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10.1245/s10434-006-9129-2
Annals of Surgical Oncology 14:695-703 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Type and Duration of Exogenous Hormone Use A3ects Breast Cancer Histology

Anjali S. Kumar, MD, MPH1,2,3, Elizabeth Cureton, MD1,2, Veronica Shim, MD1, Theadora Sakata3, Dan H. Moore, PhD4, Christopher C. Benz, MD5,6, Laura J. Esserman, MD, MBA3 and E. Shelley Hwang, MD, MPH3

1 Department of Surgery, Kaiser Permanente Oakland Medical Center, Oakland, California 94602, USA
2 Department of Surgery, University of California San Francisco—East Bay, Oakland, California 94602, USA
3 Department of Surgery, University of California San Francisco, Comprehensive Cancer Center, San Francisco, California 94143, USA
4 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA
5 Department of Medicine, Division of Hematology and Oncology, University of California San Francisco, San Francisco, California, USA
6 Buck Institute for Age Research, Novato, California 94945, USA

Correspondence: Address correspondence and reprint requests to: E. Shelley Hwang, MD, MPH, E-mail: shelley.hwang{at}ucsfmedctr.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: It is unclear whether hormone replacement therapy (HRT), in addition to increasing risk for breast cancer, affects the type of breast cancer diagnosed. We conducted this investigation to assess whether the type of hormone used (none, estrogen, progesterone, or combined) and duration of use influences subsequent breast cancer histology.

Methods: We performed a retrospective cohort analysis among women listed as incident cases of breast malignancy in the Kaiser Permanente Northern California Cancer Registry during 2003 (n = 2830). Type and duration of hormone used (none, estrogen, progesterone, or combined) before breast cancer diagnosis was obtained from electronic pharmacy records. The association between type and duration of hormone use with characteristics of subsequent breast cancers was examined.

Results: Among women aged >50 years (n = 1701), any use of estrogen, progesterone, or combination therapy was not associated with an increased risk of estrogen receptor (ER)-positive disease. However, >6 months’ use of combined HRT increased the odds of ER-positive tumors (odds ratio, 1.65; 95% confidence interval, 1.07–2.5; P = .02). Estrogen HRT patients were more likely than nonusers to present with low-grade (P = .05), and early-stage tumors (P = .03). This trend was not seen in combined HRT users.

Conclusions: Short-duration HRT did not increase the likelihood of ER-positive breast cancer. However, prolonged duration of combined HRT, but not estrogen or progesterone alone, resulted in a marked increase in ER-positive disease. Our findings suggest that the effect of combined HRT on breast cancer incidence or progression is not immediate and that long-term use is more likely to affect breast cancer histology.

Key Words: Breast cancer • Hormone replacement therapy • Estrogen receptor


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Although in vitro studies, in vivo animal studies, and epidemiologic data support the essential role of estrogens in breast cancer etiology, the role of exogenous hormone use in promoting breast carcinogenesis remains unclear. Prospective randomized studies show that exogenous estrogen alone does not increase breast cancer risk, whereas the use of combined estrogen and progesterone seems to greatly increase this risk.1–3 However, it is controversial whether antecedent hormone replacement therapy (HRT) influences the histological type (e.g., lobular vs. ductal) or hormone receptor status (estrogen receptor, ER; progesterone receptor, PR) of newly diagnosed breast cancers, and if there are different associations between single-agent HRT (estrogen HRT or pro-gesterone HRT) and combined estrogen-progesterone HRT (combined HRT).

Some studies indicate that patients with breast cancer who had used exogenous hormone before their diagnosis have smaller, lower-grade primary tumors than those who had not.4,5 This difference is speculated to relate to the hormone receptor status of these cancers. There are well-established clinical and pathologic distinctions between receptor-positive (ER-positive and/or PR-positive) breast cancers and receptor-negative breast cancers, yet these phenotypically different breast cancer types are not clearly associated with distinct epidemiological risk factor profiles.6,7

Several studies have examined the relationship between exogenous hormone use and breast cancer hormone receptor status (Table 1Go); and although most published case-control and cohort studies fail to show a relationship between either HRT or combined HRT and the selective development of receptor-positive breast cancer, three studies do report a marked relationship between use of HRT and development of receptor-positive breast cancer.8–10


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  		TABLE 1. Studies investigating the effect of hormone replacement therapy (HRT) type and categorization of use on breast cancer risk and receptor status
 
In contrast, the Women’s Health Initiative (WHI) Randomized Trial showed that invasive breast cancers associated with estrogen plus progestin use were larger, more likely to be node positive, and were diagnosed at a far more advanced stage.11 Although the number of incident cancers studied was small (n = 430), the WHI study found no difference between tumor grade, histologic type (ductal vs. lobular) or receptor status (ER and PR) between HRT and placebo groups.

To investigate the factors resulting in these discrepant analyses, we conducted a detailed retrospective cohort study of patients diagnosed with incident breast cancer at a large health maintenance organization that provided direct links to pharmacy and centralized pathology data. We hypothesized that the type of hormone used—estrogen, progesterone, or combined—and duration of use does infact influence estrogen and progesterone receptor status, degree of ER staining, tumor grade, and stage at diagnosis.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
After institutional review board approval was obtained, the Kaiser Permanente of Northern California (KPNC) Cancer Registry provided the investigators with a consecutive list of women diagnosed with ductal carcinoma in situ and primary breast cancer from January 1, 2003, to December 31, 2003, for whom ER and PR receptor status was known. Because our goal was to capture pharmacy data for a minimum of 18 months on this patient cohort, those patients who joined KPNC after June 2001 were excluded. The electronic chart was reviewed for each of the included subjects (n = 2126).

HRT Use
We recorded the type of prescribed HRT from electronic pharmacy logs. Because single formulations of combination estrogen and progesterone (i.e., Prempro—conjugated estrogens plus medroxyprogesterone acetate) are not carried in the KPNC formulary, patients classified as taking combination regimens were simultaneously prescribed separate, single preparations of estrogen and progesterone. We further defined combination therapy HRT patients as those whose estrogen tablet total and progesterone tablet total differed by ≤100 tablets.

All HRT tablets were prescribed for one tablet to be taken each day; therefore, duration and compliance were reflected in the number of pills dispensed. From these data, we generated a duration index by categorizing the number of tablets dispensed into four groups: (1) never—when no tablets were dispensed; (2) <6 months—when tablet count was <182.5; (3) 6 months to 5 years—when tablet count was from 182.5 to 1825, and (4) >5 years—when tablet count was 1826 or more. To confirm HRT use before breast cancer diagnosis, we correlated earliest prescription dates with pathology specimen dates. Because the electronic pharmacy record only lists prescriptions filled, and because patients in the KPNC system rarely obtain prescription medications outside of the KPNC system, we considered prescriptions that were consistently refilled over time to be a marker of compliance.

Tumor Type
final determination is dependent on the subjective measurement by the pathologist, all tumor specimens from KPNC are read, and often double-read, by a team of five pathologists at a single pathology laboratory (Kaiser San Francisco).

Tumor grade was determined by the pathologist on the basis of histologic features and was coded in the KPNC Cancer Registry as the highest grade present: I (low grade), II (moderate grade), and III (high grade). Tumor stage in the KPNC cancer registry is recorded according to the Surveillance, Epidemiology, and End Results (SEER) guidelines: IS (in situ carcinoma), LOC (localized malignancy), REG (regional malignancy—lymph node metastases), DIS (distant metastases).

Potential Confounders
Age stratification was used to assign menopausal categories on the basis of national averages and previously published reports: premenopausal (<50 years old) and postmenopausal ( ≥50 years old). Within the KPNC Registry, data were not available for family history, body mass index, smoking, alcohol use, or other comorbidities. Previous studies have established that older age is a statistically significant predictor of ER-positive tumors; therefore, all odds ratios (ORs) generated were adjusted for age, with age treated as a continuous variable.

Statistical Analyses
Summary statistics for continuous variables include mean, standard deviation, median, and minimum and maximum values; categorical variables are presented as counts and percentages. Standard baseline characteristics are summarized for each group. For continuous variables, means were compared by analysis of variance. Logistic regression was used to estimate the effects of predictor variables (age and exogenous hormone use) on dichotomous outcome variables (estrogen and progesterone receptor status). We used linear regression to analyze percentage of ER staining by estrogen duration. Categorical outcome variables were compared by the {chi}2 test for contingency tables; significance was set at P < .05. STATA version 9 (College Station, TX) was used to perform all analyses and to prepare all tables and figures.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient age at the time of primary breast tumor diagnosis ranged from 15.3 to 95.7 years (mean ± SD, 61.8 ± 12.9 years). There was a near-even distribution of those receiving any HRT versus those not (1128 vs. 998). As expected, women receiving any HRT were significantly older than those not receiving HRT (63.9 vs. 59.9 years; P < .0001); only 56 women <50 were receiving HRT, whereas 942 women aged ≥50 were receiving HRT. Among the 942 patients with breast cancer ≥50 years of age receiving any HRT, 16.6% were prescribed estrogen only, 2.2% were prescribed progesterone only, and 36.6% were prescribed any combination of estrogen and progesterone (any estrogen HRT and any pro-gesterone HRT). Median duration of estrogen and progesterone use was 2.2 and 1.5 years, respectively. Although 622 women (66%) aged ≥ 50 who were prescribed HRT received some combination of estrogen and progesterone, only 302 women (33%) received combined HRT, defined as comparable use of both estrogen and progesterone (within 100 tablets) (Fig. 1Go).


Figure 1
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  		FIG. 1. Scatterplots of estrogen hormone replacement therapy (HRT) vs. progesterone HRT in women aged ≥ 50 years demonstrating data of 302 patients who received comparable amounts of estrogen (dark gray) and progesterone (light gray). *Median estrogen and progesterone use.

 
Breast Tumor Receptor Status
As expected, older patient age was significantly associated with ER-positive breast cancers (P < .001), with the odds of developing an ER-positive tumor increasing by 2% per year (OR, 1.02; 95% confidence interval [CI], 1.01–1.04). The odds of developing a PR-positive tumor increased by 5% per year (P = .01) for patients between ages 15 and 50 years, and only increased by 1.3% per year for patients ≥50 years (P = .008), but when these age groups were not dichotomized, the relationship between PR-positive breast cancer and patient age was not statistically significant (P = .18).

Relative to the reference set of patients who never took HRT (OR, 1.0), those with previous use of any HRT had no marked association with tumor ER or PR status when duration of use was not accounted for (Tables 2Go and 3Go). Only 38 women aged ≥ 50 had progesterone exposure alone; however, they had a decreased risk of developing PR-positive tumors.


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  		TABLE 2. Type of hormone replacement therapy (HRT) and receptor status in women aged <50 years at diagnosis (n = 425)
 

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  		TABLE 3. Type of hormone replacement therapy (HRT) and receptor status in women aged ≥ 50 years at diagnosis (n = 1701)
 
A small group of women had brief (<6 months) exposure to any HRT. These women had a reduced risk developing an ER-positive tumor (OR, .6, P = .02 for any estrogen HRT; OR, .5, P = .02 for combined HRT) or a PR-positive tumor (OR, .5, P < .01 for any estrogen HRT; OR, .6, P < .01 for any progesterone HRT; OR, .4, P = .01 for combined HRT) (Table 4Go). Although sustained use of either any estrogen HRT or any progesterone HRT had no marked effect on tumor ER and PR status, women exposed to combined HRT for ≥6 months had a higher risk of developing receptor-positive tumors than nonusers (OR, 1.6, P < .05).


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  		TABLE 4. Duration of hormone replacement therapy (HRT) use versus estrogen receptor (ER) and progesterine receptor (PR) in women aged ≥ 50 years at diagnosis (n = 1701)
 
Because a threshold value of ER-positive tumor nuclei (>5% immunoreactive nuclei) defined ER-positive tumor status, the potential influence of HRT on the percentage of ER immunoreactive tumor nuclei was also evaluated among ER-positive subjects. Figure 2AGo shows that duration of any estrogen HRT did not significantly affect the percentage of ER-positive tumor nuclei within the ER-positive tumors of patients ≥ 50 years of age. Moreover, although prolonged combined HRT use had been shown to increase the odds of developing an ER-positive cancer, it did not affect the percentage of staining among these tumors (Fig. 2BGo).


Figure 2
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  		FIG. 2. (A) Duration of estrogen therapy does not affect percentage of estrogen receptor (ER) staining in ER-positive women aged ≥ 50 years; P = .20, P = .52 (age-adjusted). (B) Duration of combination hormone replacement therapy (HRT) does not affect percentage of ER staining in ER-positive women aged ≥ 50 years; P = .81, P = .76 (age-adjusted).

 
Breast Tumor Histology, Grade, and Stage
We found a strong association between lobular (including mixed lobular and ductal) tumor histology and ER positivity (97% of lobular tumors were ER positive, P < .001). However, no statistically significant associations were observed between lobular histology and HRT, including combined HRT, even when associations were adjusted for age.

Tumor grade was recorded in 1482 patients aged ≥50 for whom ER and PR status was known. Increasing grade was significantly associated with decreased odds of ER-positive tumors (OR, .16, P < .001) and PR-positive tumors (OR, .36, P < .001). Among women ≥50 years old, those prescribed any estrogen HRT were more likely to present with low-grade tumors than women who were not (Fig. 3Go). Increasing duration of any progesterone use was significantly associated with higher proportions of low- and intermediate-grade tumors (P = .004).


Figure 3
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  		FIG. 3. Any estrogen hormone replacement therapy (HRT) favors lower-grade tumors, whereas progesterone HRT influence depends on duration of use. *Significant differences (P < .05) when compared with reference group "No HRT".

 
When compared with women who did not receive any HRT, those who were prescribed any estrogen HRT were more likely to present with earlier-stage tumors, particularly locally invasive cancers, as opposed to regionally invasive cancers or cancers that had metastasized distantly at presentation (P = .03) Fig. 4Go). When duration of exposure to any estrogen HRT was investigated, brief exposure (<6 months) resulted in a higher proportion of early-stage tumors, whereas sustained exposure led to increasing proportions of later-stage tumors (P = .02). For combined HRT, the distribution of proportions seems similar; however, the differences are not statistically significant.


Figure 4
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  		FIG. 4. Any estrogen hormone replacement therapy favors earlier-stage tumors by any use and duration of use. *Significant differences (P < .05) when compared with reference group "No HRT".

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Breast cancer risk associated with HRT is a matter of continued discussion and debate. As is true for other complex associations, unraveling the relationship between HRT and breast cancer incidence has proven difficult and is complicated by different study designs, widely divergent durations of therapy, and varied therapy regimens. The two largest published randomized, controlled trials comparing combined HRT to placebo, the WHI and the Heart and Estrogen/Progestin Replacement Study (HERS), have yielded conflicting results.11,12 The hazard ratios for breast cancer were 1.24 (95% CI, 1.02–1.50) at a mean follow-up time of 5.2 years in the WHI, and 1.27 (95% CI, .84–1.94) after 6.8 years in HERS.

A systematic review of 52,705 women with breast cancer showed a relative risk of 1.35 (95% CI, 1.21–1.49) for women who received HRT for more than 5 years.13 However, this finding was difficult to interpret given the wide range of regimens and durations of therapy included in the analysis. Nevertheless, these studies, taken together, suggest increased odds of breast cancer with combined HRT when compared with placebo.

The biological effect of HRT on breast cancer histology, especially receptor status, has proven even more difficult to establish than the relationship between HRT and breast cancer incidence. Several studies have shown increased incidence of ER-positive tumors with HRT, particularly with combined estrogen and progesterone preparations.8–10,14 However, one study actually showed a decrease in ER-positive breast cancers with use of HRT.15 Furthermore, the effect of estrogen alone, progesterone alone, or combined HRT on subsequent breast cancer histology has not been clearly examined, and few studies have adjusted for the duration of total HRT exposure. Inherent in most survey-based studies are limitations regarding possible misclassification of hormone regimen, lack of compliance data, and inaccurate recall of duration of use.

The KPNC patient database provided an ideal opportunity to explore these associations in greater detail and with improved precision of risk estimates among diffierent HRT regimens. The electronic pharmacy database allowed a more precise calculation of total exposure to HRT; assuming no change in compliance over time, the duration of HRT use was accurately reflected in the number of prescriptions dispensed because few KPNC patients fill prescriptions outside the KPNC formulary system. This is a more accurate estimation of lifetime HRT exposure than self-report and also provides an advantage over randomized trials because total time receiving HRT is known, rather than total time of study inclusion. Further, intent-to-treat analysis may underestimate the effect of HRT. Because KPNC patients are prescribed estrogen and progesterone as separate prescriptions, the effects of single-hormone therapy versus combination therapy and duration of treatment could be compared.

Another key advantage conferred by the KPNC database is centralized pathology review, where all ER and PR immunohistochemistry staining is evaluated by a team of five pathologists at one facility. This minimized misclassification of hormone receptor status or histology and precluded concerns regarding differing antibody use or interinstitutional variation in immunohistochemical results and interpretation.

Our study shows that when adjusted for age among women aged ≥ 50 years, any use of estrogen or pro-gesterone does not increase the likelihood of ER-positive tumors regardless of duration of therapy (Tables 2Go and 3Go). When stratified by duration of therapy, combination therapy (combined HRT, defined as comparable use of both estrogen and progesterone tablets) taken for at least 6 months increased the odds of developing ER-positive disease by 65% (OR, 1.57; 95% CI, 1.00–2.45; P = .005) Table 4Go). Notably, all patients with >5 years of combined HRT had ER-positive breast cancer. In contrast, among patients with a short duration (<6 months) of any type of HRT, there was almost a 50% reduction in ER-positive or PR-positive tumors. However, it is difficult to make inferences from treatment administered for brief durations because breast carcinogenesis—especially determinants of histologic subtype—are established well before cancer is clinically detectable.16

The observed association between any estrogen HRT use and breast tumors of lower grade and stage is consistent with other retrospective studies.5 However, potentially confounding factors must be considered for retrospective studies such as these. Women who regularly see doctors for refills while receiving HRT may have their breast symptoms addressed earlier than those not receiving HRT. In addition, women receiving HRT may be more likely to be referred for mammography earlier and more consistently, and could have more detailed diagnostic work-ups as a result of increased breast density resulting from their HRT use. Although the effect of these potential confounders could clearly affect the odds of breast cancer detection, their impact on the detection of ER-positive disease in particular is difficult to estimate. Additionally, the protective effect of estrogen HRT on stage at presentation was driven by those with brief (<6 months) HRT exposure. This effect may be an artifact of early detection from better mammogram screening compliance during the early period of HRT use.

Our study is limited by the lack of data for several risk factors associated with increased breast cancer risk. These include family history, reproductive history, and self-reported menopausal status. However, because none of these factors is known to specifically increase ER-positive cancers, this would not be expected to have introduced a bias in our analysis. Importantly, body mass index, which is associated with endogenous hormone levels and postmenopausal breast cancer risk, was not recorded and therefore could have been another confounder. As well, concomitant use of nonsteroidal anti-inflammatory agents (especially aspirin) was not adjusted for, and this has been shown to selectively protect against ER-positive breast cancer.17 Most importantly, duration of exogenous hormone exposure was related to the total number of pills prescribed before diagnosis and therefore was not necessarily a consecutive measure, but rather a measure of cumulative HRT exposure from the time of first prescription to the time of breast cancer diagnosis. Previous and continued HRT use versus previous (but discontinued) HRT use are potentially important distinctions not accounted for in this analysis. Because sustained but discontinued use of HRT may have minimized associations with different breast cancer types, the potential effects of time off HRT will be addressed in a future analysis.

In conclusion, this study is a detailed analysis of the effect of different HRT regimens on subsequent breast cancer histology. Accurate ascertainment of treatment showed a duration-dependent effect of combined HRT on likelihood of hormone receptor-positive disease. Planned future analyses of this data set will include evaluation of dose-dependent effects, chronologic effects, and the effect of race on breast cancer histology with HRT to determine whether the effect of HRT on tumor histology is mitigated by intrinsic patient characteristics.


   ACKNOWLEDGMENTS
 
The authors thank Michael Oherli of the Kaiser Permanente Northern California Cancer Registry, Mohana Kumar and Christina Minami for database support, and Pamela Derish, Department of Surgery, University of California–San Francisco, for editorial support. The authors acknowledge the Association of Women Surgeons and the Breast Cancer Research Foundation for funding this work.

Received for publication June 6, 2006. Accepted for publication June 7, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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