Host-Related Factors in Breast Cancer: An Underappreciated Piece of the Puzzle?
Authors: Pamela J. Goodwin
Journal: Journal of Clinical Oncology (2008)

In recent years, a major focus of breast cancer research has been on investigation of molecular factors within the tumor to enhance understanding of the biology of breast cancer and to facilitate the development of effective targeted therapies. This research has led to the molecular characterization of tumors (such as basal, luminal A, and luminal B, with associated profile-specific treatment strategies) and to the development of highly effective molecular therapies in specific tumor types, as exemplified by trastuzumab in human epidermal growth factor receptor 2–positive breast cancer, among other innovations. These recent advances build on earlier research on markers of hormone responsiveness in breast cancer that led to improved outcomes of patients with hormone-responsive tumors, and have had a major impact on the treatment of breast cancer. It is expected that continued research of this type will almost certainly lead to greater molecular understanding of breast cancer, almost certainly accompanied by the discovery of additional individualized, tumor-specific therapies and further improvements in outcome. With this recent focus on molecular factors within the tumor itself, somewhat less attention has been paid to the role of host-related factors in breast cancer. These factors involve a spectrum, from lifestyle and environmental exposures to endogenous hormonal, metabolic, germline genetic, and related factors. A variety of host factors have been implicated in the development of breast cancer, including reproductive practices, lifestyle (eg, body size, diet, physical activity), and intake of exogenous hormones. The contribution of many of these factors to breast cancer risk is well accepted, and the biologic basis for some of the associations is understood. Recognizing that mechanisms involved in carcinogenesis differ from those involved in tumor progression, it is nonetheless plausible that host factors associated with breast cancer risk (along with others not implicated in risk) may play an important role in breast cancer prognosis and that their modification may improve outcomes. One notable example is the therapeutic benefit seen in postmenopausal hormone-responsive breast cancer when aromatase inhibitors are used to lower endogenous estrogen levels—proof of principle that host factors, and their modification, can play an important role in breast cancer outcome. The article by Barnett et al published in this issue of Journal of Clinical Oncology focuses on a group of host factors that have been associated with breast cancer risk, investigating their associations with breast cancer outcomes. At a theoretical level, host factors may influence the development of breast cancer with or without continuing to exert additional effects on tumor progression or responsiveness to therapy. In the simplest situation, there is no ongoing effect on tumor progression; however, because the breast cancer that develops when the host factor is present has characteristics that are associated with a certain prognosis and treatment responsiveness, the host factor may seem to influence prognosis. In this scenario, prognostic effects seen in univariate analyses will not be present after adjustment for the effects of tumor characteristics present at diagnosis, such as stage. An example of this is hormone replacement therapy, which is associated with the development of small, hormone-responsive tumors that tend to have a good prognosis. Barnett et al reported that long-term hormone replacement therapy seemed to be associated with good prognosis, but the effect disappeared after adjustment for tumor-related factors. Recency of pregnancy may be another example. Barnett et al found that women who reported a recent pregnancy (in the last 15 years) had poorer outcome. A similar effect has been seen in other studies; one in particular provides strong evidence that it was mainly breast cancers diagnosed within 2 years of pregnancy that were associated with poor outcomes. Those same cancers had adverse prognostic characteristics (hormone receptor–negative, axillary node–positive), and adjustment for those factors reduced the observed association between recent pregnancy and breast cancer outcome, suggesting little or no ongoing effect on tumor progression. Any residual effects of recent pregnancy could potentially be due to long-term hormonal changes that occur after pregnancy (such as have been reported for prolactin). To resolve this issue, it will be necessary to have further investigation focusing on biologic mechanisms. Alternatively, host factors implicated in breast cancer risk may continue to influence tumor progression and treatment responsiveness after breast cancer develops. In this situation, prognostic effects persist after adjustment for tumor-related factors present at diagnosis, and intervention to reverse the host factor may be beneficial. The prototypical example of this is obesity. Obesity, reflected by high body-mass index, is a recognized risk factor for postmenopausal breast cancer, and it adversely affects prognosis in both preand postmenopausal breast cancer. Barnett et al identified an adverse effect of high body-mass index that was greatest in hormoneresponsive breast cancer and that persisted after adjustment for age, stage, and grade. Several other studies have also identified significant effects in hormone-nonresponsive breast cancer. The biologic basis for a contribution of obesity to breast cancer outcomes is a major focus of ongoing research. Altered levels of sex hormones (estrogens, sex JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 20 JULY 1