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Table 1. Characteristics of Current and Never Users of Hormone Replacement Therapy*
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Table 2. S-Phase Determinations by Hormone Replacement Therapy Use and Receptor Status
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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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1.
Collaborative Group on Hormonal Factors in Breast Cancer.  Breast cancer and hormone replacement therapy.  Lancet.1997;350:1047-1059.
2.
Cobleigh MA. Hormone replacement therapy and nonhormonal control of menopausal symptoms in breast cancer survivors.  Cancer Treat Res.1998;94:210-230.
3.
Hosmer DW, Lemeshow S. Applied Logistic Regression. New York, NY: John Wiley & Sons Inc; 1989.
4.
Lippman M, Bolan G, Huff K. The effects of estrogens and antiestrogens on hormone-responsive human breast cancer in long-term tissue culture.  Cancer Res.1976;36:4595-4601.
5.
Fuqua SAW. Estrogen and progesterone receptors and breast cancer. In: Harris JR, Lippman ME, Morrow M, Hellman S, eds. Diseases of the Breast. Philadelphia, Pa: Lippincott-Raven; 1996:262-263.
6.
O'Reilly SM, Camplejohn RS, Barnes DM, Millis RR, Rubens RD, Richards MA. Node-negative breast cancer.  J Clin Oncol.1990;8:2040-2046.
7.
Sigurdsson H, Baldetrop B, Borg A.  et al.  Indicators of prognosis in node-negative breast cancer.  N Engl J Med.1990;322:1045-1053.
8.
Stal O, Dufmats M, Hatschek T.  et al.  S-phase fraction is a prognostic factor in stage I breast carcinoma.  J Clin Oncol.1993;11:1717-1722.
9.
Winchester DJ, Duda RB, August CZ.  et al.  The importance of DNA flow cytometry in node-negative breast cancer.  Arch Surg.1990;125:886-889.
10.
Clark GM, Dressler LG, Owens MA, Pounds G, Oldaker T, McGuire W. Prediction of relapse or survival in patients with node-negative breast cancer by DNA flow cytometry.  N Engl J Med.1989;320:627-633.
11.
Balslev I, Christensen IJ, Rasmussen BB, Larsen JK, Lykkesfeldt AE, Thorpe SM. Flow cytometric DNA ploidy defines patients with poor prognosis in node-negative breast cancer.  Int J Cancer.1994;56:16-25.
12.
Toikkanen S, Joensuu H, Klemi P. The prognostic significance of nuclear DNA content in invasive breast cancer.  Br J Cancer.1989;60:693-700.
13.
Witzig TE, Ingle JN, Cha SS.  et al.  DNA ploidy and the percentage of cells in S-phase as prognostic factors for women with lymph node negative breast cancer.  Cancer.1994;74:1752-1761.
14.
Muss HB, Kute TE, Case D.  et al.  The relation of flow cytometry to clinical and biologic characteristics in women with node negative primary breast cancer.  Cancer.1989;64:1894-1900.
15.
Ewers SB, Atewell R, Baldetorp B.  et al.  Prognostic significance of flow cytometric DNA analysis and estrogen receptor content in breast carcinomas.  Breast Cancer Res Treat.1993;24:115-126.
16.
Merkel DE, Winchester DJ, Goldschmidt RA.  et al.  DNA flow cytometry and pathologic grading as prognostic guides in axillary lymph node-negative breast cancer.  Cancer.1993;72:1926-1932.
17.
Bosari S, Lee AK, Tahan SR.  et al.  DNA flow cytometric analysis and prognosis of axillary lymph node-negative breast carcinoma.  Cancer.1992;70:1943-1950.
18.
Wenger CR, Beardslee S, Owens MA.  et al.  DNA ploidy, S-phase, and steroid receptors in more than 127,000 breast cancer patients.  Breast Cancer Res Treat.1993;28:9-20.
19.
Squitieri R, Tartter PI, Ahmed S, Brower ST, Theise ND. Carcinoma of the breast in postmenopausal hormone user and nonuser control groups.  J Am Coll Surg.1994;178:167-170.
20.
Holli K, Isola J, Cuzick J. Low biologic aggressiveness in breast cancer in women using hormone replacement therapy.  J Clin Oncol.1998;16:3115-3120.
21.
Jones C, Ingram D, Mattes E, Hahnel R. The effect of hormone replacement therapy on prognostic indices in women with breast cancer.  Med J Aust.1994;161:106-110.
22.
Hildreth NG, Kelsey JL, Eisenfeld AJ.  et al.  Differences in breast cancer risk factors according to the estrogen receptor level of the tumor.  J Natl Cancer Inst.1983;70:1027-1031.
23.
Colditz GA, Stampfer MJ, Willett WC.  et al.  Prospective study of estrogen replacement therapy and risk of breast cancer in postmenopausal women.  JAMA.1990;264:2648-2653.
24.
Cooper JA, Rohan TE, Cant EL, Horsfall DJ, Tilley WD. Risk factors for breast cancer by oestrogen receptor status.  Br J Cancer.1989;59:119-125.
25.
Harding C, Knox WF, Faragher EB, Baildam A, Bundred NJ. Hormone replacement therapy and tumor grade in breast cancer.  BMJ.1996;312:1646-1647.
26.
Lesser ML, Rosen PP, Senie RT, Duthie K, Menendez-Botet C, Schwartz MK. Estrogen and progesterone receptors in breast carcinoma.  Cancer.1981;48:299-309.
27.
Magnusson C, Holmberg L, Norden T, Lindgren A, Persson I. Prognostic characteristics in breast cancers after hormone replacement therapy.  Breast Cancer Res Treat.1996;38:325-334.
28.
Bonnier P, Romain S, Gacalone PL, Laffargue F, Martin PM, Piana L. Clinical and biological prognostic factors in breast cancer diagnosed during postmenopausal hormone replacement therapy.  Breast Cancer Ther.1995;85:11-17.
29.
Stanford J, Szklo M, Boring CC.  et al.  A case-control study of breast cancer stratified by estrogen receptor status.  Am J Epidemiol.1987;125:184-194.
30.
Hulka BS, Chambless LE, Wilkinson WE.  et al.  Hormonal and personal effects on estrogen receptors in breast cancer.  Am J Epidemiol.1984;119:692-704.
31.
O'Reilly SM, Camplejohn RS, Barnes DM, Millis RR, Rubens RD, Richards MA. Node-negative breast cancer.  J Clin Oncol.1990;8:2040-2046.
32.
Harvey SC, DiPiro PJ, Meyer JE. Marked regression of a nonpalpable breast cancer after cessation of hormone replacement therapy.  Am J Radiol.1996;167:394-395.
33.
Dhodapkar MV, Ingle JN, Ahmann DL. Estrogen replacement therapy withdrawal and regression of metastatic breast cancer.  Cancer.1995;75:43-46.
Brief Report
April 28, 1999

Hormone Replacement Therapy and High S Phase in Breast Cancer

Author Affiliations

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.

JAMA. 1999;281(16):1528-1530. doi:10.1001/jama.281.16.1528
Context

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.

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 χ2 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.

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).

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).

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.617 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.19,2330 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

References
1.
Collaborative Group on Hormonal Factors in Breast Cancer.  Breast cancer and hormone replacement therapy.  Lancet.1997;350:1047-1059.
2.
Cobleigh MA. Hormone replacement therapy and nonhormonal control of menopausal symptoms in breast cancer survivors.  Cancer Treat Res.1998;94:210-230.
3.
Hosmer DW, Lemeshow S. Applied Logistic Regression. New York, NY: John Wiley & Sons Inc; 1989.
4.
Lippman M, Bolan G, Huff K. The effects of estrogens and antiestrogens on hormone-responsive human breast cancer in long-term tissue culture.  Cancer Res.1976;36:4595-4601.
5.
Fuqua SAW. Estrogen and progesterone receptors and breast cancer. In: Harris JR, Lippman ME, Morrow M, Hellman S, eds. Diseases of the Breast. Philadelphia, Pa: Lippincott-Raven; 1996:262-263.
6.
O'Reilly SM, Camplejohn RS, Barnes DM, Millis RR, Rubens RD, Richards MA. Node-negative breast cancer.  J Clin Oncol.1990;8:2040-2046.
7.
Sigurdsson H, Baldetrop B, Borg A.  et al.  Indicators of prognosis in node-negative breast cancer.  N Engl J Med.1990;322:1045-1053.
8.
Stal O, Dufmats M, Hatschek T.  et al.  S-phase fraction is a prognostic factor in stage I breast carcinoma.  J Clin Oncol.1993;11:1717-1722.
9.
Winchester DJ, Duda RB, August CZ.  et al.  The importance of DNA flow cytometry in node-negative breast cancer.  Arch Surg.1990;125:886-889.
10.
Clark GM, Dressler LG, Owens MA, Pounds G, Oldaker T, McGuire W. Prediction of relapse or survival in patients with node-negative breast cancer by DNA flow cytometry.  N Engl J Med.1989;320:627-633.
11.
Balslev I, Christensen IJ, Rasmussen BB, Larsen JK, Lykkesfeldt AE, Thorpe SM. Flow cytometric DNA ploidy defines patients with poor prognosis in node-negative breast cancer.  Int J Cancer.1994;56:16-25.
12.
Toikkanen S, Joensuu H, Klemi P. The prognostic significance of nuclear DNA content in invasive breast cancer.  Br J Cancer.1989;60:693-700.
13.
Witzig TE, Ingle JN, Cha SS.  et al.  DNA ploidy and the percentage of cells in S-phase as prognostic factors for women with lymph node negative breast cancer.  Cancer.1994;74:1752-1761.
14.
Muss HB, Kute TE, Case D.  et al.  The relation of flow cytometry to clinical and biologic characteristics in women with node negative primary breast cancer.  Cancer.1989;64:1894-1900.
15.
Ewers SB, Atewell R, Baldetorp B.  et al.  Prognostic significance of flow cytometric DNA analysis and estrogen receptor content in breast carcinomas.  Breast Cancer Res Treat.1993;24:115-126.
16.
Merkel DE, Winchester DJ, Goldschmidt RA.  et al.  DNA flow cytometry and pathologic grading as prognostic guides in axillary lymph node-negative breast cancer.  Cancer.1993;72:1926-1932.
17.
Bosari S, Lee AK, Tahan SR.  et al.  DNA flow cytometric analysis and prognosis of axillary lymph node-negative breast carcinoma.  Cancer.1992;70:1943-1950.
18.
Wenger CR, Beardslee S, Owens MA.  et al.  DNA ploidy, S-phase, and steroid receptors in more than 127,000 breast cancer patients.  Breast Cancer Res Treat.1993;28:9-20.
19.
Squitieri R, Tartter PI, Ahmed S, Brower ST, Theise ND. Carcinoma of the breast in postmenopausal hormone user and nonuser control groups.  J Am Coll Surg.1994;178:167-170.
20.
Holli K, Isola J, Cuzick J. Low biologic aggressiveness in breast cancer in women using hormone replacement therapy.  J Clin Oncol.1998;16:3115-3120.
21.
Jones C, Ingram D, Mattes E, Hahnel R. The effect of hormone replacement therapy on prognostic indices in women with breast cancer.  Med J Aust.1994;161:106-110.
22.
Hildreth NG, Kelsey JL, Eisenfeld AJ.  et al.  Differences in breast cancer risk factors according to the estrogen receptor level of the tumor.  J Natl Cancer Inst.1983;70:1027-1031.
23.
Colditz GA, Stampfer MJ, Willett WC.  et al.  Prospective study of estrogen replacement therapy and risk of breast cancer in postmenopausal women.  JAMA.1990;264:2648-2653.
24.
Cooper JA, Rohan TE, Cant EL, Horsfall DJ, Tilley WD. Risk factors for breast cancer by oestrogen receptor status.  Br J Cancer.1989;59:119-125.
25.
Harding C, Knox WF, Faragher EB, Baildam A, Bundred NJ. Hormone replacement therapy and tumor grade in breast cancer.  BMJ.1996;312:1646-1647.
26.
Lesser ML, Rosen PP, Senie RT, Duthie K, Menendez-Botet C, Schwartz MK. Estrogen and progesterone receptors in breast carcinoma.  Cancer.1981;48:299-309.
27.
Magnusson C, Holmberg L, Norden T, Lindgren A, Persson I. Prognostic characteristics in breast cancers after hormone replacement therapy.  Breast Cancer Res Treat.1996;38:325-334.
28.
Bonnier P, Romain S, Gacalone PL, Laffargue F, Martin PM, Piana L. Clinical and biological prognostic factors in breast cancer diagnosed during postmenopausal hormone replacement therapy.  Breast Cancer Ther.1995;85:11-17.
29.
Stanford J, Szklo M, Boring CC.  et al.  A case-control study of breast cancer stratified by estrogen receptor status.  Am J Epidemiol.1987;125:184-194.
30.
Hulka BS, Chambless LE, Wilkinson WE.  et al.  Hormonal and personal effects on estrogen receptors in breast cancer.  Am J Epidemiol.1984;119:692-704.
31.
O'Reilly SM, Camplejohn RS, Barnes DM, Millis RR, Rubens RD, Richards MA. Node-negative breast cancer.  J Clin Oncol.1990;8:2040-2046.
32.
Harvey SC, DiPiro PJ, Meyer JE. Marked regression of a nonpalpable breast cancer after cessation of hormone replacement therapy.  Am J Radiol.1996;167:394-395.
33.
Dhodapkar MV, Ingle JN, Ahmann DL. Estrogen replacement therapy withdrawal and regression of metastatic breast cancer.  Cancer.1995;75:43-46.
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