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Prognostic Characteristics of Breast Cancer Among Postmenopausal Hormone Users in a Screened Population

Karla Kerlikowske, Diana L. Miglioretti, Rachel Ballard-Barbash, Donald L. Weaver, Diana S.M. Buist, William E. Barlow, Gary Cutter, Berta M. Geller, Bonnie Yankaskas, Stephen H. Taplin, Patricia A. Carney

From the Department of Epidemiology and Biostatistics, and the General Internal Medicine Section, Department of Veterans Affairs, University of California, San Francisco, CA; Center for Health Studies, Group Health Cooperative; Department of Biostatistics, University of Washington, Seattle, WA; Applied Research Program, DCCPS, National Cancer Institute, Bethesda, MD; Department of Pathology, and Health Promotion Research, University of Vermont, College of Medicine, Burlington, VT; Center for Research Design and Statistical Methods, University of Nevada School of Medicine, Applied Research Facility, Reno, NV; Department of Radiology, University of North Carolina, Chapel Hill, NC; Norris Cotton Cancer Center/Dartmouth-Hitchcock Medical Center/Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, NH.

Address reprint requests to Karla Kerlikowske, MD, San Francisco Veterans Affairs Medical Center, General Internal Medicine Section, 111A1, 4150 Clement St, San Francisco, CA 94121; e-mail: kerliko{at}itsa.ucsf.edu.

	ABSTRACT

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Purpose: We determined the risk of breast cancer and tumor characteristics among current postmenopausal hormone therapy users compared with nonusers, by duration of use.

Methods: From January 1996 to December 2000, data were collected prospectively on 374,465 postmenopausal women aged 50 to 79 years who underwent screening mammography. We calculated the relative risk (RR) of breast cancer (invasive or ductal carcinoma-in-situ) and type of breast cancer within 12 months of postmenopausal therapy use among current hormone users with a uterus (proxy for estrogen and progestin use) and without a uterus (proxy for estrogen use), compared with nonusers.

Results: Compared with nonusers, women using estrogen and progestin for 5 years were at increased risk of breast tumors of stage 0 or I (RR, 1.51; 95% CI, 1.37 to 1.66), stage II or higher (RR, 1.46; 95% CI, 1.30 to 1.63), size 20 mm (RR, 1.59; 95% CI, 1.43 to 1.76), size greater than 20 mm (RR, 1.24; 95% CI, 1.09 to 1.42), grade 1 or 2 (RR, 1.60; 95% CI, 1.44 to 1.77), grade 3 or 4 (RR, 1.54; 95% CI, 1.37 to 1.73), and estrogen receptor-positive (RR, 1.72; 95% CI, 1.55 to 1.90). Estrogen-only users were slightly more likely to have estrogen receptor-positive breast cancer compared with nonusers (RR, 1.14; 95% CI, 1.06 to 1.23).

Conclusion: Use of estrogen and progestin postmenopausal hormone therapy for five years or more increased the likelihood of developing breast cancer, including both tumors with favorable prognostic features and tumors with unfavorable prognostic features.

	INTRODUCTION

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POSTMENOPAUSAL HORMONE therapy (HT) has been associated with increased risk of breast cancer.^1–3 Estrogen plus progestin regimens may be associated with a greater risk of breast cancer than estrogen-only regimens^4–6; however, results are not consistent or conclusive across studies.^2,4–7 It is also unclear whether HT results in an increased risk of breast cancer with a favorable prognosis (low stage and grade), less favorable prognosis (high stage and grade), or both.

Several observational studies have reported that HT users have smaller^8–13 and lower-grade tumors,^{10,12,14–17} while others have not shown any influence of HT on tumor size^{14,15,18–23} or grade.^{9,13,18,21,23} Three studies have reported that HT users are more likely to have estrogen receptor- (ER-) positive tumors.^4,9,24 Several others have reported no association with HT use and ER status.^{8,10–15,18–20,23} The inconsistent results across studies may be because many include a small number of women who had been receiving HT when diagnosed with breast cancer (n = 29 to n = 263).^{4,8,10–21,23} In addition, many of the studies did not adequately account for breast cancer surveillance by screening mammography,^{4,8–12,15,16,18–20,23} which could result in earlier detection and fewer advanced cancers in HT users. Lastly, the studies had no information or very limited information on tumor characteristics associated with type of HT regimen or duration of use, which may influence tumor features.^4,5,8–24

The Women’s Health Initiative randomized controlled trial showed that women taking a continuous estrogen and progestin regimen for more than 4 years had an increased risk of breast cancer.³ A greater proportion of women on estrogen and progestin regimens were diagnosed with regional disease (Surveillance, Epidemiology and End Results [SEER] program staging system), compared with those using placebo.²⁵ Determining whether HT has clinically important influences on breast cancer stage or aggressiveness and cancer detection rates by mammography in a large, community-based population may contribute to a woman’s decision to start HT, or to take HT for long periods.

We evaluated the influence of HT on breast cancer risk by pooling data from six mammography registries where current HT use, history of hysterectomy, and time between mammography examinations is prospectively recorded. We inferred that history of hysterectomy is a proxy for type of HT use based on clinical practice guidelines for HT that have been in place for more than 10 years, and recommend estrogen and progestin for women with a uterus, and estrogen only for women without a uterus. We report the relative risk (RR) of breast cancer by tumor characteristics and cancer detection rates by mammography among HT users with and without a uterus by duration of use, compared with non-HT users.

	METHODS

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Data Sources
Data were pooled from six mammography registries that participate in the Breast Cancer Surveillance Consortium²⁶ (http://breastscreening.cancer.gov) funded by the National Cancer Institute: (1) San Francisco Mammography Registry, San Francisco, CA; (2) Group Health Cooperative, Seattle, WA; (3) Colorado Mammography Advocacy Project, Denver, CO; (4) Vermont Breast Cancer Surveillance System, Burlington, VT; (5) New Hampshire Mammography Network, Lebanon, NH; and (6) Carolina Mammography Registry, Chapel Hill, NC. These registries collect information on screening and diagnostic mammography examinations performed in their defined catchment area. Each mammography registry links women in their registry to a state tumor registry or regional SEER program that collects population-based cancer data. Some registries additionally link to pathology databases. Each registry obtains annual approval from their institutional review board to collect registry information. Linkage procedures are performed following human subjects protocols to maintain participant confidentiality.

Subjects
Our study included postmenopausal women aged 50 to 79 years who underwent bilateral mammography examination indicated by the radiologist as being performed for screening, between January 1996 and December 2000. Women entered the study at the time of their screening examination and were observed for 1 year, or until the next screening examination, to determine if breast cancer was diagnosed. A woman may have had more than one mammography examination during the study period, and thus, may have entered the study more than once (n = 192,511). Breast cancer was not uniformly detected during the follow-up period; rather, detection was highest immediately following a screening examination. Therefore, all analyses were performed per mammography examination rather than per person-year of follow-up. Screening examinations that occurred after December 2000 were excluded to ensure at least 12 months for reporting cancers to tumor registries after screening examinations.

Women 55 years and older were assumed to be postmenopausal. Women aged 50 to 54 years were considered to be postmenopausal if both ovaries had been removed, if they reported that their periods had stopped permanently, or if they were taking HT. Premenopausal women aged 50 to 54 years having regular menstrual periods with no HT use were excluded (66,132; 6%). We also excluded women who self-reported breast augmentation (<1%) or prior diagnosis of breast cancer (3%), and women for whom time between mammography examinations (4%), family history of breast cancer (8%), or current HT use (17%) was missing.

Measurements and Definitions
For each woman, demographic information and a self-reported breast health history were obtained at the time of each screening examination by completing a survey. The survey includes questions about menopausal status, family history of breast cancer in a first-degree relative, current HT use, history of hysterectomy, and time between mammography examinations. Women were considered to have a family history of breast cancer if they reported having at least one first-degree relative (mother, sister, or daughter) with breast cancer. Women were considered to be "current HT users" if they reported using prescription HT at a screening examination. Three registries collect information on duration of use, which was categorized as less than 5 and 5 years of use. Two registries collect detailed self-report information on type of HT regimen for women who self-reported "current HT use." Of women who reported current HT use and no history of hysterectomy, 80.4% reported taking estrogen and progestin, 17.8% reported estrogen only, and 1.8% reported progestin only. Of those who reported current HT use and history of hysterectomy, 87.3% reported taking estrogen only, 12.0% reported estrogen and progestin, and 0.7% reported progestin only. Thus, women with a uterus who were using HT were considered to be using estrogen plus progestin, whereas women without a uterus using HT were considered to be using estrogen only.

Time between mammography examinations was determined using dates of prior mammography examinations recorded in each mammography registry, or self-reported information collected at the screening examination. We used self-reported data, rather than dates of prior mammography examinations recorded in a registry, to calculate time between mammography examinations for 6.7% of nonusers, 3.5% of HT users without a uterus, and 9.3% of HT users with a uterus.

Women were considered to have breast cancer if reports from a breast pathology database, SEER program, or state tumor registry showed any invasive carcinoma or ductal carcinoma in situ (DCIS) through December 2001. Women with lobular carcinoma-in-situ only were not considered to have cancer. All breast cancers were classified according to the American Joint Committee on Cancer staging system.²⁷ Invasive cancers were categorized by tumor size, grade, and ER status. The few women (n = 55) with grade 4 tumors (undifferentiated or anaplastic) were included with the group of women with grade 3 tumors (poorly differentiated).

Statistical Analysis
We stratified the data into three groups based on self-reported current HT use and history of hysterectomy: (1) no HT use with or without a uterus, (2) HT use and no uterus (proxy for estrogen only), and (3) HT use and uterus (proxy for estrogen and progestin use). Frequency distributions of various risk factors were determined for women in these three groups. Rates and RRs were calculated using Poisson regression, adjusting for age as a continuous variable, family history of breast cancer, examination year, time between mammography examinations, and mammography registry. We standardized the rates by taking a weighted average of the rates estimated from the Poisson regression model for each covariate configuration, weighting by the proportion of women in the study with that covariate configuration. Thus, the same weights were used for nonusers, estrogen and progestin users, and estrogen-only users, resulting in an adjustment to the same population. Adjusted distributions were standardized to the study population using logistic regression for ER status, and polytomous regression for other tumor characteristics. We also adjusted all analyses for race. Since the results were similar, and to minimize the number of women excluded from analyses due to missing values, we did not adjust for race in the final analyses.

Rates of breast cancer (invasive cancer or DCIS diagnosed within 12 months of a screening examination and HT use) and 95% CIs were calculated per 1000 examinations for the three groups and by decade of age. Adjusted rates and distributions were calculated for stage (0, I, II, and III and IV combined), tumor size (invasive cancer 10 mm, 11 to 20 mm, and > 20 mm), tumor grade (1, 2, and 3 and 4 combined), and ER status (positive and negative).

We calculated RRs comparing those taking estrogen and progestin and those on estrogen only, with to non-HT users by duration of treatment. We also calculated RRs comparing the risk of tumor characteristics in estrogen and progestin users and estrogen-only users, with that of nonusers. We compared the risk of each more favorable tumor feature (stage 0 or I, size 20 mm, grade 1 or 2, ER-positive) and each less favorable tumor feature (stage II or higher, size > 20 mm, grade 3 or 4, ER-negative). We dichotomized tumor size at 20 mm and stage at 0 or I since both parameters are considered early stage disease. To evaluate the impact of study parameters on our findings, two sensitivity analyses were performed using the same Poisson regression models described above: 1) for a subset of women whose time between screens ranged from 9 to 18 months with a median of 13 months, and 2) including all breast cancers occurring within 24 months of a screening examination.

We calculated the true-positive and false-negative rates per 1000 examinations for the three study groups. Adjusted rates were calculated using the same method as described above. We used simulation to estimate the 95% confidence intervals, sampling 100,000 values of the regression coefficients from their joint multivariate normal distribution and calculating the rates for each sample. We estimated upper and lower limits by the simulated 2.5 and 97.5 percentiles. A screening examination was considered a false-negative examination if breast cancer was diagnosed within 12 months of a negative examination (BI-RADS [American College of Radiology, Philadelphia, PA] assessment of 1, 2, or 3 when associated with short-interval follow-up only or routine follow-up). A screening examination was considered a true-positive examination if breast cancer was diagnosed within 12 months of a positive examination (BI-RADS assessment of 0, 4, 5, or 3 when associated with a recommendation for immediate follow-up).

	RESULTS

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A total of 373,265 postmenopausal women underwent 683,435 screening mammography examinations between January 1996 and December 2000, of whom 3,202 developed breast cancer (2,619 invasive and 583 DCIS) within 12 months of an examination.

HT users were more likely to be younger, white, have had a previous breast biopsy or surgery, and shorter time period between mammography examinations and less likely to have a family history of breast cancer (Table 1).

View larger version (15K): [in this window] [in a new window]   Fig 1. White bars indicate a false-negative rate; vertical striped bars indicate a false-negative rate associated with stage II, III, or IV disease; solid bars indicate a true-positive rate; and vertical striped bars indicate a true-positive rate associated with stage II, III, or IV disease. HT, hormone therapy.

	DISCUSSION

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We determined the risk of breast cancer and compared the tumor characteristics among current HT users with those of nonusers undergoing screening mammography. The likelihood of being diagnosed with breast cancer was increased 46% among current estrogen and progestin users who had used HT for 5 years compared with nonusers, but not among estrogen and progestin users who had used HT for less than 5 years, or estrogen only users irrespective of duration of use. This supports previous evidence demonstrating an increased risk of breast cancer among postmenopausal women who use estrogen and progestin hormone therapies for a long duration.^3–6,25 The risk of breast cancer was increased both for tumors with favorable and unfavorable prognostic characteristics with the excess risk somewhat greater for early-stage, small, low-grade, ER-positive tumors than for tumors with a higher stage and grade. Estrogen-only users were slightly more likely to have ER-positive breast cancer compared with nonusers, but overall risk of breast cancer was not increased compared with nonusers.

Current HT use has been reported to increase a woman’s RR of breast cancer by 2% to 3% per year.^2,5–7 Some studies have reported that estrogen plus progestin regimens may be associated with a greater risk of breast cancer than estrogen-only regimens,^4–6,28 while other studies report that the increased risk with estrogen is similar to estrogen plus progestin.^2,7 It has been reported that HT users tend to have more in situ or localized tumors at detection, possibly because of earlier detection by mammography.^2,29 On the other hand, studies have reported that the extent of disease among HT users is the same as non-HT users³⁰ or possibly greater, with more stage II or higher disease cases, and high S phase fraction tumors.^19,20 Also, it has been reported among current or recent users of HT that increased duration of use may increase the risk of disease spread.² In the largest study to date with 3,202 breast cancer cases, we have shown that after taking into account factors that enhance the chance of detecting a tumor with good prognostic features, such as older age³¹ and routine screening, women using estrogen and progestin for 5 years are at increased risk of early stage tumors with a more favorable prognosis. Importantly, we also found that women using estrogen and progestin are at increased risk of tumors, with a less favorable prognosis consistent with the Women’s Health Initiative randomized controlled trial results.²⁵

One explanation of why HT users have tumors with more favorable prognosis is that current or recent use of HT promotes growth of pre-existing, clinically latent, hormone-dependent cancers of low malignant potential, that may not otherwise become clinically apparent. In support of this hypothesis are the findings reported by Beral et al² that risk of breast cancer decreases as time since last HT use increases, such that past users who have not had HT in more than 5 years are not at increased risk of breast cancer, regardless of prior duration of use. In addition, recent oral contraceptive use has been associated with increased detection of localized tumors that does not persist 10 years or more after cessation of use.³² Other evidence in support of current or recent HT use acting as a cancer promoter are the findings that well-differentiated invasive tumors with favorable histology (papillary, tubular, mucinous, medullary) have been reported to be more prevalent among HT users than nonusers,³³ and that HT users are diagnosed at a younger age compared with nonusers.¹⁵ Our findings that estrogen and progestin users were younger at diagnosis and more likely to have ER-positive tumors of smaller size and lower grade compared with nonusers supports the hypothesis that HT promotes growth of preexisting clinically latent cancers.

Why would women taking HT undergoing routine screening mammography be at increased risk of breast cancer with less favorable prognostic characteristics? Taking HT for more than a year has been shown to increase mammographic breast density in approximately 16% to 20% of women,^34,35 with greater increases in mammographic density associated with estrogen and progestin than with estrogen alone.^34,36,37 Increased mammographic density among women taking HT has been associated with decreases in the sensitivity and specificity of mammography^38–40 and increases in the minimal detectable size of tumor.⁴¹ Consistent with these reports, we found that women using estrogen and progestin for 5 years have a higher rate of false-negative examination results, and that these false-negative examination results are associated with a higher rate of stage II or higher disease as compared with nonusers. Thus, the increase in less favorable tumors among long-term estrogen and progestin users may be due, in part, to tumors obscured by mammographically dense breasts, that progress between screening examinations. The higher rate of true-positive examination results associated with stage II or higher disease in long-term estrogen and progestin users as compared with nonusers, suggests that estrogen and progestin also may act synergistically to promote tumorigenesis and more rapid tumor growth than estrogen alone.^42,43

Most studies have found no significant differences in the ER profiles of breast cancer in HT users and nonusers.^{8,10–15,18–20,23,25} One small study reported current HT users are more likely to be diagnosed with ER positive tumors.⁹ Another study reported that only long-term HT use of 57 months or more is associated with having an ER-positive tumor,⁴ while one study reported that estrogen and progestin use is associated with having an ER-positive tumor, but that estrogen therapy is not.²⁴ Given that estrogen causes proliferation of ER-positive breast cells in vitro and in vivo,^44,45 it is not surprising that we found that women using estrogen and progestin and estrogen only were more likely to be diagnosed with an ER-positive tumor. We evaluated a large sample of women recently diagnosed with breast cancer from 1996 to 2001. During that period, ER status would have been measured with current, new immunohistochemical assays that minimize misclassification. Our large sample size and recent period of evaluation with improved ER detection methods could account, in part, for our ability to detect a difference in ER status among HT users and nonusers.

We studied a large number of women with breast cancer with extensive information on tumor characteristics for these women. Our ability to control for screening interval (surveillance bias) is another strength of this study. The accuracy of our data depends on completeness of cancer reporting to the SEER program, state tumor registries, and pathology laboratories at the mammography registries, which has been estimated to be more than 94.3% complete.⁴⁶ In addition, the cancer rates reported are within the range of those reported in the literature, for which follow-up has been reported to be 99.6%.^47,48 Tumor size, stage, grade, and ER status were missing for between 12% to 33% of tumors, due in part to a change in coding of tumor size and stage by SEER programs between July 1998 and 1999, which resulted in some invasive cancers with an in situ component to be coded with an unknown size. We are not aware of a tumor-reporting bias to cancer registries related to HT status or history of hysterectomy. Our finding of similar proportions of missing tumor characteristic parameters among the three study groups does not support a tumor-reporting bias. We inferred that women on HT with a uterus were taking estrogen and progestin, and that women without a uterus were taking estrogen only, as consistent with recommended clinical guidelines⁴⁹ and detailed information from a subset of mammography registries in this study. Any misclassification according to type of regimen would make it more difficult to find an association between HT use and tumor characteristics and, thus may have attenuated our findings. In addition, our finding of enhanced risk of breast cancer among estrogen and progestin users compared to estrogen only users is consistent with other reports.^4–6 We collected information on HT use at the time of mammography, lessening the possibility of recall bias. Information on hormone use was self-reported, perhaps leading to some misclassification, but this is likely to have been random and to lead to an underestimation of the association between HT use and tumor characteristics. We were not able to determine if tumor characteristics vary by dose or specific HT regimens.

Millions of women either consider using or begin HT in the United States each year. Although most use HT for short-term symptom management, some women may choose to stay on HT for longer periods. Postmenopausal women with a uterus who are considering whether to take or stay on HT should be informed that: (1) using estrogen and progestin HT for 5 years increases the likelihood of developing breast cancer; (2) estrogen and progestin and estrogen-only hormone therapies increase the risk of an ER-positive tumor with a higher risk associated with combination HT regimens; and (3) cancers associated with estrogen and progestin hormone therapies include both tumors with favorable prognostic features and unfavorable prognostic features.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	NOTES

 
This work was supported by a National Cancer Institute–funded Breast Cancer Surveillance Consortium cooperative agreement (U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040).

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Submitted May 21, 2003; accepted September 8, 2003.

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