Influence of HRT on prognostic factors for breast cancer: a systematic review after the Women’s Health Initiative trial

Caroline Antoine, Fabienne Liebens, Birgit Carly, Anne Pastijn and Serge Rozenberg1

Department of Obstetrics and Gynaecology, Free Universities of Brussels (VUB-ULB) CHU Saint-Pierre, Hoogstrasse 322, 1000 Brussels, Belgium

1 To whom correspondence should be addressed. e-mail: serge.rozenberg{at}skynet.be


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
INTRODUCTION: Mortality due to breast cancer has been reported to be the same or even lower in HRT users than in non-users. This has been attributed to earlier diagnosis and to better prognosis. Nevertheless, more advanced disease in HRT users was reported recently by the Women’s Health Initiative (WHI) study. The objective of this study was to assess, using a systematic review of current literature, whether the data of the WHI study are in contradiction to observational data. METHODS: We selected 25 studies, for which we evaluated the methodology, the characteristics of the studied populations, confounding breast cancer risk factors and prognostic indicators. RESULTS: The WHI study, showing a worsening of some prognostic parameters, is in contradiction to most published observational studies. Most observational studies are retrospective, not well matched and did not consider most confounding factors. Their methodology and selection criteria varied considerably and the number of patients was often small. No differences in the distributions of histology, grade or steroid receptors were observed in the WHI trial, while this was the case in some of the observational studies. Other parameters (S phase, protein Neu, Bcl-2 gene, protein p53 and E-cadherin, cathepsin D) were not reported in the WHI trial. CONCLUSIONS: In view of these data, the current clinical message to patients should be changed: one can no longer declare that breast cancers developed while using HRT are of better prognosis.

Key words: breast cancer/HRT/prognosis/systematic review


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
An increased risk of breast cancer has been shown by many observational studies, and more recently confirmed by the Women’s Health Initiative (WHI) double-blind study evaluating a particular combined HRT regimen [0.625 mg conjugated estrogens (CEE) + 2.5 mg of medroxyprogesterone acetate (MPA)] versus placebo (Collaborative Group on Hormonal Factors in Breast Cancer, 1997Go; Gapstur et al., 1999Go; Ross et al., 2000Go; Rossouw et al., 2002Go; Weiss et al., 2002Go). Nevertheless, it was reported before the WHI study that mortality due to breast cancer is either the same or even lower in women who were diagnosed while using HRT than in non-HRT users (Bergkvist et al., 1989Go; Persson et al., 1996Go; Grodstein et al., 1997Go; Faiz et al., 1998Go; Jernström et al., 1999Go; Schairer et al., 1999Go; Nanda et al., 2002Go). It is believed that this may be due in part to earlier diagnosis or better prognosis (Jones et al., 1994Go; Squitieri et al., 1994Go; Harding et al., 1996Go; Magnusson et al., 1996Go; Holli et al., 1998Go; O’Connor et al., 1998Go; Bilimoria et al., 1999Go; Gapstur et al., 1999Go; Bonnier et al., 2000Go; Delgado et al., 2001Go; Cheek et al., 2002Go; Estève et al., 2002Go; Sacchini et al., 2002Go). The latter statement in particular is often cited in review articles concerning HRT. However, an increased risk of advanced disease was reported recently by the WHI study (Chlebowski et al., 2003Go). The aim of this study was to assess, using a systematic review, whether these recent data are in contradiction with earlier data, and if so, why this might be the case.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In order to identify all published trials assessing the effect of HRT on prognostic factors we conducted a MEDLINE search using the following key words: breast neoplasm, breast cancer, prognosis, prognostic factors, hormone replacement therapy and estrogen replacement therapy. The references of each study identified and of review articles were then cross-checked for other potentially relevant studies. We also searched other databases (Cochrane Controlled Trials Register) and abstract books of recent congresses, both on HRT and on breast cancer. We established the following inclusion criteria: articles should be written in English or French. The studies should have assessed prognostic factors in HRT users and non-users, with a minimum of 20 patients per group. The following parameters for prognosis of breast cancer were considered: the size of the tumour, node extension, grade, histological type, hormonal receptors, expression of Neu protein, markers of proliferation (Ki-67, S-phase fraction, ploidy, p53 and Bcl-2 gene) and of invasion (E-cadherin, cathepsin D). Some authors analysed only globally whether HRT use was associated with better prognosis, but others also investigated whether the HRT regimens (Jones et al., 1994Go; Magnusson et al., 1996Go; Delgado et al., 2001Go) and duration of exposure (Gapstur et al., 1999Go; Delgado et al., 2001Go; Sacchini et al., 2002Go) or mode of administration (Sacchini et al., 2002Go) had an effect on prognostic factors. We considered mainly the global results for our systematic review. Nevertheless, we also mention their significant results in subgroups.

In addition to the recent article by Chlebowski et al. (2003)Go, we found 29 studies that met the inclusion criteria. However, we eliminated duplicate publications involving the same cohorts (Squitieri et al., 1994Go; Bonnier et al., 1995Go; Salmon et al., 1995Go; Holli et al., 1997Go; Bonnier et al., 1998Go; Henrich et al., 1998Go). In such cases we selected the article with the highest number of patients (Salmon et al., 1999Go; Bonnier et al., 2000Go; Gajdos et al., 2000Go) or the article that provided the most information (Holli et al., 1998Go; LeBlanc et al., 1999Go). Finally, we selected 25 studies for which we evaluated the methodology, the characteristics of the studied populations, confounding breast cancer risk factors and prognostic indicators.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Characteristics of the studied populations
WHI study. The WHI study is the only randomized trial that has been reported on this topic. The study assessed a large number of postmenopausal women (n = 16 608) aged 50–79 years, among which about two-thirds were >60 years old at inclusion. They were randomized to receive either 0.625 mg CEE + 2.5 mg MPA or a placebo. About 25%, both among the HRT users and among the placebo users, were past or current HRT users before entering the trial. Among the total population, 199 HRT users and 150 non-users developed invasive breast cancer during a mean (± SD) follow up of 5.6 (± 1.3) years (Chlebowski et al., 2003Go).

Former studies. Among the other 24 studies, there were no randomized trials. Twelve studies were stated to be retrospective by the authors and seven were reported to be prospective; however, for some of these studies only part of the methodology occurred prospectively. We determined that the remaining five studies were retrospective (Table I). The number of patients included varied between 60 and 1480. The number of patients using HRT varied between 29 and 561. In three studies, women using HRT were matched to women not using HRT based on their age at the time of diagnosis. One study compares cases with the general population. Most studies provided information about the age of the patients at diagnosis; however, some mentioned only the age distribution of the patients who were screened. Six studies found that HRT users were younger than non-users, while in one study, HRT users were older than control patients. Generally, the age distributions were younger than in the WHI study. All except five studies mentioned exclusion criteria, although these criteria varied from one study to the next. For instance, the histological criteria varied: some studies included only ductal and lobular invasive cancers (IDC, ILC), while others excluded only lobular carcinoma in situ cancers (LCIS) and not ductal carcinoma in situ (DCIS). Patients with a previous history of breast cancer were excluded in some studies, but not in others (Table I). Three studies among six that analysed the body mass index (BMI) observed that HRT users had, on average, a lower BMI than did the control group (Bonnier et al., 2000Go; Gajdos et al., 2000Go; Aerts et al., 2003Go).


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Table I. Influence of HRT on prognostic factors of breast cancer: characteristics of the studies and studied populations
 
Ten studies provided details about the HRT regimen used (Jones et al., 1994Go; Magnusson et al., 1996Go; Holli et al., 1998Go; Bilimoria et al., 1999Go; Fowble et al., 1999Go; LeBlanc et al., 1999Go; Salmon et al., 1999Go; Bonnier et al., 2000Go; Delgado et al., 2001Go; Sacchini et al., 2002Go) and five provided information on the duration of HRT use (Gapstur et al., 1999Go; LeBlanc et al., 1999Go; Lower et al., 1999Go; Delgado et al., 2001Go; Sacchini et al., 2002Go). Six studies performed post hoc subanalyses in relation to the HRT regimen or the duration of its use.

Influence of HRT on prognostic factors
WHI study. In the WHI trial, a large number of risk factors were controlled (Table I). The prognostic factors that were evaluated are shown in Table II. Tumour size was significantly larger among HRT users who developed breast cancer than among placebo users (mean ± SD: 1.7 cm ± 1.1 versus 1.5 cm ± 0.9; P = 0.04). Similarly, node invasion (25.9% versus 15.8%; P = 0.03) occurred more frequently, and the stage was more advanced in HRT users (regional/metastatic: 25.4% versus 16.0%; P = 0.04). There were no differences in the distribution of histology, grade, or estrogen receptors (ER) and progestin receptors (PR) between HRT and placebo users (Chlebowski et al., 2003Go).


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Table II. Influence of HRT on histological prognostic factors of breast cancer
 
Former studies. Only seven studies compared the presence of some confounding risk factors for breast cancer in the two groups of patients; Gapstur et al. (1999)Go and Delgado et al. (2001)Go considered a rather complete list of risk factors: family history of breast cancer, menarche, age of first pregnancy and delivery, parity, use of contraception and age of menopause. The other studies considered between one and six risk factors only (Fowble et al., 1999Go; LeBlanc et al., 1999Go; Gajdos et al., 2000Go; Manjer et al., 2001Go; Cheek et al., 2002Go). None of these studies found that these risk factors were significantly different between HRT users and non-users.

Three studies found that HRT users developed significantly smaller tumours than non-users, when clinically evaluated (Fowble et al., 1999Go; Bonnier et al., 2000Go; Delgado et al., 2001Go). Delgado et al. (2001)Go also found that HRT users less often had invaded lymph nodes (P < 0.05). Similar results were also found by 10 investigators, when evaluated histologically (Table II). No differences were reported in relation to the duration of HRT use (Magnusson et al., 1996Go; Delgado et al., 2001Go). However, some authors observed smaller tumours when using combined estrogen–progestin regimens, and less nodal invasion when using unopposed estrogens (P < 0.05) (Delgado et al., 2001Go). Three studies showed that HRT users had stage I disease more often than controls (Delgado et al., 2001Go; Manjer et al., 2001Go; Cheek et al., 2002Go). Using subgroup analyses, Delgado et al. (2001)Go found a significant increase of stage I diseases in HRT users for 36 months or more. Diel et al. (2002)Go observed fewer patients with metastases among HRT users than among non-users (P < 0.001).

The prognostic histological factors are shown in Table II. Contradictory results have been published concerning ER positivity: three studies reported that women using HRT have significantly more tumours expressing ERs (Lower et al., 1999Go; Gajdos et al., 2000Go; Delgado et al., 2001Go), but two other studies found the opposite (Cheek et al., 2002Go; Sacchini et al., 2002Go). In subanalyses, Delgado et al. (2001)Go found higher rates of positive ERs among women using combined estrogen–progestin regimens (P = 0.03).

Three studies out of 14 found that HRT users had significantly more frequent tumours with favourable histology (in situ, tubular, medullary, papillary and mucinous carcinoma) (Stolier et al., 1997Go; Gapstur et al., 1999Go; Manjer et al., 2001Go), but also more frequent invasive lobular carcinomas (Manjer et al., 2001Go; Klein et al., 2003Go).

Ten studies out of 17 found that HRT users more frequently had well-differentiated tumours than non-users (Table II). However, in Delgado’s study, a favourable grade was found particularly in women using a combined HRT regimen (P < 0.05) (Delgado et al., 2001Go). Two studies evaluated the Nottingham Prognostic Index (which simultaneously assesses the size, nodal invasion and histological grade), but only one study found significantly decreased indices (translating to a better prognosis) among HRT users (Manjer et al., 2001Go).

Eight studies evaluated ploidy among HRT users and non-users, but none found a significant difference concerning this parameter between HRT users and non-users.

A significant difference in the amount of cells in S phase, was found in two studies out of seven evaluating this parameter. Nevertheless, these two studies found contradictory results. Holli et al. (1998)Go found a lower S-phase fraction among HRT users (P < 0.05), and even more so in current users (P = 0.001), while Cobleigh et al. (1999)Go found the opposite (P < 0.05) among women who had tumours expressing positive ERs (P < 0.01).

No difference in expression of protein Neu, Bcl-2 gene, protein p53 and E-cadherin could be observed (Holli et al., 1998Go; O’Connor et al., 1998Go). Sacchini et al. (2002)Go observed significantly more frequent vascular emboli among HRT users (32.7%) than among non-users (23.9%). No difference in the Ki-67 proliferation index could be observed, even after adjustment for age and tumour size. Nevertheless, using subanalyses these authors found that Ki-67 was enhanced in women using HRT for <1 year and diminished in women using HRT for >5 years (Sacchini et al., 2002Go). Finally, one study reported increased levels of cathepsin D in women using HRT (95% compared with 59% among control patients), which is known to be associated with a worse prognosis (Jones et al., 1994Go). One should note, however, that the increase in cathepsin did not reach the threshold level that indicates a bad prognosis (>60 fmol/mg).


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This systematic review of the literature indicates that the results obtained by the WHI, showing a worsening of breast cancer prognosis using two prognostic factors (size and lymph nodes), are in contradiction with most observational studies that were published previously. One may attribute this major difference to the fact that the WHI refers only to one HRT regimen, largely in women in an older age group whereas in the observational studies mostly younger women were included. On the other hand, most observational studies are retrospective and therefore might be associated with a number of biases, such as those of collection and selection (Grodstein et al., 2003Go). Another source of possible bias is the absence of adjustments for some confounding factors. For instance, among 13 studies that reported a significant decrease of the tumour size or of the nodal invasion in HRT users, only one study verified that this was not due to a surveillance bias (Cheek et al., 2002Go). On the other hand, in the WHI study, where these biases are non-existent, an increase in tumour size of 0.2 cm and of nodal involvement (25.9% versus 15.8%) was observed. It is tempting to believe that the worsening of the prognosis in terms of modest increase in size and nodes is at least partially due to loss of screening detection by the mammography, as observed by Chlebowski et al. (2003)Go and previously observed by many other authors (Laya et al., 1996Go; Kavanagh et al., 2000Go). Nevertheless, one cannot rule out the possibility that HRT not only increases the global risk of development of breast cancer, but also favours the development of more aggressive tumours. No difference in grade was observed in the WHI study between HRT users and non-users, although 10 observational studies out of 17 observed that HRT users had well-differentiated tumours more frequently than non-users (Table II). Nevertheless, one should remain cautious in the interpretation of these data, since a large heterogeneity characterizes these different studies. Many studies were performed on rather small samples. Furthermore, in many studies, multiple subanalyses were carried out without reporting statistical corrections for this multiplicity of analysis.

Few studies have analysed their results in relation to the HRT regimen that was used: limited data suggest that prolonged use of combined regimens are more often associated with better prognosis (Magnusson et al., 1996Go; Delgado et al., 2001Go; Sacchini et al., 2002Go). However, again, since these results concern observational studies and subgroups, the interpretation should remain cautious. Furthermore, although only one regimen was evaluated in the WHI study, it concerned a continuous combined regimen.

We also found some contradictory results: for example, the proportion of tumours with positive ERs and a higher S-phase fraction was found to be higher or lower in HRT users by different investigators (Table II). More favourable histology was reported in HRT users, but also more invasive tumours (Gapstur et al., 1999Go). More recently, seven studies reported that HRT users more frequently develop ILC (Li et al., 2000Go; 2003Go; Manjer et al., 2001Go; Chen et al., 2002Go; Daling et al., 2002Go; Klein et al., 2003Go; Newcomer et al., 2003Go). Five studies among these analysed subgroups and reported that the increase in lobular cancers could be attributed to the use of combined HRT regimens (Li et al., 2000Go; Chen et al., 2002Go; Daling et al., 2002Go; Li et al., 2003Go; Newcomer et al., 2003Go). On the other hand, in the WHI study, no difference could be found for steroid receptors or histological parameters between HRT users and non-users affected by breast cancer, but even in this study the number of women affected by breast cancer was low (n = 309 cases with known ER status) in proportion to the cases that were initially recruited in the cohort (n = 16 608). The proportion of S phase was not reported in the WHI study.

The Ki-67 proliferation index was only reported in one study. These authors suggested that HRT is associated with less invasive tumours (Sacchini et al., 2002Go). Higher proliferation rates were found in HRT users for <1 year, suggesting that these tumours began their development before the initiation of the HRT, while lower proliferation indices, were detected in long-term users (of >5 years), suggesting that these tumours are less aggressive. Only two studies evaluated new markers of breast cancer prognosis such as Neu protein, and the gene product of Bcl-2, p53 protein and E-cadherin: no differences were found between users and non-users (Holli et al., 1998Go; O’Connor et al., 1998Go).

Finally, to be complete, one should also note that cathepsin D and the presence of vascular emboli, two markers of worsening prognosis, were very rarely studied but were nevertheless reported to be more often associated with HRT use (Jones et al., 1994Go; Sacchini et al., 2002Go). Similarly, LeBlanc et al. (1999)Go found that HRT users had more frequently tumours with a bad prognosis (tumours of >2 cm, invaded nodes, negative hormonal receptors) than tumours with a good prognosis (tumours of <2 cm, no node invasion, positive hormonal receptors) than non-users [odds ratio 4.48; 95% confidence interval (CI) 1.10–18.30].

While it has been repeatedly cited in the literature that HRT is associated with a benefit in breast cancer prognosis, we cannot rule out the possibility that a publication and/or citation bias has existed in favour of this statement. The data that we found and the WHI study do not permit us to conclude that HRT favourably influences the prognosis of breast cancer. The observational studies provided data that are limited, and often contradictory. The results of the WHI study should be considered as providing a higher degree of evidence, since only this study was a prospective, randomized trial. However, since this study assessed only one particular HRT regimen, its results cannot be considered as definitive. A recent meta-analysis that evaluated the effect of HRT on mortality concluded that the risk of death from breast cancer among post-menopausal women who use HRT is reduced (Nanda et al., 2002Go), but a borderline increase risk of mortality was found in the Million Women Study Collaborators (relative risk 1.22; 95% CI 1.00–1.48) (Beral, 2003Go). Even in the latter study, however, insufficient data were collected to investigate the relationship between mortality and HRT regimen or duration. It is therefore difficult to provide explanations for these contradictory observations. One has to rule out possible biases influencing lower mortality among estrogen users affected by breast cancer. Alternatively, other prognostic factors, such as ploidy, S-phase fraction, Ki-67 proliferation index, overexepression of protein Neu, p53 protein, Bcl-2 expression, E-cadherin and cathepsin D, as well as vascular emboli, should also be considered. Finally, if the prognosis of breast cancer is investigated prospectively in the future, newly discovered prognostic factors, such as genes expressed by the tumour, should also be added (van de Vijver et al., 2002Go; Huang et al., 2003Go).

In summary, although only one combined estrogen–progestin HRT regimen (CEE associated with MPA) was studied, the latest results of the WHI trial indicate that breast cancers occur more frequently in women who use this regimen (hazard ratio 1.24). Contrary to what was previously thought and often cited, breast cancer in these HRT users was also associated with some worse prognostic indices, associated with a small increase in size and number of involved lymph nodes, compared with breast cancers occurring in non-HRT users. In view of these data, although no difference in mortality was found in the WHI study, we hypothesize that the reduced mortality that has been reported previously among HRT users in observational studies may be essentially due to biases involving detection and surveillance inherent to the populations that were studied.

We therefore believe that the current clinical message to our patients should be changed, and that one can no longer declare that breast cancers developed while using HRT are of better prognosis and associated with lower mortality.


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 Abstract
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 Results
 Discussion
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Submitted on July 14, 2003; resubmitted on October 2, 2003; accepted on November 10, 2003.