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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.03.012 on December 8, 2003

Annals of Surgical Oncology 11:52-58 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

The Characteristics of Malignant Breast Tumors in Hormone Replacement Therapy Users Versus Nonusers

Itzhak Pappo, MD, Ioana Meirshon, MD, Tamar Karni, MD, Nava Siegelmann-Danielli, MD, Varda Stahl-Kent, MD, Judith Sandbank, MD, Ilan Wasserman, MD and Ariel Halevy, MD

From The Comprehensive Breast Care Institute (IP, TK, AH), the Division of Surgery (IP, IM, TK, IW, AH), and the Institutes of Oncology (NS-D), Radiology (VS-K), and Pathology (JS), Assaf Harofeh Medical Center, Zerifin (affiliated with the Sackler Faculty of Medicine, University of Tel Aviv), Israel.

Correspondence: Address correspondence and reprint requests to: Itzhak Pappo, MD, The Comprehensive Breast Care Institute, Assaf Harofeh Medical Center, Zerifin 70300, Israel; Fax: 972-8-977-8192; E-mail: pappo{at}zahav.net.il


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The purpose of this study was to investigate the characteristics of breast cancer in hormone replacement therapy (HRT) users vs. nonusers.

Methods: We investigated the characteristics of all patients between the ages of 50 and 75 years with breast tumors. Then, an age-adjusted group of 55 nonusers was chosen to match and compare with HRT users.

Results: Of the 243 patients available for evaluation, 55 (22.6%) used HRT. Disease stages in HRT users vs. nonusers were as follows: ductal carcinoma in situ (DCIS), 20% and 17.1%; stage I, 45.5% and 41.7%; stage II, 30.9% and 26.2%; stage III, 3.6% and 13.4%; and stage IV, 0% and 1.6% (P = .27). In the age-adjusted cohort, stages in nonusers were as follows: DCIS, 7.3%; stage I, 47.3%; stage II, 25.5%; stage III, 20%; and stage IV, 0% (P = .03). Tumor grades in HRT users vs. nonusers were as follows: grade I, 30.4% and 15.7%; grade II, 52.2% and 52.2%; and grade III, 17.4% and 32.1% (P = .035). Grades in cohort nonusers were as follows: I, 13.2%; II, 52.8%; and III, 34% (P = .05). In the invasive tumors, the positive estrogen receptor (ER) rates were 81.6% and 85.7% (P = .89); positive progesterone receptor (PR) rates were 53.1% and 54% (P = .95); and Her 2-neu positive rates were 18.4% and 17.6% (P = .95), respectively. No significant difference was found in intratumor DCIS, vascular invasion, and Ki-67 (P = .14, .9, and .79, respectively). The rate of lobular and favorable histological types was higher in the HRT user group: 26.6% vs. 15%.

Conclusions: Breast tumors in HRT users vs. nonusers were of a significantly lower stage and grade and accounted for a higher number of favorable histological types, but all other parameters were similar in the two groups.

Key Words: Breast cancer • Hormone replacement therapy • HRT • Tumor characteristics


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hormone replacement therapy (HRT) has gained widespread popularity during the past 30 years and is used to reduce postmenopausal symptoms, maintain bone density, and reduce cardiovascular diseases.1 This increasing popularity has been reported in the United States and other Western countries, in which a twofold to threefold increase has been reported in the past decade.2,3 A similar increase in the use of HRT has also been reported in Israel.4 In a study conducted to examine the attitudes of Israeli and American gynecologists toward HRT, it was found that 86.4% of American gynecologists vs. 66.3% of Israeli gynecologists prescribe HRT for a period of at least 10 years to women with an intact uterus.

During the 1960s and 1970s, HRT was prescribed as unopposed estrogen, when first reports raised the causal connection between HRT and endometrial cancer.5 As a result of this observation, therapy using progestin concomitantly with estrogen gradually became the most popular standard of care for women with an intact uterus.6

The majority of medical studies until the mid 1990s did not demonstrate any associated increased incidence of breast cancer among women who were treated with HRT in the general population7–10 or in high-risk families.11 However, most of these studies included mainly women who used estrogen-based compounds for HRT. As the number of women using combined therapy with estrogens and progestins has increased, the relation between HRT and a higher risk for developing breast cancer has become evident.12–16

The exact mechanism by which gonadal hormones increase the risk of breast cancer is not clear, but the fact that the risk of breast cancer drops following cessation of HRT suggests that HRT promotes the growth of existing dormant tumor cells rather than converting them from benign to malignant cells.

Despite the increased incidence of breast cancer in HRT users, a decrease in mortality rates among patients with breast cancer using HRT has been documented.17 The reduced mortality rate may be attributed to a possible low aggressiveness documented in malignant breast tumors developing in HRT users.18–20

In this retrospective study, we examined the possibly different biological characteristics of malignant breast tumors in HRT users and compared them to those of tumors in nonusers.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Between June 2000 and November 2002, 462 new patients with breast cancer were diagnosed in The Comprehensive Breast Cancer Institute at the Assaf Harofeh Medical Center, in Zerifin, Israel. All patients were interviewed, and a questionnaire regarding their personal and hormonal history was filled out. The clinical records of all these patients were examined and a group of patients aged 50 to 75 years was chosen for our study.

The following data were evaluated: tumor size, involvement of lymph nodes, tumor grade, histological type, proliferative fraction (Ki-67), estrogen receptors (ERs), progesterone receptors (PRs), receptors for Her 2-neu, peritumoral vascular invasion, and extent of ductal carcinoma in situ (DCIS) involvement. Patients were divided into two groups: HRT users and nonusers.

We defined an HRT user as any patient who used estrogen alone or estrogen and progestin not more than 5 years prior to breast cancer diagnosis. In order to prove a significant impact on breast cancer characteristics, we selected only those women who used HRT continuously for at least 1 year. This time limit was suggested following the experience of Holli et al.,19 who reported that the effect of HRT is reduced after cessation of HRT and largely disappears after approximately 5 years. Colditz et al.13 defined the relative risk of developing breast cancer 5 years following cessation of HRT therapy to be .95.

We restricted our study to women in menopause older than 50 years.

After comparing the whole group of consecutive patients who did not use HRT to HRT users, we selected a group of 55 women among the nonusers who were randomly matched on the basis of age, and this group was studied as the adjusted group for statistical comparison with the HRT users. This comparison of the age-matched group was used to overcome the possible differences in the tumors of nonusers due to higher age at diagnosis.

Biological Characteristics
The histological classification, tumor staging, and grading were based on The World Health Organization (WHO) classification of tumors,21 The American Joint Committee on Cancer rules,22 and the grading system suggested by Elston and Ellis.23

ERs, PRs, and Ki-67 were evaluated according to the instructions of The College of American Pathologists (Immunohistochemistry Survey UK 2001, CAP2001). We defined two classes of invasive carcinoma with a DCIS component: absent or mild involvement of DCIS or extensive involvement of DCIS. Extensive involvement was defined as an invasive tumor in which 25% or more of the involved area of the invasive tumor was composed of or involved with DCIS. We defined a few subclasses as being invasive carcinoma with a favorable histology: medullary, papillary tubular, and mucinous tumors. These tumors are known to have lower chances of axillary node metastases.

Statistical Analysis
The statistical analysis was done with the Pearson {chi}2, PHI coefficient, and Cramer V tests, which were applied on the entire group of patients and on the age-adjusted group. The P values were calculated for the whole group and for the age-adjusted group separately.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
In the cohort of 462 consecutive patients who had breast cancer diagnosed, 243 were found to be between 50 and 75 years of age and were available for evaluation. Fifty-five (22.6%) of them used HRT before the diagnosis of breast cancer and were defined as HRT users. The mean ages of HRT users and nonusers were 58.5 and 60.8 years, respectively. The mean age of the age-adjusted group of nonusers was 58.2 years.

Stage
Tumor stage at diagnosis was lower in HRT users than in nonusers, and there was a significantly higher number of stage III and IV breast cancer patients among nonusers (Table 1). These differences were highly significant in the age-adjusted group. The relative risk (RR) of an HRT user vs. a nonuser to have stage III or IV breast cancer diagnosed was found to be 0.33, and it was 0.18 in the age-adjusted group.


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  		TABLE 1. Stage of the tumor
 
Size
Tumors 2 cm in diameter or smaller were significantly more frequent in HRT users (72.2% vs. 48.4%), whereas tumors larger than 5 cm in diameter were diagnosed more frequently in the nontreated group (8.6% vs. 3.7%). The difference between the groups was significant (Table 2). The RR of an HRT user vs. a nonuser to have a breast tumor larger than 2 cm was found to be 0.53, and it was 0.51 in the age-adjusted group.


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  		TABLE 2. Tumor size
 
Grade
A significantly higher number of HRT users were found to have grade I tumors (30.4% vs. 15.7%), whereas nonusers had a higher number of grade III tumors (32.1% vs. 17.4%) (Table 3). The RR for an HRT user vs. a nonuser to have a grade III breast tumor diagnosed was found to be 0.54, and it was 0.51 in the age-adjusted group.


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  		TABLE 3. Histological grade
 
Biological Properties
The rate of positive ER/PR was found to be similar among HRT users and nonusers.

Among the 208 patients for whom Her 2-neu data were available, we did not find significant differences in the percentage of negative or +2 and +3 tumors between HRT users and nonusers (Table 4).


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  		TABLE 4. Estrogen, progesterone receptors, and Her 2-neu
 
We examined three different factors indicating histological tumor aggressiveness: Ki-67, vascular invasion, and the amount of intralesional DCIS (Table 5). None of these parameters was found to be different between HRT users and nonusers.


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  		TABLE 5. Tumor histological characteristics
 
Histological Types
Histological types (Table 6) were slightly different between the groups. Lobular carcinoma (14.3% vs. 7.6%) as well as favorable histological types of breast carcinoma (10.7% vs. 6.6%) were more prevalent in HRT users. The relative chance of an HRT user vs. a nonuser having a breast tumor with favorable histology diagnosed was found to be 1.7, and it was 1.6 in the age-adjusted group. This difference was not significant statistically.


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  		TABLE 6. Histological type
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The medical literature dealing with the impact of HRT on the nature of malignant breast tumors is almost unanimous in defining the tumors in HRT users as having more favorable prognostic factors. However, it is not clear whether this difference arises from a lower stage at diagnosis or better grade and higher differentiation status at presentation.

Our study, similarly to other studies, demonstrated that the biological nature of breast cancer diagnosed after or during the use of HRT is less aggressive in some parameters than that in nonusers. This was reflected by the lower stage as well as lower grade at diagnosis. These findings are in concordance with those of other investigators who reported that tumors in HRT users were more likely to present as T1 and node-negative lesions.19,20,24–26 In our series, 72.2% of the tumors in HRT users were smaller than 2 cm in diameter, whereas only 3.2% were larger than 5 cm. The overall stage was also lower: only 3.6% of tumors in HRT users, vs. 15% of tumors in nonusers, were diagnosed as stage III or IV.

Tumor grade in HRT users was also lower: grade I tumors were found in 30.4% of HRT users but only 15.7% of nonusers, whereas grade III tumors were less common in users (17.4% vs. 32.1%). This difference in the grade of tumors has also been demonstrated by others.18

The lower stage and lower grade reflect two possibly different mechanisms by which the use of HRT may influence the nature of breast cancer.

Lower stage at diagnosis may reflect higher awareness of women who use HRT for frequent manual and mammographic screening, as has been suggested by a few authors.12,26,27

Cheek et al.,24 as well as other investigators,19,25,26 found a higher rate of patients who had received HRT whose tumors were diagnosed mammographically, whereas more tumors in nonusers were larger and detected by palpation. This finding could have been the result of more frequent mammographic screening among HRT users and greater compliance with regular manual examination. However, when the mean period between mammograms was compared in the two groups of patients, it was found that the average interval between screening mammograms was close to 2 years in both groups, with no significant difference between HRT users and nonusers.

Women who use HRT tend to belong to the higher socioeconomic classes and have easier access to health facilities. Therefore, these women tend to have cancer diagnosed at an earlier stage. Merom and her colleagues27 studied the nature of HRT users in Israel and found that their profile is that of more highly educated, nonobese women who pay regular visits to the gynecologist and have a high awareness of preventive health care systems. This social behavior was also found in our study among HRT users, in comparison with nonusers.

The other significant difference between the two groups of patients in our study is the lower average grade of the tumors, a fact that cannot be explained by early detection. A similar difference in tumor grade was found by others, both when only those tumors detected by screening were evaluated and when palpable tumors were evaluated.18,28

These findings cannot be the result of more frequent screening procedures or higher awareness of patients to breast problems, but they can be attributed to the different biological nature of the tumors.

Other diminished aggressive biological parameters of breast tumors in women who are prescribed HRT have also been reported. Magnusson29 found a decreased relative risk of aneuploid tumors in these patients. Holli,19 who studied 477 women with breast cancer, found that tumors among HRT users had a lower mean proliferation rate as measured by s-phase fraction.

Another parameter that may reflect lower biological aggressiveness of the tumors is their histological type. Chen,16 Li,30 and Daling31 found that postmenopausal women who take combined HRT have a higher risk of developing lobular carcinoma of the breast. They connected this fact to the recent increased incidence of lobular carcinoma in some parts of the United States, which may be related to the higher rate of women using HRT.

Gapstur and her colleagues, who reported the results of the Iowa Women’s Health Study,32 found that the RRs of invasive carcinoma with favorable histology in current users of HRT were 4.42 for 5 or fewer years of use and 2.63 for more than 5 years of use.

In the present study, we found a higher number of invasive lobular carcinomas and carcinomas of more favorable histology among women who used HRT, but this difference was not significant.

The rate of DCIS in the present study was similar in the two groups of patients and comparable to the findings of Schairer and colleagues.14 Gapstur,32 on the other hand, found a higher rate of DCIS among HRT users. Higher rates of DCIS among HRT users can reflect both early detection of tumors by more intensive screening and lower biological aggressiveness; therefore, this fact does not add significant information about the influence of HRT on the characteristics of breast tumors. However, the emergence of less common breast tumors in HRT users suggests that HRT may have a selective growth-promoting effect on these tumors that is connected to some unknown biological cell characteristics that they possess.

The fact that ER status is of predictive value for the prognosis of breast cancer is well established.33 However, in the present study, we did not find any significant differences in the ER or PR status between HRT users and nonusers. This finding is in agreement with those of other studies that examined the same issue and did not find a significant difference in the abundance of ER receptors in the two groups of tumors.17,19,27,34 Sacchini and his colleagues,20 on the other hand, found that the percentage of tumors positive for ER and PR increased with increased length of HRT administration, in spite of the fact that even in their study the rate of ER expression was similar in the HRT user and nonuser groups. To investigate this question, a small experimental study was performed of healthy women for whom the ER-{alpha} expression in breast samples (from 11 subjects) was examined.35 A strong correlation between ER-{alpha} expression in normal breast epithelial cells and body mass index (BMI) was found in normal women who currently use HRT. These findings may suggest that a subgroup of women, such as those with high BMI, may react differently to HRT.

A few other experimental studies have examined the influence of HRT on tumor cell proliferation relating to the hormone receptor status. All demonstrated a stimulatory effect on proliferation, restricted to ER-positive cells, but the sample size in all studies was small.36,37

The lack of a significant association between the tumor hormone status and HRT, as described in most clinical study reports,17,19,28,34 may suggest that the mechanism responsible for the different biological characteristics of tumors in HRT users is mediated through an intact ER/PR pathway.

Her 2-neu protein is found in approximately 25% of human breast cancer cells,38 and its expression signifies poor prognosis for the breast cancer patient.39 We did not find any difference between HRT users and nonusers in the expression of Her 2-neu protein on tumor cells. Experience related to the influence of HRT on the expression of Her 2-neu protein is limited. Another study also addressed this question and did not find any difference in the expression of Her 2-neu between HRT users and nonusers.19

Although it is obvious from most observational studies that breast cancer is more frequent following the use of HRT, the effect of HRT on breast cancer mortality is controversial. As may be suggested from the findings in the present study, the mortality in the present group of HRT users may be lower. Several other studies that demonstrated lower staging and grading of tumors in HRT users suggested also a reduced rate of death in breast cancer patients who used HRT.7,11,40 However, the large Nurses’ Health Study demonstrated an increase in mortality associated with breast cancer in current users of HRT for more than 10 years.41 This finding and the discovery made by The Collaborative Group that the risk for breast cancer fell rapidly after cessation of HRT, so that by 5 years the risk for breast cancer almost normalized and did not differ from that for normal women, suggest a time-dependent mechanism for the influence of HRT on the growth of breast cancer.

These findings suggest there is a mechanism by which HRT acts as a promoter of preexisting breast cancer cells rather than initiating the growth of premalignant tumor cells and transforms them to cancer cells. This mechanism has been described to be independent of family history or other risk factors.15,42

The findings of lower tumor grades and more favorable histological factors may suggest an effect of HRT on early carcinogenesis or an increased promotional effect on less aggressive subpopulations of breast cancer cells. This enables the early detection of these slow-growing tumors and may explain why tumors of HRT users are of both low grade and early stages.


   FOOTNOTES
 
We investigated the nature of breast cancer in hormone replacement therapy (HRT) users and nonusers, comparing tumor stage, grade, estrogen and progesterone receptor and Her 2-neu status, and other tumor characteristics. We found a lower stage and grade in HRT users, but all other characteristics were similar in the two groups.

Received for publication March 6, 2003. Accepted for publication September 17, 2003.


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TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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