Re: C-reactive protein and risk of breast cancer.

Zhang et al. ( 1 ) reported no association between plasma levels of C-reactive protein (CRP) in apparently healthy women 45 years of age and older and subsequent breast cancer risk. The large study size (892 patients among 27 919 participants in the Women’s Health Study) argues against lack of power as an explanation for this lack of association. To minimize a potential infl uence of prediagnostic tumors on CRP levels, analyses excluding patients who were diagnosed within the fi rst 2 and 5 years of follow-up were conducted, which also showed null results. However, it also would be of interest to see the association between CRP and breast cancers diagnosed within 2 or 5 years of blood collection. The microenvironment of a substantial proportion of breast cancers is characterized by diffuse, low-degree infl ammation, with immune cells present ( 2 ). Cytokines and other mediators produced by these cells are known to promote tumor growth. Some of these cytokines, especially interleukin-6 (IL-6), are known to stimulate hepatic release of CRP ( 3 ). An association of circulating CRP with breast cancer occurring fairly shortly after blood donation would provide evidence of infl ammatory involvement in prediagnostic breast cancer. We observed such an association ( Table 1 ) in the New York University Women’s Health Study, a prospective cohort of 14 274 women ( 4 ). The Behring NA latex test ( 5 ) was used to measure serum CRP in 85 postmenopausal women with breast cancers who were diagnosed 6 months to 5.5 years after blood donation and two agematched control subjects per case subject. Because of the short intervals between blood donation and cancer diagnosis, tumors are likely to have been present at the time of blood donation in most cases. One of the only two interactions observed by Zhang et al. ( 1 ) was with body mass index (BMI). Because BMI is positively associated with breast cancer risk only in postmenopausal women, it would be of interest to see the effect of BMI on the CRP – breast cancer association by stratifying by menopausal status. In our study, which was limited to women who were postmenopausal at both blood donation and diagnosis, we observed strong correlations of CRP with BMI and circulating total and sex hormone – binding globulin – bound estradiol (Spearman correlation coeffi cient, r = 0.46, r = 0.34, and r = 0.53, respectively), and the CRP – breast cancer association was attenuated after ad justing for either BMI or estradiol ( Table 1 ). One interpretation is that BMI and estradiol confound the CRP – breast cancer association. But because IL-6 may stimulate estrogen synthesis in peripheral tissues ( 6 ), another possible interpretation is that IL-6 and endogenous estrogens contribute to the development of breast cancer in postmenopausal women through a common pathway. Namely, women with more adipose tissue produce more IL-6 than lean women ( 7 ) and elevated IL-6 leads to both increased hepatic production of CRP and increased aromatization of androgens to estrogens in peripheral tissues. Prospective epidemiologic studies with measurement of cytokines thought to affect tumor growth would be of interest. In these studies, it would be important to consider lag time between blood donation and diagnosis, menopausal status, and the relationships between BMI, cytokines, and levels of circulating estrogens.