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The Ups and Downs of the Estrogen Receptor

The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL

IN THE 40 years since its discovery,¹ the estrogen receptor (ER) has proved to be not only a valuable predictor for the success of ablative endocrine therapy in advanced breast cancer^2,3 but also an ideal target for molecular therapeutics with tamoxifen and with the aromatase inhibitors.^4–6 Most important, the purported link between estrogen and the initiation and promotion of breast cancer forms the cornerstone of the successful strategy of using tamoxifen to reduce breast cancer in women at high risk for the disease.⁷ Only the ER-positive disease is reduced by tamoxifen, so any changes in the incidence of ER-positive disease will influence the overall success of an antiestrogenic chemoprevention strategy.

In this issue of the Journal of Clinical Oncology, Li et al⁸ use the 1992 to 1998 age-adjusted, age-specific breast cancer incidence rates from the 11 population-based cancer registries in the United States that participate in the Surveillance, Epidemiology, and End Results program to illustrate that the proportion of hormone receptor–positive tumors is rising, while the proportion of receptor-negative tumors is declining. The increase in the proportion of ER-positive tumors occurs only in stage I cancers in younger women (40 to 69 years of age). These findings lead the authors to conclude that this implicates hormonal factors, primarily an increased use of hormone replacement therapy (HRT).

We have known of the link between breast cancer incidence and female hormones, including HRT, for 30 years.^9–11 Indeed, during the time frame of the Li et al⁸ study (1992 to 1998), 1992 guidelines from the American College of Physicians advised postmenopausal women who had had a hysterectomy and women at risk for coronary heart disease to receive preventive HRT.^12,13 Despite the encouragement for the use of HRT from the medical profession^13,14 (in the absence of prospective data on benefits), it is not easy to document a recent increased use of HRT by postmenopausal women. However, one small study¹⁵ found that white women of higher socioeconomic status were the group most likely to use HRT, regardless of the level of cardiovascular risk. In this study,¹⁵ fewer than 20.0% of women who had not had hysterectomies and 58.7% of women who had had hysterectomies were using HRT. In support of the possibility that HRT could increase breast cancer incidence, the Women’s Health Initiative¹⁶ study has prospectively demonstrated that there was little benefit for HRT, other than a modest reduction in fractures, but that there has been an increase in the incidence of breast cancer. Although it can be argued that in the Li et al⁸ study, more women were taking HRT, resulting in more ER-positive tumors, other hormonal factors may be responsible for these findings. For example, it is not possible to accurately estimate the impact of increased obesity, which enhances aromatization enzymes and increases circulating estrogen, on the incidence of ER-positive disease. In addition, the increased use of health foods, which contain variable quantities of phytoestrogens, could also promote ER-positive disease.

There is every reason to believe, based on laboratory studies, that estrogens from any source will maintain the ER-positive phenotype in breast cancer for decades. Conversely, ER-positive breast cancer cells can lose hormone responsiveness if maintained for prolonged periods in an estrogen-free environment.^17,18 In other words, estrogens in the environment are effective in maintaining breast cancer cell regulation through the estrogen receptor, which is necessary to retain hormone responsiveness to antihormonal therapeutic modalities.

Another dimension that creates additional uncertainty in interpreting the SEER database in the Li et al study⁸ is the methodology used to assign ER-positive and ER-negative status. Historically, the estrogen receptor assay was a ligand-binding assay that used high specific activity–labeled estradiol to quantitate unoccupied estrogen receptor in a breast tumor extract. ER-positive and ER-negative classification was based on a cutoff point, which varied from laboratory to laboratory.

Throughout the late 1980s, a change in assay methodology occurred, with a shift away from ligand-binding assays to immunohistochemical (IHC) assays performed on tumor biopsies. By the early 1990s, several central laboratories were still performing ligand-binding assays, but most hospitals were using IHC assays performed on tissue sections. Assessment of ER positivity, therefore, went from being quantitative to being subjective. Most important, with IHC technology, small primary tumors were also more likely to be ER-positive. A major problem with the ligand-binding assay was that it tended to produce an ER-negative result for small tumors. This, coupled with the increased detection of small tumors during the study period, could explain some of the reported findings.⁸ Furthermore, IHC was able to ascribe ER-positive status to women who were premenopausal and who had a low proportion of unoccupied receptors because of high-circulating steroids. This result can occur because IHC reports total receptor pools, whereas ligand-binding assays report only unoccupied receptor pools. Thus, the database for ER positivity could potentially have increased throughout the 1990s both because IHC assays were used to determine ER status and as a result of increased HRT use. This might be consistent with the observation by Li et al⁸ that only the incidence stage I ER-positive tumors increased during the 1990s but would not be consistent with their observation that the rise in ER-positive breast cancer is observed only in the white population. However, if the primary cause for the phenomenology was HRT, one would anticipate significant increases in ER-positive status in only 50- to 59- or 60- to 69-year-olds, who are most likely to be taking HRT. This was not observed, as the strongest trend toward an increased incidence of ER-positive tumors was noted in 40- to 49-year-olds, who were most likely to be premenopausal (see Table 3 in⁸).

The analysis by Li et al⁸ is complemented by the analysis of the same database by Chu and Anderson.¹⁹ In their analysis, Chu and Anderson¹⁹ use the age-specific rates for breast cancer diagnosed from 1992 to 1998, confirming that there is a higher rate of ER-negative breast cancer in younger African-Americans compared with whites, but which levels off for both groups after the age of 50. Overall, ER-positive rates are higher for whites than African-Americans, but both increase after the age of 50. In addition, the annual age-adjusted rate of ER-positive and ER/progesterone receptor (PgR)–positive breast cancer is higher in stage I than in stage II. Both studies^8,19 stress that not all breast cancers are the same, and they can be subclassified into ER/PgR-positive, ER-positive/PgR-negative, ER-negative/PgR-positive, and ER/PgR-negative. This is the standard classification used for the past 25 years in medical oncology. The questions to be answered now are, of what relevance are any of the analyses to the practicing oncologist, and what advantage can be derived for women at risk or women who have been diagnosed with the disease? It is clear that there has been an overall trend toward an increased diagnosis of ER-positive and PgR-positive disease. Sixty to sixty-five percent of patients are in this category.^8,19 The finding is primarily of interest in light of an increasing body of data that indicate that the use of tamoxifen decreases the incidence of new ER-positive breast cancers by 65%.^7,20 In addition, the use of raloxifene (a selective ER modulator) to prevent osteoporosis also reduces the incidence of ER-positive breast cancer as a beneficial side effect.^21,22 The increased use of tamoxifen or raloxifene for prevention indicates that the incidence of receptor-positive breast cancer should decrease in the future, not increase. Although concern has been expressed that both tamoxifen and raloxifene will increase the incidence of aggressive, ER-negative breast cancer, the available data indicate that both drugs reduce the overall breast cancer incidence by approximately 50%. The absolute number of ER-negative cancers is unchanged, although the proportion of cancers that are ER negative is increased.

Two decades from now, when selective ER modulators and aromatase inhibitors may be used routinely to reduce the incidence of ER-positive breast cancer, the requirement will be to find a target as good as the ER, to allow destruction of ER-negative disease and ultimately to prevent breast cancer completely.

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