Third generation aromatase inhibitors may prevent endometrial growth and reverse tamoxifen-induced uterine changes in postmenopausal breast cancer patients

L. Morales1,2, D. Timmerman2, P. Neven2,5, M. L. Konstantinovic2, A. Carbonez6, S. Van Huffel7, L. Ameye7, C. Weltens4,5, M.-R. Christiaens3,5, I. Vergote2 and R. Paridaens1,5,*

1 Departments of Medical Oncology, 2 Obstetrics and Gynecology, 3 Surgery, 4 Radiation Oncology, 5 Multidisciplinary Breast Center, University Hospitals Leuven; 6 University Center for Statistics, 7 Department of Electrical Engineering, Catholic University of Leuven, Leuven, Belgium

* Correspondence to: Dr R. Paridaens, Department of Medical Oncology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. Tel: +32-16-34-69-00; Fax: +32-16-34-69-01; Email: robert.paridaens{at}uz.kuleuven.ac.be


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion and conclusions
 References
 
Background: Tamoxifen may induce uterine abnormalities of clinical concern. Our aim was to compare early uterine changes occurring in postmenopausal breast cancer patients treated in first-line with tamoxifen or third generation aromatase inhibitors. We also assessed the effect of aromatase inhibitors on tamoxifen-induced uterine changes.

Patients and methods: Seventy-seven consecutive postmenopausal breast cancer patients scheduled to start endocrine treatment were included in this prospective study. Transvaginal ultrasonography (TVUS) was carried out before and after 3 months of therapy. No interventions were done on pre-existing asymptomatic uterine abnormalities seen on baseline sonography.

Results: After 3 months of therapy, tamoxifen significantly increased endometrial thickness and uterine volume. Additionally, tamoxifen induced endometrial cysts and polyps, and increased the size of pre-existing fibroids. In contrast, aromatase inhibitors did not stimulate endometrial growth and were not associated with endometrial pathologies seen under tamoxifen. Furthermore, aromatase inhibitors decreased endometrial thickness and uterine volume in patients previously treated with tamoxifen.

Conclusions: Our study demonstrates that tamoxifen induces uterine abnormalities from as early as 3 months of therapy. In contrast, these abnormalities are not seen in patients on aromatase inhibitors. Furthermore, our data indicate that tamoxifen therapy followed by an aromatase inhibitor may lead to a reduction in endometrial pathologies associated with tamoxifen.

Key words: aromatase inhibitors, breast cancer, endometrial thickness, SERM, tamoxifen, uterine changes


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion and conclusions
 References
 
Tamoxifen is a selective estrogen receptor modulator with a proven benefit in all stages of breast cancer. Its uterine effect increases the risk of endometrial hyperplasia, polyps [1Go, 2Go] and cancer [3Go]. The benefit of screening is controversial since most of these uterine changes are benign [4Go, 5Go]; however, many women undergo interventions to exclude malignant disease. Strategies to protect the endometrium from tamoxifen-induced changes using progestagens have been evaluated [6Go, 7Go]. However, the potential detrimental effect of such agents on the breast remains a matter of concern [8Go, 9Go]. Nowadays, third-generation non-steroidal aromatase inhibitors such as anastrozole and letrozole, and the steroidal type exemestane are increasingly being used in the management of breast cancer [10Go, 11Go]. These agents suppress estrogen synthesis by inhibiting aromatase, blocking the conversion of androgens to estrogens in postmenopausal women to almost undetectable circulating levels [12Go–14Go]. In the adjuvant ATAC trial, anastrozole when compared to tamoxifen was associated with less uterine abnormalities [15Go], while the uterine effects of letrozole and exemestane have not yet been fully documented. Our aim was to compare early changes in double endometrial thickness (DET) and uterine volume (UV) occurring in postmenopausal breast cancer patients receiving either tamoxifen or aromatase inhibitor in first-line. We also assessed the uterine effects of aromatase inhibitors in patients previously exposed to tamoxifen.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion and conclusions
 References
 
We conducted a prospective single-center study in all fit non-hysterectomised postmenopausal breast cancer patients scheduled to start endocrine treatment. Postmenopausal status was defined as cessation of menses for more than 1 year. In case of doubt, follicle stimulating hormone and estradiol levels were assessed and had to be in the postmenopausal range. Women on hormone replacement therapy while being diagnosed with breast cancer had stopped therapy for at least 1 month before the start of this study. Two investigators (DT and MLK), who were blinded on the hormonal treatment patients were receiving, carried out transvaginal ultrasonography (TVUS) before the start of endocrine treatment and after 3 months of therapy. The uterus was completely assessed in sagittal and coronal planes with uterine size recorded in three diameters (D1, 2, 3). The volume (ml) was estimated as (D1xD2xD3x3.14)/6. DET was measured in the sagittal plane, from one endometrial–myometrial interface to another excluding intracavitary fluid. Endometrial abnormalities such as internal cysts and polyps were recorded. The presence of internal cysts was defined by visualization of more than one anechogenic area greater than 2 mm. No interventions were done on pre-existing asymptomatic uterine abnormalities seen on baseline sonography. The study was conducted according to the guidelines for clinical studies described in the Declaration of Helsinki (as revised by the World Medical Association, http://www.wma.net). The protocol was approved by the Ethical Committee for Clinical Studies and all participants provided written informed consent.

Statistical analysis was done with SAS (Version 8). ANOVA was used to determine differences in mean DET and UV between the different treatment groups. If significant differences were detected, appropriate post-hoc comparisons were done. Multiple regression analysis was carried out to detect variables influencing DET. Table 1 shows the six different treatment groups. Groups 1 to 4 comprised patients receiving adjuvant therapy with either tamoxifen, letrozole, anastrozole, or a blinded treatment with either tamoxifen or letrozole (randomized FEMTA trial with equal chances of receiving either treatment). Group 5 patients received exemestane after tamoxifen. Group 6 patients received exemestane after letrozole.


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Table 1. Transvaginal sonographic changes of the uterus from baseline to 3 months of treatment

 

    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion and conclusions
 References
 
The 77 women included in this study had a mean age of 60 years, were on average 10 years postmenopausal, and had a mean BMI of 25 kg/m2. Fifty-nine patients (77%) received adjuvant hormonal treatment whereas the remaining patients were treated for advanced disease. Table 1 shows that at baseline, a significantly higher mean DET of 9.89 mm was recorded in patients previously treated with tamoxifen (P < 0.0001) while no significant difference in the baseline DET and UV was seen between the other groups. Three months on tamoxifen led to a 65% increase in mean DET and a 38% increase in UV (P < 0.0001 and P=0.0062, respectively). Patients on first-line letrozole or anastrozole and patients on exemestane after exposure to letrozole did not have significant changes in both parameters. In contrast, crossing-over to exemestane because of breast cancer progression under tamoxifen resulted in a 37% decrease in mean DET and a 26% decrease in UV. Compared with the tamoxifen group, this change from baseline mean DET and UV for patients on exemestane was significant (P < 0.0001 and P=0.0035, respectively). The mean DET and UV observed at 3 months in the FEMTA group was in agreement with the results expected from a 50/50 mixture of patients on tamoxifen or letrozole. In five patients not belonging to any of the previously described six groups, formal statistical analysis was not done due to the limited number. Two of them crossed-over from tamoxifen to letrozole, which induced mean DET and UV decreases of 3.35 mm and 12 cm3, respectively, after 3 months. The last three patients who were therapy naive received adjuvant exemestane. TVUS was done after 3 months therapy (one patient) and was postponed to 6 months (two patients) for patients' convenience. In all three patients, adjuvant exemestane induced further uterine atrophy with a 1.23 mm mean decrease in DET and an 8 cm3 decrease in UV. The change in DET from baseline to 3 months treatment of each individual patient is illustrated in Figure 1.



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Figure 1. Changes in DET from baseline to 3 months of treatment. Each line represents each individual patient. (A) First-line treatment; solid line, tamoxifen. (B) First-line treatment; solid line, anastrozole; dashed line, letrozole; dotted line, exemestane. Second TVUS was done after 6 months in two patients receiving first-line exemestane. (C) Second- and third-line treatments; solid line, exemestane after tamoxifen; dotted line, exemestane after letrozole; dashed line, letrozole after tamoxifen. Abbreviations: DET, double endometrial thickness.

 
Apart from the above mentioned DET and UV changes, other sonographic findings after 3 months are shown in Table 2. Those on tamoxifen developed internal cysts (40%), endometrial polyps (15%) and an increase in size of pre-existing fibroids (25%), whereas those receiving aromatase inhibitors did not develop internal cysts or polyps and 28% had a decrease in the size of pre-existing polyps or fibroids. On multiple regression analysis, the presence of internal cysts and polyps significantly correlated with DET (P=0.0051 and P=0.0164, respectively). There were two patients in whom DET could not be measured after 3 months: one developed a symptomatic endometrial polyp diagnosed at 8 weeks of tamoxifen use and one had a hysterectomy and bilateral salpingo-oophorectomy for an ovarian tumor discovered on baseline TVUS (mucinous cystadenoma on histopathology).


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Table 2. Transvaginal sonographic abnormalities of the uterus at 3 months of treatment

 

    Discussion and conclusions
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion and conclusions
 References
 
Our study demonstrates that tamoxifen significantly increases endometrial thickness and uterine volume after only 3 months of therapy. Likewise, very early uterine abnormalities induced by tamoxifen, such as endometrial cysts, polyps and an increase in size of pre-existing fibroids, are already evident. In contrast, steroidal and non-steroidal aromatase inhibitors induce uterine atrophy and are not associated with uterine pathologies seen under tamoxifen. Furthermore, an important finding is that aromatase inhibitors can decrease endometrial thickness and uterine volume in patients treated with tamoxifen.

To date, the early uterine effect of tamoxifen after only 3 months of therapy has not been assessed. Furthermore, studies on the uterine effects of aromatase inhibitors, particularly their effects on tamoxifen-associated abnormalities, are limited. The lack of endometrial effect of anastrozole, a non-steroidal aromatase inhibitor has recently been reported [16Go]. Letrozole was shown to reverse tamoxifen-induced endometrial thickening in a preliminary report of 24 patients [17Go]. However, this study did not mention the effect of letrozole on other tamoxifen-associated abnormalities such as polyps and fibroids. While the atrophic effect of letrozole may be anticipated from what is known with the other non-steroidal aromatase inhibitor, anastrozole, the observation on exemestane patients is novel. Since exemestane belongs to another category of aromatase inhibitors, being steroidal in structure, its uterine effects cannot be presumed to be identical to non-steroidal aromatase inhibitors. It is devoid of total cross-resistance with non-steroidal aromatase inhibitors [18Go] and displays a different action (possibly androgen-mediated) on organ systems such as serum lipids [19Go–23Go] and the bone [13Go, 24Go]. However, our data on the favorable effect of exemestane on tamoxifen-induced endometrial abnormalities have to be confirmed in larger studies with a longer follow-up period, such as the endometrial substudy of the Intergroup Exemestane Study [25Go].

TVUS is a relatively non-invasive procedure which enabled us to demonstrate the distinct uterine effects of tamoxifen and aromatase inhibitors early in the course of therapy. A study such as this with a detailed systematic pre-treatment uterine evaluation allowed us to attribute accurately the uterine changes observed after 3 months to a particular treatment. Although routine screening is not recommended in asymptomatic women receiving tamoxifen, the application of TVUS in clinical trials looking at endometrial safety of different endocrine treatments can be considered an adequate procedure, having shown equal accuracy and better acceptability than relatively more invasive procedures [26Go].

Our results have some important clinical implications. First, steroidal and non-steroidal aromatase inhibitors seem safe from a gynecological point of view. They all induce uterine atrophy which fit with their putative mechanism of action of inhibiting estrogen synthesis. This is reassuring because these compounds are increasingly being used in the adjuvant and even in the preventive setting. Secondly, on the assumption that tamoxifen-induced endometrial thickening by TVUS is often a precursor or surrogate marker of endometrial pathologies [2Go], the reversal of such suggests that tamoxifen therapy followed by an aromatase inhibitor may not only be more effective as shown in the recent MA-17 trial [27Go] but may, in the end, lead to a reduction in endometrial pathologies associated with tamoxifen.

Although it is interesting to consider the possibility that a short treatment with aromatase inhibitors in patients with tamoxifen-induced uterine abnormalities could possibly reduce or obviate invasive procedures such as hysteroscopy or curettage, the validity and safety of such an approach warrants further evaluation. Future clinical trials looking at endometrial safety of endocrine treatments, particularly those trials involving sequential treatments with selective estrogen receptor modulators and aromatase inhibitors, should also take into account the potential effect on the uterus of a wash-out period after tamoxifen treatment. The studies will determine whether tamoxifen-induced changes would eventually resolve over time or whether aromatase inhibitors can offer a protective effect on the endometrium of patients treated with tamoxifen.


    Acknowledgements
 
We thank all the women who took part in this study. The statistical analysis in connection with SVH and LA was supported by interdisciplinary research grants of the research council of the Katholieke Universiteit Leuven, Belgium (IDO/99/03 and IDO/02/09 projects), by the Belgian Programme on Interuniversity Poles of Attraction (IUAP PhaseV-22) and by the Concerted Action Project MEFSTO-666 of the Flemish Community.

Received for publication April 26, 2004. Revision received August 31, 2004. Accepted for publication September 2, 2004.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion and conclusions
 References
 
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