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Annals of Surgical Oncology 9:266-271 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Pathologic and Biological Prognostic Factors of Breast Cancers in Short- and Long-Term Hormone Replacement Therapy Users

Virgilio Sacchini, MD, Stefano Zurrida, MD, Gisella Andreoni, MD, Alberto Luini, MD, Viviana Galimberti, MD, Paolo Veronesi, MD, Mattia Intra, MD, Giuseppe Viale, MD and Umberto Veronesi, MD

From the Breast Service (VS), Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York; and the Breast Department (SZ, GA, AL, VG, PV, MI, UV) and Pathology Department (GV), European Institute of Oncology, Milan, Italy.

Correspondence: Address correspondence and reprint requests to: Virgilio Sacchini, MD, Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., MRI-1026, New York, NY 10021; Fax: 212-794-5812; E-mail: sacchinv{at}mskcc.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Breast cancer tumors occurring in hormone replacement therapy (HRT) users are less aggressive, but no studies have compared tumor aggressiveness among HRT users by length and mode of therapy.

Methods: A total of 1105 consecutive postmenopausal patients treated for operable breast cancer at the European Institute of Oncology were identified. Women exposed to HRT were compared with HRT nonusers by clinical stage at presentation and pathologic and biological tumor characteristics. HRT duration and administration modality were analyzed in relation to tumor characteristics in the HRT group.

Results: Better stage distribution, including smaller pathologic tumor diameter and fewer involved axillary lymph nodes, was seen in the HRT group. Estrogen receptor-positive tumors were more frequent in the control group, but this tendency was reversed with longer exposure to HRT. Histological grade III tumors were less frequent in the HRT group. More favorable prognostic factors were associated with HRT >5 years. The proliferative fraction was higher in patients with exposure <1 vs. >5 years and in oral versus transdermal users.

Conclusions: Breast cancers developing during HRT have better prognostic characteristics than those seen in HRT nonusers. A trend toward better prognostic characteristics with increasing duration of HRT was seen.

Key Words: Breast cancer • Hormone replacement therapy • Prognostic factors • Tumor aggressiveness


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hormone replacement therapy (HRT) is widely used in postmenopausal women to maintain bone density and cognitive capacity and to protect against heart disease. However, these benefits must be weighed against the increased risk of breast cancer with long-term HRT use. When administered as HRT, estrogen has been shown to increase the risk of breast cancer in postmenopausal women. In the largest prospective study to date, the Nurses Health Study,1 the relative risk of breast cancer in women receiving HRT was 1.2 times that of women who had never taken HRT. A meta-analysis of 52,705 women with breast cancer and 108,411 women without breast cancer confirmed this trend, and the risk was found to increase with increasing duration of HRT use.2 Several authors have suggested that cancers occurring during HRT use are less aggressive, but strong supporting evidence is lacking. A bias, such as greater awareness of the risk of breast cancer among HRT users, may explain the finding of earlier-stage breast cancers in these women.1

Uncertainty also exists regarding the optimal administration modality for HRT. Oral and transdermal administration modalities seem to produce different ratios of free estrogen to estrogen bound to sex hormone-binding globulin, which could influence the carcinogenic processes.

We performed a retrospective case-control study to determine whether the pathologic and biological prognostic factors associated with breast cancer in women receiving HRT differed from those seen in breast cancer patients who had never taken HRT, who were operated on over the same time period. The HRT group was stratified according to mode of administration (transdermal vs. oral) and length of treatment. Our working hypothesis was that breast cancers in patients exposed to HRT have more favorable prognostic factors than breast cancers in patients receiving no HRT.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
The clinical records of 1105 consecutive postmenopausal patients treated for operable breast cancer at the European Institute of Oncology in Milan, Italy, from June 1994 to December 1997 were examined retrospectively to abstract age, pathologic tumor size, histological type, presence of peritumoral vascular invasion (PVI), proliferative fraction (Ki-67), estrogen-receptor (ER) and progesterone-receptor (PR) status, and axillary lymph node involvement. The clinical record of each patient contained a section, completed by the physician during an interview, regarding the use of HRT; from this, duration of use, mode of administration (oral vs. transdermal), dosage, and last exposure were abstracted. In 32 records (2.9%), the data were missing or incomplete, and these cases were excluded from the study. The same surgeons, pathologists, and medical oncologists were involved throughout the entire study period.

Pathologic and Biological Determinations
The cancers were classified according to the World Health Organization’s International Histological Classification of Tumours,3 as modified by Rosen and Oberman.4 Tumor grading was performed according to the system of Elston and Ellis.5 The presence of PVI was assessed in accordance with Rosen and Oberman.4 ERs, PRs, and the Ki-67 of the tumor were evaluated by immunohistochemistry (Techmate 500TM automatic immunostainer, Dako, Glostrup, Denmark) on paraffin sections, with use of indirect avidin-biotinylated peroxidase staining6 after antigen retrieval by microwave in citrate buffer (pH 6.0).7 Primary monoclonal antibodies to ERs and PRs (Dako, Glostrup, Denmark) were used at a 1/100 dilution; MIB-1 monoclonal antibody to the Ki-67 antigen (Immunotech, Marseilles, France) was used at a 1/200 dilution. ERs and PRs were considered positive when the percentage of immunoreactive neoplastic cells was >10%. The Ki-67 proliferation index threshold was set at 20%.8

Patient Stratification and Statistical Analysis
The patients were divided into two groups: HRT users and those who had never used HRT (nonusers). HRT users were further divided into three subgroups according to duration of HRT use: <1 year, from 1 to 5 years, and >5 years. Users were also stratified according to HRT formulation (estrogen alone or in combination with progesterone) and oral versus transdermal administration. The data set for each patient consisted of postmenopausal hormonal exposure and the ordered categorical disease outcome variables.

The relationship between duration of HRT use and biological and pathologic variables was tested with the {chi}2 test. Logistical regression was used to assess the association between HRT use and investigated variables allowing for adjustment for age and tumor size.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Nineteen percent of the study population was taking or had taken HRT. This is a rather high proportion and reflects the increasing use of HRT among Italian postmenopausal women.9 The two groups did not differ in terms of age (Table 1). All of the women receiving HRT discontinued it on diagnosis of breast cancer; they were operated on at least 6 days after the treatment had been discontinued. Among HRT users, 16.6% took the preparation for more than 5 years, 66.3% from 1 to 5 years, and 17.1% for <1 year (Table 2). Women with longer HRT exposure were older than those with shorter exposure (HRT >5 years, median age, 59 years; HRT <1 year, median age, 54 years). Most HRT users took estrogens with progesterone (78.7%); estrogen-only HRT was administered chiefly to hysterectomized women. HRT was administered orally in 56.4% and transdermally in 43.6%.


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  		TABLE 1. Clinical and pathologic characteristics of 1105 postmenopausal breast cancer patients by hormone replacement therapy (HRT) user/nonuser status
 

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  		TABLE 2. Distribution of prognostic factors according to length of exposure to HRT
 
The clinical and pathologic characteristics of the HRT users and nonusers are listed in Table 1. Tumor stage distribution was more favorable among HRT users than nonusers, with significantly smaller tumor size and significantly fewer metastatic nodes seen in the former group. With regard to biological factors indicating tumor aggressiveness, significantly more ER-positive tumors were present in the control than the HRT group. This tendency reverses with longer exposure to HRT (Table 2). Grade III tumors were significantly more frequent in the nonuser group than the HRT user group, whereas PVI was more prevalent in the HRT group (32.7% vs. 23.9; P < .01) and remained similar in the three HRT subgroups on the basis of length of HRT use (Table 2).

The percentage of ER- and PR-positive tumors increased with increased length of HRT administration, and this trend did not change after correction for age. In the group with exposure of >=1 year, 72.9% of tumors were ER positive, versus 55.6% in the group with exposure <1 year. The Ki-67 was significantly higher in patients with <1 year of exposure compared with those exposed for >5 years (61.1% vs. 25.7%; P < .01). Furthermore, well-differentiated cancers (grade I) were slightly more frequent among those taking HRT for >5 years than in those taking HRT for <1 year (34.3% vs. 22.2%; P = .11). The distribution of factors indicating tumor aggressiveness according to HRT administration modality is listed in Table 3. The proliferation index was slightly higher in oral than transdermal users (63.9% vs. 52.2%; P < .09). No difference was found for PVI: 33.6% vs. 31.5%, respectively (P < .75). The oral and transdermal groups did not differ in terms of ER status and tumor grade.


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  		TABLE 3. Distribution of prognostic factors according to HRT administration modality
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
More favorable prognostic factors in breast cancers developing under HRT compared with those seen in women not taking HRT have been reported in several studies.10–13 These findings are supported by a significantly decreased risk of breast cancer mortality in HRT users reported by some studies.1,14 Many attempts have been made to explain this finding. An increased probability of earlier diagnosis because of greater awareness of the risk of breast cancer in women taking HRT has been postulated, and in fact a less advanced clinical stage in HRT users was evident in a large meta-analysis that considered 54 epidemiological studies.2 Our study also found a less advanced clinical stage in the HRT user group, with significantly smaller tumor size and fewer involved nodes in the HRT group compared with the nonuser group (Table 1). Holli et al.,11 who had similar results, included the effect of the cancer-detection method in the logistical regression analysis, but it had a minimal effect on the association between HRT use and tumor size and proliferation rate.

Magnusson et al.10 also found that, in women who took a combined estradiol/progestin regimen compared with controls, with adjustments for indicators of earlier detection (lead-time bias), the pattern or magnitude of the risk estimates was not influenced. These authors also compared survival in the HRT user and nonuser groups. No differences were found, but the small number of deaths probably limited the significance of the statistical analysis.

These data seem to indicate that tumors developing under HRT are less aggressive than those seen in the general population of breast cancer patients. The biological reasons for better-differentiated cancers with estrogen exposure have not been explained. A complex interaction among estrogens, growth factors, and angio-genesis is thought to play a role in carcinogenesis, but no definitive explanation has been found.15,16 These interactions may be more important in the early stages of carcinogenesis than in the late stages. Thus, our finding of better-differentiated cancers with prolonged HRT use indicates that the selection of more favorable prognostic factors occurs in the foci of tumors newly forming during HRT, rather than in older, pre-HRT tumoral foci. In the group receiving HRT for <1 year, Ki-67 and grading were comparable to those of patients who had never used HRT (Table 2).

ER expression was similar in the HRT user and nonuser groups. In terms of ER distribution, the percentage of ER-negative tumors was greater among HRT users of <1 year than in nonusers (44.4% vs. 22.7%), whereas the percentage of ER-negative tumors decreased in the HRT group with increasing length of exposure (Table 2). Other studies have found no difference in ER distribution between HRT users and nonusers; however, these studies did not stratify study subjects by length of use.11,12,16

This picture remains constant when a different definition of receptor positivity is used. Thus, Holli et al.11 considered tumors to be ER positive when more than 20% of cancer cells were immunopositive. We chose a 10% threshold in light of recent articles in which the response to hormonal treatment was maintained for very low estrogen expression.17 Magnusson et al.10 used two different methods—isoelectric focusing18,19 and modern immunoassays—for assessing ER and PR status in different sets of patients. The first technique, which detects only unoccupied receptor sites, may have underestimated the total number of hormonal receptors (free plus bound), especially in the HRT group, in which the administered estrogens may have occupied the receptor sites. Bonnier et al.16 also used two different techniques, radioligand-binding assays and enzyme immunoassays, again in different sets of patients. They obtained the same results in terms of ER distribution in users and nonusers.

The real prognostic significance of PVI is still controversial. Some authors have considered PVI an independent prognostic variable that is particularly important in node-negative breast carcinomas and that is more effective in predicting disease-free than overall survival.20,21 Others have found no negative effect on survival when this factor was present and determined according the European standard recommendations.22 It is therefore difficult to interpret our finding of more PVI in HRT users. The constant percentage of this biological parameter in cancers occurring after different HRT exposure times may indicate a nonquantitative effect of estrogens on PVI.

Some studies have reported that HRT is protective against cardiovascular disease and osteoporosis when administered either orally or transdermally, provided that adequate doses are given.23–26 Different administration modalities may have differing biological effects on breast carcinogenesis. In our series, 43.6% of the women taking HRT used estradiol patches. Thus, it was possible to compare the characteristics of tumors occurring in the two different administration modalities.

The growth hormone insulin-like growth factor (IGF)-I axis seems to be involved in modulating the proliferation of normal breast epithelial cells27 and breast cancer,28 and a direct relationship between circulating IGF-I levels and risk of breast cancer has been reported, although only in premenopausal women.29 Estrogens and IGF-I have synergistic effects on cell proliferation.30 Oral estrogen replacement therapy in postmenopausal women has been shown31 to decrease IGF-I serum concentrations by 20% to 30%, and it probably also decreases the IGF-I biological activity by increasing the levels of IGF-binding proteins.32,33 This effect of oral estrogen, which is most likely caused by the direct effect on hepatocytes (circulating IGF-I is mainly produced in the liver) and enhanced by the strong first-pass effect on the liver when estrogens are administered orally, has been suggested to have a potentially favorable effect on the risk of breast cancer34 and possibly also on the biological characteristics of the disease. Conversely, transdermal administration of estradiol largely avoids the first-pass effect of the liver and would not have the same favorable effect on the IGF-I system. Specifically, transdermal administration causes a lesser decrease of serum levels of IGF-I compared with that caused by oral administration,35 although the transdermal effect of estrogen may be bimodal: decreasing circulating IGF-I if basal levels are high but increasing them if basal levels are low.36

It has been suggested that oral estrogens may also have another potentially protective effect against breast cancer. Oral estrogens increase serum levels of sex hormone-binding globulin, thereby decreasing the biological activity of free circulating estrogens.34 Because this effect depends on the metabolic modifications caused by the liver first-pass effect, it does not occur with transdermal estradiol.37 However, transdermal patches provide lower and more constant therapeutically effective blood concentrations of estradiol and estrone, whereas the daily administration of oral estrogen produces large pulses of estradiol and estrone and exposes women to much higher hormone concentrations.38 Although the ratio of 2-hydroxyestrone to 16 {alpha}-hydroxyestrone, the more potent mitogen, may remain similar for both administration modalities, metabolite concentrations are higher after oral estrogen administration.39 These different pharmacokinetic characteristics of the two administration modalities are enough to hypothesize differing effects on promotion and growth of breast cancer. Our data cannot provide information on risk evaluation according to mode of administration, but they can demonstrate that cancers occurring under transdermal HRT are similar to, if not more favorable than, oral administration in terms of prognostic factors.

In conclusion, our study demonstrated reduced aggressiveness in breast cancers occurring during HRT. This finding has been demonstrated by numerous other studies.1,2,40–42 This reduced aggressiveness is evidenced by decreased axillary nodal involvement, lower cellular grade, and a lower percentage of Ki-67. It is more apparent in long-term users and seems to be independent of the method of HRT administration used.

Received for publication June 21, 2001. Accepted for publication October 12, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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