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
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Abstract |
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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
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Introduction |
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Patients and methods |
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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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Results |
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Discussion and conclusions |
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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 [16]. Letrozole was shown to reverse tamoxifen-induced endometrial thickening in a preliminary report of 24 patients [17
]. 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 [18
] and displays a different action (possibly androgen-mediated) on organ systems such as serum lipids [19
23
] and the bone [13
, 24
]. 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 [25
].
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 [26].
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 [2], 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 [27
] 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.
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Acknowledgements |
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Received for publication April 26, 2004. Revision received August 31, 2004. Accepted for publication September 2, 2004.
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References |
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