In this cohort of breast cancer survivors, we found a significant association between acute phase proteins (CRP or SAA) and adiposity as measured by DEXA. Women with higher measures of adiposity had higher CRP and SAA concentrations compared to women with lower adiposity regardless of lifestyle or medical factors. Our analysis indicates that percent body fat as measured by DEXA is a strong predictor of CRP and SAA levels. Furthermore, our data suggest recent use of NSAIDS modifies the observed association of adiposity with acute phase proteins. We found that obese women who recently used NSAIDs had significantly lower geometric mean concentrations of SAA than women who did not use NSAIDS. A similar pattern was found for CRP, although the association did not reach statistical significance. The potential modifying effects of weight change did not reach statistical significance for SAA or CRP, perhaps because small numbers of women in some of the strata limited statistical power.
DEXA may provide a more accurate measure of body fat for studies of acute phase proteins than other anthropometric measures because DEXA can distinguish between bone, muscle and fat mass
. The accuracy of BMI as a measure of percent body fat may vary by age, gender, race or ethnicity and physical conditioning. It is an overall measure of body mass and does not provide measures of body composition. Thus, there is no absolute cross-tabulation for the DEXA definition of fat by standard BMI. Body fat determined through clinical measures of bio-impedance also may be less reliable than DEXA, as the measure tends to underestimate adiposity
[16, 17]. Additionally, while BMI, waist-hip ratio, and waist circumference have been used as indicators of body fatness, these measurements were found to be more closely correlated with each other than with body fatness measured by DEXA based on data from a nationally representative US population sample (National Health and Nutrition Examination Survey)
. In our HEAL sample, we were not able to distinguish differences in correlation between acute phase proteins (i.e. CRP or SAA) and DEXA or BMI, possibly due to the small sample.
The association between acute phase proteins and adiposity we found is consistent with earlier reports based on anthropometric measures that found increased adiposity was significantly correlated with elevated levels of CRP and SAA among breast cancer patients
[14, 31]. A previous study of HEAL participants (n = 741) using anthropometric measures (BMI, waist circumference) found significant associations between BMI and inflammatory proteins
. The association of percent body fat with levels of acute phase proteins suggests that circulating inflammatory markers are associated with greater adiposity and not just greater weight.
We also found a suggestive association between weight gain and circulating acute phase proteins in our sample. If this association is causal, weight control or weight loss may be one mechanism for controlling elevated levels of circulating inflammatory proteins in breast cancer survivors. However, one concern related to unmonitored weight loss in breast cancer survivors is sarcopenia
, and the potential impact of concomitant fat and muscle loss on survival. In HEAL participants, sarcopenic women were approximately 3 times as likely to die from any cause and 2 times as likely to die from breast cancer as women without sarcopenia
. Therefore, any efforts to maintain or lose weight would need to focus on retaining lean body mass while maintaining or losing body fat
In the literature, weight loss and physical activity have inconsistently been associated with circulating acute phase proteins. A study of obese individuals found that weight reduction following caloric-restriction was associated with reduced plasma CRP levels
. One study found that weight loss was associated with a significant reduction in IL-6 levels in both plasma and adipose; the authors also found a non-statistically significant reduction in CRP
. Bochud et al. suggested that the lack of statistical significance with CRP in this study may be due to the short duration of weight loss and the overall small amount of weight lost
. However, a subsequent intervention study involving 40 overweight breast cancer survivors showed no association between weight loss and CRP
. With respect to physical activity, it has been indicated that aerobic exercise may be more effective than flexibility or resistance training for CRP reduction
. The absence of differences in effect by physical activity in the current study may be due to our small sample or that the type or level of exercise was not adequately variable to produce a measurable effect. A large proportion of HEAL participants reported high levels of physical activity, such that even the obese participants reported an average of 28.5 MET-hours per week of activity.
Our data suggest that use of NSAIDs may be one way to control circulating levels of CRP/SAA in breast cancer survivors. Additional data from randomized intervention trials are needed to confirm this potential benefit. One concern is that a meta-analysis of the available evidence on cardiovascular safety of NSAIDs found that use of some types of NSAIDs were associated with elevated risk of myocardial infarction, stroke, and cardiovascular death
. However, cardiovascular risk varies by type of NSAID
, which in some cases may be protective (e.g. aspirin). An analysis of data from the Nurses' Health Study (n = 4,164) found that aspirin use is associated with decreased risk of breast cancer specific death and death from any cause in breast cancer patients
. A meta-analysis also showed daily use of aspirin reduced incidence and metastasis of colorectal cancers and several other cancers including breast cancer
[40, 41]. Thus, further assessment of the association between NSAID such as aspirin and acute phase proteins in breast cancer survivors may be of value, as lower levels of CRP have been linked with longer survival and NSAIDs have been suggested as an adjuvant treatment for breast cancer
A strength of this study is the use of DEXA measurement as a precise estimate of adiposity. Our study includes both non-Hispanic white and Hispanic breast cancer survivors. Differences in percent body fat and CRP or SAA levels by race/ethnicity may be expected due to previous studies that have indicated fat-patterning differs by race and ethnicity. Specifically, higher measures of central adiposity have been found in Hispanic women
. Since higher CRP and SAA levels adversely affect survival among breast cancer survivors, using a more precise measure of body fat (a predictor of CRP and SAA) may be useful for accurately identifying those women who could improve prognosis by decreasing body fat
The primary limitation of this study is that despite being the largest study to date with comprehensive measures of body composition, BMI and inflammation, it remains a relatively small study. Therefore, a lack of difference in stratified analyses to examine the effects of various lifestyle factors and medical conditions must be interpreted with caution as statistical power is limited. The wide variance in weight and adiposity measures also is a limitation. Other limitations in our methods that may make associations more difficult to detect include differences in DEXA equipment used in Seattle and New Mexico and use of different methods of data collection (in person vs. mailed questionnaire) to collect demographic, lifestyle and medical history information. However, the impact of study center was evaluated as a covariate in all models and women from a range of BMI and percent body fat levels were measured at each center.