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Vol. 05 Issue 1, Winter 2000

Research Commentary: Hormone Replacement Therapy and Other Possible Risk Factors for Breast Cancer
The Ribbon 

H. Leon Bradlow, PhD, Professor, Weill Medical College of Cornell University

Previously accepted risk factors for breast cancer, such as gene defects (BrCa1, BrCa2, Her2Neu, etc.), early age at menarche, and late age at first pregnancy, account for only perhaps 15% of the annual incidence of breast cancer. There has therefore been a near feverish search for other breast cancer risk factors. Much of this search has focused on drugs, diet, and the environment as possible explanations for breast cancer risk.

Hormone Replacement Therapy

For many years the role of hormone replacement therapy (HRT), primarily Premarin in this country (although estradiol benzoate has been used in Scandinavia), has been the object of numerous studies with inconclusive results, both positive and negative. Cutting through this murkiness, a recent study by Gapstur and colleagues provided some surprising results. In this study, carried out on a large population base in Iowa, they analyzed breast cancer incidence by type in patients who used HRT and a control population who did not use HRT. In this study they found no significant increase in ductal carcinoma in situ (DCIS), or ductal or lobular carcinoma; they did find an increase in a rare (<5% of all tumors) type of invasive carcinoma, which has a relatively favorable histology and a low mortality. The reason for this slight shift in cancer incidence remains elusive. No such shift was found by Persson and colleagues in Sweden, who reported a relative risk of 1.4 in women using estrogen progestin combinations for 1-6 years but no increase in breast cancer risk in women using estrogen alone. However, in women using only estrogen the risk of endometrial cancer increased 4-fold but was non-significant in women using the combined drug. They did not analyze in terms of tumor type, preventing any direct comparison with the study of Gapstur and colleagues. A more complicated risk issue is the safety of HRT in women with a history of breast cancer. In a recent review Seifert et al concluded that, despite the possible benefits in postmenopausal women, the potential risks remain uncertain and do not justify their use in such women, pending a suitable clinical trial.

The state of flux of research in this field is illustrated by the fact that two more recent papers have reported quite different findings. Stallard and colleagues in a recent paper in the British Medical Journal reported that HRT treatment neither generated tumors with a more favorable prognosis nor did it result in poorer prognosis tumors, in marked contrast to the results reported by Gapstur et al. The other paper by Schairer et al in JAMA reported still a different result, with a slight increase in risk with HRT treatment particularly in lean women with a Body Mass Index of less than 24.4. All of the studies had substantial study populations and appear to have been competently carried out. While the overall results suggest that the risk from HRT treatment is minimal, it is clear that additional studies are needed to sort out these widely varying results and arrive at a generally accepted assessment of the risk from HRT treatment.

Oral Contraceptives

A similar controversy still exists on oral contraceptives (OCs) as a risk for breast cancer. There have been innumerable studies on this topic, but the results are still inconclusive for the most part. Some studies have found no effect, while others have reported a modest increase in risk. There have been suggestive data for a slight increase in risk in teenagers taking OCs between the ages of 16 and 20. Compensating for any slight increases in breast cancer risk is the fact, reported by Henderson, Ross, and Pike that use of OCs for 4-5 years results in a permanent 50% decrease in ovarian and endometrial cancer. This is a real benefit which needs to be kept in mind in evaluating the medical benefits of OC use. The OC studies have not categorized cases in terms of cancer type as has been done for HRT. An exploration of cancer type in patients taking OCs would be of great interest and is likely to be undertaken in the near future.

Other Factors Impacting Body Estrogen

The role of obesity and diet is equally murky, partly because food intake is frequently confused with body composition, particularly in the popular press. There is clear evidence that the risk of obesity is age-related. Among premenopausal women the risk is higher for women of average weight than it is for very thin or - surprisingly - very obese women. Among post-menopausal women, however, obesity is clearly a risk factor. These paradoxes can be explained, but not in the limited space of this article.

Diet is important, but not as it is often understood. Although much attention has been paid to dietary fat consumption this concern is misplaced since total calories consumed, not total fat consumed, is the key to amount of body fat. There are ample data demonstrating that excess calories as carbohydrate result in increased fat deposition. It is certainly true that, because of the concentrated calorie content of fat, it is an easy cause of obesity. It is also true that, in the absence of parallel carbohydrate consumption, dietary fat does not end up as stored fat. This is because glycerol-phosphate required for resynthesis of body fat comes only from carbohydrate, not from fat. Dietary restriction, particularly of carbohydrate, and increased exercise, are sensible approaches to decreasing diet-related breast cancer risk. (This is not meant to dismiss the possible benefits of decreased fat intake in terms of heart disease and other metabolic problems.)

Extensive studies have shown that a variety of micronutrients can act to decrease breast cancer risk. These include a diverse group of compounds found primarily in vegetables. Examples include such compounds as indole-3-carbinol, its dimer diindolylmethane, sulfuraphane, all found in cruciferous vegetables; epigallocatechin gallate (EGCG), found in green tea; curcumin, found in tumeric; vitamin E and a host of other antioxidants. These compounds act in various ways. Thus the indoles and EGCG act in part by altering estrogen metabolism to increase the level of the protective estrogen metabolite, 2-hydroxyestrone. Other protective mechanisms include increasing phase II conjugating activity, increasing apoptosis (cell death), and inhibiting cyclin D.

Decreased risk for breast cancer in women who exercise regularly was first reported by Frisch, and more recently by Bernstein and colleagues, as well as in the Nurses Health Study. One of the actions of exercise is to increase the conversion of estradiol to 2-hydroxyestrone, the "good" estrogen, which is only weakly estrogenic. The action is indirect, with the intermediate step being a decrease in fat depots. This has been demonstrated by Frisch and Snow. This reduction in fat depots decreases the release of a protein that inhibits 2-hydroxylation.

The most confusing and speculative issue has been the risk-promoting effect of the environment. This includes the possible effects of a varied group of compounds and environmental parameters, including electromagnetic fields (EMF), aryl hydrocarbons (benzpyrene, dimethylbenzanthracene and related compounds), pesticides, PCBs, etc. Recent studies have rendered EMF an unlikely risk factor for breast cancer. While aryl hydrocarbons are clearly tumor-promoting in rodent models, the evidence for a comparable role in human disease has not been strong and current case control studies have been negative. There has been considerable interest in the possible carcinogenic role of chlorinated pesticides. Cell culture studies showed that chlorinated pesticides promoted 16a-hydroxylation of estradiol, while no such effect was observed in the presence of phosphorus-based pesticides. Several earlier human studies were highly suggestive, while more recent studies have for the most part been negative, except for a Danish study using old blood samples, which showed a correlation between dieldrin levels and cancer risk. Because the widespread use of chlorinated pesticides has been markedly curtailed in this country and in much of Europe, circulating levels of these compounds have declined - creating the illusion that these compounds are harmless and decreasing the chance of seeing significant differences between cases and controls. The same is true for PCBs, whose circulating levels have also dropped significantly as the use of these compounds has been curtailed.

Despite the enormous amount of effort that has gone into looking for risk factors we still have no certainty about the risk factors causing the majority of breast cancers. At best we have some working hypotheses and a number of well-publicized speculations. We may have to make decisions and take action, on both the personal and governmental levels, in the face of incomplete knowledge; but we should not confuse speculation with fact.


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