients without metastases. Børge G. Nordestgaard

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Acknowledgment
We thank Anja Jochumsen for technical assistance.

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