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Host-Related Factors in Breast Cancer: An Underappreciated Piece of the Puzzle?

Samuel Lunenfeld Research Institute at Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

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)¹ 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,² 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 al³ 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 al³ 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 al³ 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 particular⁴ 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 pre- and postmenopausal breast cancer. Barnett et al³ identified an adverse effect of high body-mass index that was greatest in hormone-responsive 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.⁵ 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 hormone–binding globulin) are often postulated to play important roles in mediating this effect; however, the presence of an effect of obesity in hormone-nonresponsive breast cancer and in premenopausal women (in whom obesity is a weak determinant of estradiol levels) suggest that other mechanisms may be more important. There is growing evidence that insulin and, to a lesser extent, insulin-like growth factors are key biologic mediators.^6-8 Reports that obesity is an adverse prognostic factor (but not a risk factor) in premenopausal breast cancer raise the intriguing possibility that some host factors may affect tumor progression but not carcinogenesis. Intervention research to determine effects of lifestyle change to promote weight loss is ongoing. The Women's Intervention Nutrition Study⁹ recently reported improved event-free survival in women randomly assigned to a reduced fat diet (associated with weight loss), providing the first clinical evidence that modifying host lifestyle factors influences outcome.

Barnett et al³ have recommended caution in attributing a prognostic role to alcohol intake on the basis of the evidence they present. Given the relative weakness of their evidence, and inconsistency of effect in the published literature, this recommendation for caution is wise. Plausible but tenuous biologic links (eg, alcohol dehydrogenase) should not be a substitute for valid, strong, and consistent epidemiologic or clinical data. The modest attenuation of the beneficial effect seen by Barnett et al³ after adjustment for other factors suggests that any prognostic effect of alcohol may be due, at least in part, to its effect on tumor presentation. In that respect, advanced-stage patients had lower alcohol consumption, possibly reflecting the fact that they were sicker at diagnosis, rather than to biologic effects. Inconsistency across studies should be resolved before any clinical recommendations are developed regarding alcohol intake by patients with breast cancer. Furthermore, caution should be exercised in attributing prognostic effects to sociodemographic host factors that cause delay in diagnosis and result in presentation at a more advanced tumor stage without influencing the underlying cancer biology.

The common, almost universal overexpression of insulin receptors on breast cancer cells¹⁰ may explain the relative ease with which obesity has been identified as a prognostically important host factor. For other host factors, prognostic effects may depend on molecular characteristics of tumors that are less commonly present or are currently unrecognized. As a result, prognostic effects of these factors may be harder to detect in unselected series of breast cancers. This underscores the importance of understanding the biologic basis for the contribution of specific host factors to breast cancer outcomes and the need to link what is known about each host factor to the rapidly evolving understanding of the molecular biology of breast cancer.

It is possible that identification of prognostically important host factors (other than estrogens) will be particularly important in understanding the biology of hormone-receptor negative (including triple negative) breast cancers. Nonestrogenic growth factors (such as insulin) linked to host characteristics (such as obesity) may prove to be clinically important in these cancers. A potential example of this effect was seen in the Women's Intervention Nutrition Study⁹ described previously—the beneficial effect of the lifestyle intervention was greater in hormone-nonresponsive than in hormone-responsive breast cancer. Enhanced understanding of factors driving the growth of hormone-nonresponsive breast cancer would be an important advance, particularly if those factors were reversible.

Additional research is needed to understand the role of host factors in breast cancer and should not be limited to those factors studied by Barnett et al.³ Exercise, diet, and other lifestyle and environmental factors, as well as hormones and metabolic factors, should also be investigated. Breast cancer cells do not exist in isolation; they are bathed in a plethora of growth factors and hormones that reflect host lifestyle, environmental exposures, reproductive practices, and inborn metabolism. It is likely that all but the most undifferentiated of breast cancers will be influenced by these factors to some extent and that tumor growth may be modifiable through their manipulation. Research in this area should be firmly rooted in biology. Further evaluation of the role of host factors should strive to address biologic and molecular mechanisms. It should also address many of the unique challenges of work in this area. These challenges include difficulties inherent in measuring many host factors, such as diet and physical activity, in obtaining appropriately timed and collected physiologic specimens for evaluation of potential hormone and metabolic mediators, and fostering the transdisciplinary collaborations that are an essential part of translational research. If these challenges can be overcome, with careful attention to detail and openness to new paradigms, it is quite possible that important advances will result, which will have a clinically important impact on breast cancer outcomes.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

ACKNOWLEDGMENTS

Funded by the Breast Cancer Research Foundation.

REFERENCES

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4. Phillips KA, Milne RL, Friedlander ML, et al: Prognosis of premenopausal breast cancer and childbirth prior to diagnosis. J Clin Oncol 22:699-705, 2004[Abstract/Free Full Text]

5. Goodwin PJ: Energy balance and cancer prognosis: Breast cancer, in McTiernan A (ed): Cancer Prevention and Management Through Exercise and Weight Control. Boca Raton, FL, Taylor and Francis Group, 2006, pp 405-435

6. Goodwin PJ, Ennis M, Pritchard KI, et al: Fasting insulin and outcome in early stage breast cancer: Results of a prospective cohort study. J Clin Oncol 20:42-51, 2002[Abstract/Free Full Text]

7. Pasanisi P, Berrino F, De Petris M, et al: Metabolic syndrome as a prognostic factor for breast cancer recurrences. Int J Cancer 119:236-238, 2006[CrossRef][Medline]

8. Pollak MN, Chapman JW, Shepherd L, et al: Insulin resistance, estimated by serum C-peptide level, is associated with reduced event-free survival for postmenopausal women in NCIC CTG MA 14 adjuvant breast cancer trial. J Clin Oncol 24:9s, 2006(abstr 524)[CrossRef]

9. Chlebowski RT, Aiello E, McTiernan A: Weight loss in breast cancer patient management. J Clin Oncol 20:1128-1143, 2002[Abstract/Free Full Text]

10. Mulligan AM, O'Malley FP, Ennis M, et al: Insulin receptor is an independent predictor of a favorable outcome in early stage breast cancer. Breast Cancer Res Treat 106:39-47, 2007[CrossRef][Medline]

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