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Hormone Replacement Therapy and High S Phase in Breast Cancer
Melody A. Cobleigh, MD;
Frances E. Norlock, DO, MPH;
Denise M. Oleske, PhD;
Alexander Starr, MD
JAMA. 1999;281:1528-1530.
ABSTRACT
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Context Prolonged postmenopausal hormone replacement therapy (HRT) is associated with increased incidence of breast cancer and, paradoxically, reduced breast cancer mortality. The biological rationale for this discrepancy has not been explored.
Objective To compare the prognostic characteristics of cancers arising in women who have used HRT with those in women who never have used HRT.
Design Prospective cohort study from December 1989 to November 1996.
Setting Teaching hospital in a large midwestern metropolitan area.
Patients Cohort of 331 postmenopausal women who presented consecutively with 349 invasive breast cancers.
Main Outcome Measures Estrogen receptor (ER) status (ER positive vs ER negative) and S phase (low vs high) for current HRT users vs never users.
Results The frequency of high S-phase fraction among cancers in women who were using HRT was markedly increased compared with that in women who had never used HRT (adjusted odds ratio [OR], 2.82; 95% confidence interval [CI], 1.04-7.66). However, the greater frequency of high S-phase fraction was limited to women with ER-positive cancers (for HRT users vs never users, OR, 5.25; 95% CI, 1.36-20.28; for ER-negative cancers in HRT users vs never users, OR, 1.08; 95% CI, 0.20-5.86).
Conclusions Use of HRT appears to stimulate growth of ER-positive but not ER-negative breast cancer as measured by S-phase fraction. The prognostic significance of high S-phase fraction in current HRT users who have ER-positive tumors is unknown.
INTRODUCTION
Prolonged use of hormone replacement therapy (HRT) correlates with increasing incidence of breast cancer,1 which is counterbalanced by lower mortality from the disease.2 We studied the influence of HRT use on prognostic factors in primary invasive breast cancer in an attempt to formulate a biological rationale for this paradox.
METHODS
Study Subjects
Beginning in 1989, postmenopausal patients with invasive breast cancer who presented consecutively to a medical oncologist (M.A.C.) at a teaching hospital in a large midwestern metropolitan area were entered prospectively into a database. In 1996, all postmenopausal subjects presenting consecutively to medical oncologists were entered prospectively. Variables included birth date, diagnosis date, pathologic tumor size (unknown when patients received preoperative chemotherapy), number of involved nodes (unknown when axillary dissection was not performed), last menstrual period, gynecologic surgery, HRT use, estrogen receptor (ER) and progesterone receptor (PR) values, ploidy, and percentage of cells in S phase (measured by flow cytometry).
Receptor and S-phase cut points were taken from the laboratories in which they were analyzed. About half the patients underwent primary surgery at our hospital; flow cytometry was performed in our Clinical Laboratory Improvement Act–approved laboratory. Other patients referred from community hospitals usually had flow cytometry performed in reference laboratories.
Hormone replacement therapy was defined as estrogen with or without progestin. Menopause was defined as no menstruation for 12 months, simple hysterectomy and patient older than 55 years, or bilateral oophorectomy.
Categories of HRT included never users (no HRT exposure), current users (HRT use within 1 month of diagnosis, with most using HRT at diagnosis), prior users (HRT stopped  1 month before diagnosis, with most having a remote history of use), and tamoxifen users (developed contralateral breast cancer during adjuvant tamoxifen therapy).
Statistical Analysis
Bivariate comparisons were assessed using a Yates corrected  2 test. Crude odds ratios were computed to represent the likelihood of high S phase relative to the hypothesized high risk of a prognostic factor (HRT use, tumor size >2 cm, ER-negative status, PR-negative status, aneuploidy, and nodal involvement). Logistic regression analysis was used to determine the multivariate likelihood of high S phase among HRT users, adjusting for age at diagnosis, tumor size, ER and PR status, ploidy, and nodal status. Model fit was evaluated.3 Tetraploid tumors were excluded because of small numbers. Analyses were performed using SPSS/PC+ software, Version 5.0 (SPSS Inc, Chicago, Ill). Probability values are 2-tailed, with P<.05.
RESULTS
There were 349 breast cancers among 331 women (bilateral cancers included 4 synchronous and 14 metachronous). There were 142 current HRT (40.7%), 165 never (47.3%), 38 prior (10.9%), and 4 tamoxifen users (1.1%). Prior and tamoxifen users were excluded because of their small numbers.
Current users were significantly younger (mean [SD] age, 57 [7] years) than never users (mean [SD], 62 [9] years; P<.001) and more likely to have high S-phase cancers and PR-positive status (Table 1). Controlling for age did not change the significance of these associations. Other prognostic factors did not vary with HRT use.
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Table 1. Characteristics of Current and Never Users of Hormone Replacement Therapy*
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S phase was evaluated by ER status and HRT use. Estrogen receptor–positive cancers were affected by HRT; nearly half of current users had high S-phase cancers compared with only about a fifth of never users. Use of HRT did not affect the S phase of ER-negative cancers; the majority had a high S phase (Table 2).
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Table 2. S-Phase Determinations by Hormone Replacement Therapy Use and Receptor Status
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Estrogen receptor–negative status, aneuploidy, and current use of HRT correlated significantly with high S phase in the regression analysis (Table 3). When sorted by receptor status, the model confirmed a significant association of current HRT use with high S phase in ER-positive cancers only. Current users with ER-positive cancers were 5 times more likely to have a high S phase than never users (Table 4).
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Table 3. Multiple Logistic Regression Model for Predicting High S Phase*
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Table 4. Multiple Logistic Regression Model for Predicting High S Phase Among Estrogen Receptor–Positive Patients Only*
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COMMENT
In this study, ER-positive cancers were more likely to have a high S phase in current users of HRT. To our knowledge, this is the first report of such an association. This result was expected based on preclinical models. Estrogen causes proliferation of ER-positive but not ER-negative human breast cancer cells in vitro4 and in vivo.5
High S phase was independently and significantly predictive of breast cancer recurrence in 8 trials of 9901 women, while 4 trials including 1044 women found no such evidence.6-17 History of HRT use was not included in these models.
In a large database of 127,000 breast cancers, high S phase correlated with aneuploidy and ER-negative and PR-negative status (these results were not stratified by HRT use).18 Our results support and extend those observations and suggest that high S phase is also more common in ER-positive cancers among current HRT users.
Use of HRT has been correlated with low S phase19; however, the results of that study were not stratified by receptor status. Use of HRT was associated with low S phase in ER-positive cancers, but the analysis did not control for other variables that affect S phase, such as aneuploidy and nodal status.20
Others have evaluated the relationship between HRT and ER status of primary cancers. Although occasional correlations have been described,21-22 most studies found no significant difference in ER profiles between users and nonusers of HRT.19, 23-30 Our study supports this consensus.
Relationships between HRT use and other prognostic characteristics have been reported. Although trends toward smaller tumors, negative nodal findings, and diploid/tetraploid cancers were observed, these were not statistically significant in multivariate analysis.31 Others have reported a high rate of well-differentiated tumors in HRT users, but this observation was not subjected to multivariate analysis.20, 28
A strength of this study is the collection of information on HRT use at the time of presentation, lessening the possibility of recall bias. Limitations of our study include the fact that it is not population based and that not all variables for every patient were known.
Most studies have reported reduced survival in node-negative women with high S-phase cancers. Some use such retrospective correlative data to recommend systemic adjuvant therapy, even for women with small (<1 cm) node-negative cancers. However, it is possible that high S phase may be iatrogenic in ER-positive cancers diagnosed in women taking HRT.
Use of HRT may promote preexisting clinically occult cancers, bringing them to light sooner in their natural biological history. This may account for the better survival of breast cancer patients who have used HRT. This cohort will be followed up and expanded to assess survival. Hormone withdrawal may also prove therapeutic. Precedents for this have been reported in studies of primary tumor regression32 and metastatic breast cancer regression after HRT withdrawal.33
AUTHOR INFORMATION
Funding/Support: This study was supported by the Diane O'Brien Breast Cancer Research Fund.
Acknowledgment: We thank Janet Wolter, MD, John Coon, MD, PhD, Thomas Witt, MD, and Sabet Siddiqui, MD, for their assistance.
Corresponding Author and Reprints: Melody A. Cobleigh, MD, Rush-Presbyterian-St Luke's Medical Center, 1725 W Harrison St, Suite 821, Chicago, IL 60612.
Author Affiliations: Section of Medical Oncology (Dr Cobleigh) and Departments of Medicine (Drs Norlock and Starr), and Preventive Medicine (Dr Oleske), Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill.
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