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Aromatase inhibitors and the endometrium
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Maturitas 59 (2008) 285–292
Review
Aromatase inhibitors and the endometrium Ilan Cohen ∗ Department of Obstetrics and Gynecology, Meir Medical Center, Kfar-Saba, Affiliated with Sackler Faculty of Medicine, Tel Aviv University, Ramat-Aviv 44281, Israel Received 31 July 2007; received in revised form 19 December 2007; accepted 9 March 2008
Abstract Objective: To investigate the potential impact of aromatase inhibitors, given after stopping tamoxifen treatment, on the endometrium of postmenopausal breast cancer patients. Methods: Review of all available literature of studies on aromatase inhibitor therapy in postmenopausal breast cancer patients previously treated with tamoxifen. Results: (1) Endometrial thickness was found to be significantly lower in patients switched from tamoxifen treatment to aromatase inhibitor therapy, compared to those who continued tamoxifen treatment. This significant difference between the 2 groups was maintained throughout the entire treatment. (2) Vaginal bleeding was significantly more common in patients who continued tamoxifen therapy as compared to those who switched to aromatase inhibitors. (3) Replacement of tamoxifen treatment by aromatase inhibitors in postmenopausal breast cancer patients resulted in the appearance of only few, benign endometrial pathologies. The different endometrial pathologies were more common in patients who continued tamoxifen therapy, compared to patients who switched to aromatase inhibitors. (4) Endometrial cancer was recovered in significantly more patients who continued tamoxifen therapy as compared to those switched to aromatase inhibitors. However, some studies showed no significant statistical differences in the frequency of endometrial cancer diagnosed in the tamoxifen group as compared to the aromatase inhibitor group. Conclusion: These findings may hint on the possibility that aromatase inhibitors may provide a potential protective effect on the endometrium in patients previously treated with tamoxifen. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Tamoxifen; Switching; Aromatase inhibitors; Endometrium
Contents 1. 2. 3. 4. ∗
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial thickness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vaginal bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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5. 6. 7.
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Benign endometrial pathologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Tamoxifen (TAM) is the antihormonal treatment of choice for postmenopausal breast cancer patients with positive estrogen receptors (ERs) [1]. TAM competes with estrogens for binding to cytoplasmic estrogen receptors and prevents estrogen/estrogen receptormediated gene transcription, DNA synthesis, and breast cancer cell growth. It prevents the transmission of G1 to mid-G1 phase in the cell cycle, and the number of cells in the S, and G2 plus M-phases are decreased [2]. One of the most significant and deleterious side effects of postmenopausal TAM treatment appears to be its proliferative effect on the endometrium, provoking a high rate of endometrial pathologies including hyperplasia, polyps, carcinoma and malignant mixed mesodermal tumors [3–8]. The relative risk of endometrial cancer is gradually increased with longer duration of TAM treatment [4] especially when extended beyond 5 years [5]. Endometrial cancer also might appear for at least 5 years after the last treatment [5]. Long-term TAM users showed higher proportions of non-endometrioid tumors than non-users [32.7% vs. 17.4%; P = 0.004], especially serous adenocarcinoma and carcinosarcomas. An increased proportion of FIGO stage III and IV tumors was also observed [20.0% vs. 11.3%; P = 0.049]. Three-year uterine corpus cancerspecific survival was worse for long-term TAM users than for non-users [82% vs. 93%; P = 0.0001] [8]. It has also been reported that more than one third of past users of TAM developed uterine and endometrial cancer with worse prognosis and with more invasive histologic features than current TAM users [6,7]. Transvaginal ultrasonography (TVS) has been extensively used in the investigation and evaluation of endometrial thickness among postmenopausal breast cancer TAM-treated patients [9–18], demonstrating significant thickening of the endometrium in asymptomatic, postmenopausal breast cancer TAM-treated patients as compared with similar non-treated patients [9,10,13] and healthy postmenopausal patients [12].
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There was also a notable increase in mean endometrial thickness measured before TAM treatment and up to more than 3 years of treatment [16]. Lately, TAM treatment is being challenged by third-generation aromatase inhibitors (AIs) that have demonstrated improved disease-free survival in a variety of adjuvant settings for early breast cancer with promising clinical results [19–23]. The non-steroidal AIs anastrazole and letrazole (LET) and steroidal AI exemestane, are the most commonly used. TAM can function as an estrogen agonist in the low estrogenic environment of menopause [24], activating and upregulating endometrial estrogen receptors [25], and ultimately inducing endometrial thickening and endometrial pathological changes [3–8]. AIs inhibit aromatase enzyme function and thus, block the conversion of androgens to estrogens, leading to suppressed estrogen synthesis [19–23]. Thus, it may be speculated that AIs might prevent endometrial thickening and the formation of endometrial pathologies in postmenopausal breast cancer patients. In the new treatment protocols for postmenopausal breast cancer patients, long-term TAM treatment is replaced by AI, therefore it is necessary to investigate AIs’ potential influence on the endometrium.
2. Clinical data In a combined analysis of data from two prospective, multicenter, randomized, open-label trials, with nearly identical inclusion criteria [ABCSG trial 8 and ARNO 95 trial], postmenopausal women with hormone-sensitive early breast cancer who had completed 2 years of adjuvant TAM were randomized to receive 1 mg of anastrozole (ANA) [1618 patients] or 20–30 mg TAM [1606 patients] daily. All patients were followed for 28 months. There was a trend towards fewer endometrial cancer cases [1 (<1%)] in the ANA
I. Cohen / Maturitas 59 (2008) 285–292
group than in the TAM group [7 (<1%)]. Frequency of vaginal bleeding or discharge was similar in both groups [177 (16%) events in the TAM group and 198 (18%) events in the ANA group] [22]. Another prospective, randomized trial tested the efficacy of switching postmenopausal breast cancer patients [node-positive, estrogen receptor-positive tumors] who were already treated for 2–3 years with TAM, to receive ANA 1 mg daily [223 patients] or to continue receiving 20 mg of TAM [225 patients] for a total duration of 5 years. Significantly less events of gynecological changes, including endometrial carcinoma, were reported in the ANA-treated group as compared to the TAM-treated group [2 (1.0%) and 17 (11.3%), respectively; P = 0.002]. However, the authors did not specify the proportions of the different types of endometrial pathologies identified. There was no significant difference with regard to overall gynecological symptoms between the 2 groups [12 (8.0%) in the TAM group and 15 (7.4%) in the ANA group]. Again, the authors did not specify the proportions of the different types of gynecological symptoms [20]. The authors of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial, consisting of a total of 9366 postmenopausal women with localized breast cancer, of which, 3092 patients were switched from TAM treatment to ANA therapy and 3094 patients continued to receive TAM for overall 5 years, reported on the results following a median follow-up of 68 months. Vaginal bleeding and vaginal discharge were significantly more common in the TAM-treated patients as compared to the ANA-treated patients [vaginal bleeding: 317 (10.2%) and 167 (5.4%), respectively; P < 0.0001. Vaginal discharge: 408 (13.2%) and 109 (3.5%), respectively; P < 0.0001]. Endometrial cancer was also significantly more common among the patients continuously treated with TAM as compared to those switched to ANA [17 (0.8%) and 5 (0.2%), respectively; P = 0.02] [21]. The ATAC endometrial sub-protocol was the first double-blind, randomized study to prospectively investigate the incidence of abnormal endometrial histology findings amongst those patients receiving ANA 1 mg compared with those receiving 20 mg of TAM. A total of 285 gynaecologically asymptomatic women from 31 centers in 10 countries underwent baseline investigation, comprised of TVS scanning, a hysteroscopy and
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endometrial biopsy, at entry to the sub-protocol and after 1 year and 2 years of treatment. The baseline incidence of histologically confirmed endometrial abnormalities was 9.0% (24 of 268 patients assessed at baseline). The commonest abnormalities were polyps (without atypia), occurring in 23 (8.5%) patients. No change in TVS measured median endometrial thickness from baseline (3.0 mm) was observed in patients treated with ANA after 2 years, while median endometrial thickness increased with TAM therapy from 3.8 mm at baseline to 6.5 mm after 1 year, and to 7.0 mm after 2 years. There were no significant statistical differences in the overall number of endometrial abnormalities at 1 and 2 years in the ANA group as compared to the TAM group [at 1 year: 4 vs. 7 abnormalities; OR = 0.54 (95% CI: 0.147, 1.971); P = 0.35. At 2 years: 6 vs. 10 abnormalities; OR = 0.44 (95% CI: 0.146, 1.314); P = 0.28] [26]. The lack of significant statistical differences in the overall number of endometrial abnormalities was likely to be because the number of patients recruited was insufficient based on the original power calculations [26]. The majority of abnormalities in all treatment groups were polyps (without atypia or atypia unknown) with no significant differences between the groups at either 1 or 2 years of treatment. In the BIG I-98 randomized, phase 3, double-blind trial, postmenopausal women with operable invasive breast cancer with positive estrogen receptors, progesterone receptors (PR), or both, were randomly assigned to receive therapy with LET 2.5 mg daily or TAM 20 mg daily for 5 years (overall 1835 patients). Another 6193 women were randomly assigned, later in the study, to receive LET or TAM for 2 years followed by TAM for 3 years, or TAM for 2 years followed by LET for 3 years. As compared to TAM, LET was associated with a significantly lower rate of vaginal bleeding [132 (3.3%) vs. 263 (6.6%), respectively; P < 0.001], significantly fewer endometrial biopsies [72 of 3089 women (2.3%) vs. 288 of 3157women (9.1%); P < 0.001] and nonsignificantly fewer invasive endometrial cancers [4 of 3089 women (0.1%) vs. 10 of 3157 women (0.3%); P = 0.18)] [19]. To investigate the effect of switching from adjuvant TAM to ANA treatment in postmenopausal
– – – [29]
27
–
–
–
4.3 ± 1.6
3.6 ± 1.2
0.0001 4 8 4 7 .5 3.3 ± 1.2 6.7 ± 2.4 88 [27]
83
– <5 7.0 <5 6 .5 – – 89 [26]
97
Endometrial thickness at 24 months ANA (mm) Endometrial thickness at 24 months TAM (mm) Endometrial thickness at 12 months ANA (mm) Endometrial thickness at 12 months TAM (mm) Endometrial thickness at 6 months ANA (mm) Endometrial thickness at 6 months TAM (mm) ANA patients (no.) TAM patients (no.) Reference
breast cancer patients having proven TAM-induced benign endometrial pathologies, 226 women, who were treated with 20 mg of TAM (≥12 months, ≤48 months) and developed abnormal vaginal bleeding and/or asymptomatic endometrial thickness >10 mm were prospectively investigated using hysteroscopy and dilatation and curettage. Thereafter, 171 patients were randomized in a phase III study to continue TAM treatment (88 patients) or switch to 1 mg of ANA (83 patients). The mean endometrial thickness at entry to the study was comparable in the ANA and TAM groups [12.4 ± 5.8 and 12.9 ± 5.6 mm, respectively; P = 0.59]. Six months after randomization, endometrial thickness was significant lower in patients switched to ANA therapy [3.3 ± 1.2 mm] compared to those who continued TAM treatment [6.7 ± 2.4 mm; P < 0.0001]. This significant difference between the 2 groups was maintained throughout the entire treatment period. In the ANA group, no patients presented with an endometrial thickness >10 mm, while in the TAM group 30 (34.1%) presented with an endometrial thickness of >10 mm [range 11–24 mm; P < 0.0001] [27]. Four patients in the ANA group had a second endometrial biopsy (due to vaginal bleeding). All had endometrial atrophy. Of the 29 patients in the TAM group undergoing a second hysteroscopy and endometrial biopsy, polyps were recovered in 14 (48.3%), hyperplasia in 8 (27.6%) [2 having atypical hyperplasia] and atrophy in 7 (24.1%). There was no significant difference in recurrent vaginal bleeding between the 2 groups [27]. In a recent prospective, open-label, randomized study, 979 postmenopausal breast cancer women were randomized, following 2 years of TAM treatment, to continue 20 mg of TAM (452 patients) or to switch to 1 mg of ANA (445 patients) for an additional 2 years. Patients were monitored every 6 months during 1–3 years and annually thereafter. There were no significant statistical differences in different types of endometrial pathologies recovered in the TAM group as compared to the ANA group [endometrial cancer: 2 (0.4%) vs. 0 (0%), respectively; endometrial hyperplasia: 39 (8.6%) vs. 8 (1.8%), respectively; endometrial polyps: 15 (3.3%) vs. 4 (0.9%)]. There was also no significant difference between the 2 groups with regard to vaginal bleeding [TAM group 9 (2.0%) vs. ANA group 7 (1.6%)] [23].
P value
I. Cohen / Maturitas 59 (2008) 285–292 Table 1 Distribution of endometrial thickness in postmenopausal breast cancer patients who completed adjuvant tamoxifen and who were randomized to receive anastrozole or tamoxifen
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Table 2 Distribution of endometrial thickness in postmenopausal breast cancer patients whose tamoxifen treatment was replaced by aromatase inhibitors Reference
No. of patients
Duration of tamoxifen treatment (months)
Endometrial thickness before discontinuation of TAM (mm)
Duration of aromatase inhibitor treatment (Months)
Endometrial thickness (mm)
P value
[28] [29]
36 27
24.9 ± 9.8 24.1 ± 20.8
11.4 ± 4.6 8.2 ± 5.0
6.1 ± 2.8 36 ± 48
4.8 ± 2.9 3.0 ± 1.2
0.001 –
A prospective TVS evaluation of the dynamics of endometrial thickness performed in 36 postmenopausal breast cancer patients whose TAM treatment was replaced with AIs, revealed a significant decrement of endometrial thickness following 24.9 ± 9.8 months of TAM treatment, from a value of 11.4 ± 4.6 mm, measured at the last ultrasonographic measurement performed before discontinuation of TAM treatment, down to a value of 6.1 ± 2.8 mm, measured following 4.8 ± 2.9 months of AI therapy (P = 0.001). In 12 patients (80%), endometrial thickness was reduced following the administration of AIs, one patient (6.7%) had no change and 2 (13.3%) patients demonstrated a light increase of endometrial thickness [28]. All study patients, except one, were free of endometrial pathologies, following the switching to AI treatment. In one patient, whose endometrial thickness increased from 7.6 to 12 mm, hysteroscopy revealed benign endometrial polyp [28]. Similar results were also recorded by Garuti et al. [29], showing gradual decrease in endometrial thickness in 27 patients switched from TAM to AI therapy (8.2 ± 5.0 mm at baseline, 4.3 ± 1.6 mm at 12 months, 3.3 ± 1.3 mm at 24 months and 3.0 ± 1.2 mm at 36–48 months). Simple endometrial hyperplasia was detected only in 1 (3.7%) patient, following 12 month of AI therapy [29].
3. Endometrial thickness Endometrial thickness was found to be significantly lower in patients switched from TAM treatment to ANA therapy compared to those who continued TAM treatment [26–29]. This significant difference between the 2 groups was maintained throughout the entire treatment [27]. Endometrial thickness was also higher in patients treated with a combination of TAM and AI [26]. Thus, replacement of TAM treatment by AI in postmenopausal breast cancer patients, resulted in a significant decrease of endometrial thickness [26–29] (Tables 1 and 2).
4. Vaginal bleeding In most studies, vaginal bleeding was reported in significantly more patients who continued TAM therapy compared to those switched to AIs [19–21]. However, in one study a similar amount of patients suffered from vaginal bleeding in both groups [22] (Table 3).
5. Benign endometrial pathologies Replacement of TAM treatment by AI in postmenopausal breast cancer patients resulted in the
Table 3 Distribution of vaginal bleeding in postmenopausal breast cancer patients whose tamoxifen treatment was replaced by aromatase inhibitors Reference
TAM-treated patients (no.)
ANA-treated patients (no.)
Vaginal bleeding in TAM-treated patients (no.)
Vaginal bleeding in ANA-treated patients (no.)
OR
P value
[19] [20] [21] [22]
3157 225 3094 1117
3089 223 3092 1120
263 (6.6%) 12 (8.0%) 317 (10.2%) 195 (17%)
132 (3.3%) 15 (7.4%) 167 (5.4%) 198 (18%)
– – – 1.02
<0.001 0.5 <0.0001 –
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Table 4 Distribution of endometrial pathologies in postmenopausal breast cancer patients who completed adjuvant tamoxifen and who were randomized to receive anastrozole or tamoxifen Reference No. of tamoxifen patients No. of anastrozole patients Endometrial atrophy with tamoxifen (no.) Endometrial atrophy with anastrozole (no.) Endometrial polyp with tamoxifen (no.) Endometrial polyp with anastrozole (no.) Endometrial hyperplasia with tamoxifen (no.) Endometrial hyperplasia with anastrozole (no.)
23 452 445
27 88 83 7 (8.0%) 4 (4.2%) 14 (16.0%) 0 (0.0%) 8 (9.1%) 0 (0.0%)
15 (3.3%) 4 (0.9%) 39 (8.6%) 8 (1.8%)
Table 5 Distribution of endometrial cancer in postmenopausal breast cancer patients who completed adjuvant tamoxifen and who were randomized to receive anastrozole or tamoxifen Reference
TAM-treated patients (no.)
ANA-treated patients (no.)
Endometrial cancer in TAM-treated patients (no.)
Endometrial cancer in ANA-treated patients (no.)
OR
P value
[19] [20] [21] [22] [23]
3157 225 3094 1117 452
3089 223 3092 1120 445
10 (0.3%) 17 (11.3%)a 17 (0.8%) 7 (<1%) 2 (0.4%)
4 (0.1%) 2 (1.0%)a 5 (0.2%) 1 (<1%) 0 (0.0%)
– – – 1.14 –
0.18 0.0002 0.02 – –
a
Overall endometrial pathologies (including endometrial cancer).
appearance of only few, benign endometrial pathologies [23,26–29]. In some studies different endometrial pathologies were more common in patients who continued TAM therapy as compared to patients switched to AIs [23,27]. However, in other study there were no significant statistical differences in different types of endometrial pathologies recovered in the TAM group as compared to the ANA group [26] (Table 4).
6. Endometrial cancer Endometrial cancer was recovered in significantly more patients who continued TAM therapy as compared to those switched to AIs [19–21]. However, in other studies there were no significant statistical differences in the frequency of endometrial cancer diagnosed in the TAM group as compared to the ANA group [22,23] (Table 5).
7. Conclusions and discussion The data reported in this review may hint on the possibility that AIs may provide a potential protective effect on the endometrium in postmenopausal breast cancer patients previously treated with TAM. However, the changes in endometrial thickness, reported following the administration of AIs, should be regarded with caution, as it may well be that the decrement of the endometrial thickness was mainly due to the discontinuation of TAM treatment, regardless of the administration of AIs, as it has been shown that median endometrial thickness significantly decreases within 6 months following TAM discontinuation [14,17], and remains constantly low thereafter [14]. Patients switched from TAM treatment to AIs should be continuously monitored by TVS, as detecting TVS endometrial echo thicker than that recorded before discontinuation of TAM, or detecting a thickening of endometrium following the administration of AIs, should alert the clinician to the possible existence of endometrial pathology.
I. Cohen / Maturitas 59 (2008) 285–292
These potential changes in endometrial thickness following discontinuation of TAM treatment may have extreme importance, as it has been reported that more than one third of past users of TAM developed uterine and endometrial cancer with worse prognosis and with more invasive histologic features than current TAM users [6,7]. Moreover, in several studies endometrial cancer was diagnosed in breast cancer patients following replacement of TAM by AIs [19–23]. Therefore, until we shall have enough data on the severity of endometrial cancer developed in patients switched from TAM to AIs, it is reasonable to continue monitoring these patients by TVS.
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[12] Exacoustos C, Zupi E, Cangi B, Chiartti M, Arduini D, Ramanini C. Endometrial evaluation in postmenopausal breast cancer patients receiving tamoxifen: an ultrasound colour flow Doppler, hysteroscopic and histologic study. Ultrasound Obstet Gynecol 1995;6:435–42. [13] Cecchini S, Ciatto S, Bonardi R, et al. Screening by ultrasonography for endometrial carcinoma in postmenopausal breast cancer patients with tamoxifen treatment. Gynecol Oncol 1996;60:409–11. [14] Love CDB, Muir BB, Scrimgeour JB, Leonard RCF, Dillon P, Dixon JM. Investigation of endometrial abnormalities in asymptomatic women treated with tamoxifen and an evaluation of the role of endometrial screening. J Clin Oncol 1999;17:2050–4. [15] Gerber B, Krause A, Muller H, et al. Effects of adjuvant tamoxifen on the endometrium in postmenopausal women with breast cancer: a prospective long-term study using transvaginal ultrasound. J Clin Oncol 2000;18:3464–70. [16] Fong K, Kung R, Lytwyn A, et al. Endometrial evaluation with transvaginal US and hysterosonography in asymptomatic postmenopausal women with breast cancer receiving tamoxifen. Radiology 2001;220:765–73. [17] Nahari K, Tepper R, Beyth Y, Flex D, Figer A, Cohen I. Longterm transvaginal endometrial follow-up in postmenopausal breast cancer patients with tamoxifen treatment. Gynecol Oncol 1999;74:222–6. [18] Cohen I, Beyth Y, Azaria R, Flex D, Figer A, Tepper R. Ultrasonographic measurement of endometrial changes following discontinuation of tamoxifen treatment in postmenopausal breast cancer patients. Br J Obstet Gynecol 2000;107:1083–7. [19] The Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrazole and tamoxifen in postmenopausal omen with early breast cancer. N Engl J Med 2005;353:2747–57. [20] Boccardo F, Rubagotti A, Puntoni M, et al. Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: preliminary results of the Italian tamoxifen anastrozole trial. J Clin Oncol 2005;23:5138–47. [21] ATAC Triallists’ Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005;365:60–2. [22] Jakesz R, Jonat W, Gnant M, et al. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 2005;366:455–62. [23] Kaufmann M, Jonat W, Hilfrich J, et al. Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 study. J Clin Oncol 2007;25:2664–70. [24] Gusberg SB. Tamoxifen for breast cancer: associated endometrial cancer (editorial). Cancer 1990;65:1463–4. [25] Gorodeski GI, Beery R, Lunenfeld B, Geier A. Tamoxifen increases plasma estrogen-binding equivalents and has an agonistic effect on histologically normal premenopausal and postmenopausal endometrium. Fertil Steril 1992;57: 390–7.
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[26] Duffy S, Jackson TL, Lansdown M, et al. The ATAC (‘Arimidex’, Tamoxifen, Alone or in Combination) adjuvant breast cancer trail: first results of the combination sub-protocol following 2 years of treatment. Human Reprod 2006;21: 545–53. [27] Gerber B, Krause A, Reimer T, et al. Anastrozole versus tamoxifen treatment in postmenopausal women with endocrineresponsive breast cancer and tamoxifen-induced endometrial pathology. Clin Cancer Res 2006;12:1245–50.
[28] Markovitch O, Tepper, Fishman A, Aviram R, Cohen I. Aromatase inhibitors reverse tamoxifen induced endometrial ultrasonographic changes in postmenopausal breast cancer patients. Breast Cancer Res Treat 2007;101: 185–90. [29] Garuti G, Cellani F, Centinaio G, Montanari G, Nalli G, Luerti M. Prospective endometrial assessment of breast cancer patients treated with third generation aromatase inhibitors. Gynecol Oncol 2006;103:599–603.
Maturitas 59 (2008) 285–292
Review
Aromatase inhibitors and the endometrium Ilan Cohen ∗ Department of Obstetrics and Gynecology, Meir Medical Center, Kfar-Saba, Affiliated with Sackler Faculty of Medicine, Tel Aviv University, Ramat-Aviv 44281, Israel Received 31 July 2007; received in revised form 19 December 2007; accepted 9 March 2008
Abstract Objective: To investigate the potential impact of aromatase inhibitors, given after stopping tamoxifen treatment, on the endometrium of postmenopausal breast cancer patients. Methods: Review of all available literature of studies on aromatase inhibitor therapy in postmenopausal breast cancer patients previously treated with tamoxifen. Results: (1) Endometrial thickness was found to be significantly lower in patients switched from tamoxifen treatment to aromatase inhibitor therapy, compared to those who continued tamoxifen treatment. This significant difference between the 2 groups was maintained throughout the entire treatment. (2) Vaginal bleeding was significantly more common in patients who continued tamoxifen therapy as compared to those who switched to aromatase inhibitors. (3) Replacement of tamoxifen treatment by aromatase inhibitors in postmenopausal breast cancer patients resulted in the appearance of only few, benign endometrial pathologies. The different endometrial pathologies were more common in patients who continued tamoxifen therapy, compared to patients who switched to aromatase inhibitors. (4) Endometrial cancer was recovered in significantly more patients who continued tamoxifen therapy as compared to those switched to aromatase inhibitors. However, some studies showed no significant statistical differences in the frequency of endometrial cancer diagnosed in the tamoxifen group as compared to the aromatase inhibitor group. Conclusion: These findings may hint on the possibility that aromatase inhibitors may provide a potential protective effect on the endometrium in patients previously treated with tamoxifen. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Tamoxifen; Switching; Aromatase inhibitors; Endometrium
Contents 1. 2. 3. 4. ∗
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial thickness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vaginal bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Tel.: +972 9 747 2561; fax: +972 9 747 2212. E-mail address: [email protected].
0378-5122/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2008.03.001
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5. 6. 7.
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Benign endometrial pathologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Tamoxifen (TAM) is the antihormonal treatment of choice for postmenopausal breast cancer patients with positive estrogen receptors (ERs) [1]. TAM competes with estrogens for binding to cytoplasmic estrogen receptors and prevents estrogen/estrogen receptormediated gene transcription, DNA synthesis, and breast cancer cell growth. It prevents the transmission of G1 to mid-G1 phase in the cell cycle, and the number of cells in the S, and G2 plus M-phases are decreased [2]. One of the most significant and deleterious side effects of postmenopausal TAM treatment appears to be its proliferative effect on the endometrium, provoking a high rate of endometrial pathologies including hyperplasia, polyps, carcinoma and malignant mixed mesodermal tumors [3–8]. The relative risk of endometrial cancer is gradually increased with longer duration of TAM treatment [4] especially when extended beyond 5 years [5]. Endometrial cancer also might appear for at least 5 years after the last treatment [5]. Long-term TAM users showed higher proportions of non-endometrioid tumors than non-users [32.7% vs. 17.4%; P = 0.004], especially serous adenocarcinoma and carcinosarcomas. An increased proportion of FIGO stage III and IV tumors was also observed [20.0% vs. 11.3%; P = 0.049]. Three-year uterine corpus cancerspecific survival was worse for long-term TAM users than for non-users [82% vs. 93%; P = 0.0001] [8]. It has also been reported that more than one third of past users of TAM developed uterine and endometrial cancer with worse prognosis and with more invasive histologic features than current TAM users [6,7]. Transvaginal ultrasonography (TVS) has been extensively used in the investigation and evaluation of endometrial thickness among postmenopausal breast cancer TAM-treated patients [9–18], demonstrating significant thickening of the endometrium in asymptomatic, postmenopausal breast cancer TAM-treated patients as compared with similar non-treated patients [9,10,13] and healthy postmenopausal patients [12].
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There was also a notable increase in mean endometrial thickness measured before TAM treatment and up to more than 3 years of treatment [16]. Lately, TAM treatment is being challenged by third-generation aromatase inhibitors (AIs) that have demonstrated improved disease-free survival in a variety of adjuvant settings for early breast cancer with promising clinical results [19–23]. The non-steroidal AIs anastrazole and letrazole (LET) and steroidal AI exemestane, are the most commonly used. TAM can function as an estrogen agonist in the low estrogenic environment of menopause [24], activating and upregulating endometrial estrogen receptors [25], and ultimately inducing endometrial thickening and endometrial pathological changes [3–8]. AIs inhibit aromatase enzyme function and thus, block the conversion of androgens to estrogens, leading to suppressed estrogen synthesis [19–23]. Thus, it may be speculated that AIs might prevent endometrial thickening and the formation of endometrial pathologies in postmenopausal breast cancer patients. In the new treatment protocols for postmenopausal breast cancer patients, long-term TAM treatment is replaced by AI, therefore it is necessary to investigate AIs’ potential influence on the endometrium.
2. Clinical data In a combined analysis of data from two prospective, multicenter, randomized, open-label trials, with nearly identical inclusion criteria [ABCSG trial 8 and ARNO 95 trial], postmenopausal women with hormone-sensitive early breast cancer who had completed 2 years of adjuvant TAM were randomized to receive 1 mg of anastrozole (ANA) [1618 patients] or 20–30 mg TAM [1606 patients] daily. All patients were followed for 28 months. There was a trend towards fewer endometrial cancer cases [1 (<1%)] in the ANA
I. Cohen / Maturitas 59 (2008) 285–292
group than in the TAM group [7 (<1%)]. Frequency of vaginal bleeding or discharge was similar in both groups [177 (16%) events in the TAM group and 198 (18%) events in the ANA group] [22]. Another prospective, randomized trial tested the efficacy of switching postmenopausal breast cancer patients [node-positive, estrogen receptor-positive tumors] who were already treated for 2–3 years with TAM, to receive ANA 1 mg daily [223 patients] or to continue receiving 20 mg of TAM [225 patients] for a total duration of 5 years. Significantly less events of gynecological changes, including endometrial carcinoma, were reported in the ANA-treated group as compared to the TAM-treated group [2 (1.0%) and 17 (11.3%), respectively; P = 0.002]. However, the authors did not specify the proportions of the different types of endometrial pathologies identified. There was no significant difference with regard to overall gynecological symptoms between the 2 groups [12 (8.0%) in the TAM group and 15 (7.4%) in the ANA group]. Again, the authors did not specify the proportions of the different types of gynecological symptoms [20]. The authors of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial, consisting of a total of 9366 postmenopausal women with localized breast cancer, of which, 3092 patients were switched from TAM treatment to ANA therapy and 3094 patients continued to receive TAM for overall 5 years, reported on the results following a median follow-up of 68 months. Vaginal bleeding and vaginal discharge were significantly more common in the TAM-treated patients as compared to the ANA-treated patients [vaginal bleeding: 317 (10.2%) and 167 (5.4%), respectively; P < 0.0001. Vaginal discharge: 408 (13.2%) and 109 (3.5%), respectively; P < 0.0001]. Endometrial cancer was also significantly more common among the patients continuously treated with TAM as compared to those switched to ANA [17 (0.8%) and 5 (0.2%), respectively; P = 0.02] [21]. The ATAC endometrial sub-protocol was the first double-blind, randomized study to prospectively investigate the incidence of abnormal endometrial histology findings amongst those patients receiving ANA 1 mg compared with those receiving 20 mg of TAM. A total of 285 gynaecologically asymptomatic women from 31 centers in 10 countries underwent baseline investigation, comprised of TVS scanning, a hysteroscopy and
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endometrial biopsy, at entry to the sub-protocol and after 1 year and 2 years of treatment. The baseline incidence of histologically confirmed endometrial abnormalities was 9.0% (24 of 268 patients assessed at baseline). The commonest abnormalities were polyps (without atypia), occurring in 23 (8.5%) patients. No change in TVS measured median endometrial thickness from baseline (3.0 mm) was observed in patients treated with ANA after 2 years, while median endometrial thickness increased with TAM therapy from 3.8 mm at baseline to 6.5 mm after 1 year, and to 7.0 mm after 2 years. There were no significant statistical differences in the overall number of endometrial abnormalities at 1 and 2 years in the ANA group as compared to the TAM group [at 1 year: 4 vs. 7 abnormalities; OR = 0.54 (95% CI: 0.147, 1.971); P = 0.35. At 2 years: 6 vs. 10 abnormalities; OR = 0.44 (95% CI: 0.146, 1.314); P = 0.28] [26]. The lack of significant statistical differences in the overall number of endometrial abnormalities was likely to be because the number of patients recruited was insufficient based on the original power calculations [26]. The majority of abnormalities in all treatment groups were polyps (without atypia or atypia unknown) with no significant differences between the groups at either 1 or 2 years of treatment. In the BIG I-98 randomized, phase 3, double-blind trial, postmenopausal women with operable invasive breast cancer with positive estrogen receptors, progesterone receptors (PR), or both, were randomly assigned to receive therapy with LET 2.5 mg daily or TAM 20 mg daily for 5 years (overall 1835 patients). Another 6193 women were randomly assigned, later in the study, to receive LET or TAM for 2 years followed by TAM for 3 years, or TAM for 2 years followed by LET for 3 years. As compared to TAM, LET was associated with a significantly lower rate of vaginal bleeding [132 (3.3%) vs. 263 (6.6%), respectively; P < 0.001], significantly fewer endometrial biopsies [72 of 3089 women (2.3%) vs. 288 of 3157women (9.1%); P < 0.001] and nonsignificantly fewer invasive endometrial cancers [4 of 3089 women (0.1%) vs. 10 of 3157 women (0.3%); P = 0.18)] [19]. To investigate the effect of switching from adjuvant TAM to ANA treatment in postmenopausal
– – – [29]
27
–
–
–
4.3 ± 1.6
3.6 ± 1.2
0.0001 4 8 4 7 .5 3.3 ± 1.2 6.7 ± 2.4 88 [27]
83
– <5 7.0 <5 6 .5 – – 89 [26]
97
Endometrial thickness at 24 months ANA (mm) Endometrial thickness at 24 months TAM (mm) Endometrial thickness at 12 months ANA (mm) Endometrial thickness at 12 months TAM (mm) Endometrial thickness at 6 months ANA (mm) Endometrial thickness at 6 months TAM (mm) ANA patients (no.) TAM patients (no.) Reference
breast cancer patients having proven TAM-induced benign endometrial pathologies, 226 women, who were treated with 20 mg of TAM (≥12 months, ≤48 months) and developed abnormal vaginal bleeding and/or asymptomatic endometrial thickness >10 mm were prospectively investigated using hysteroscopy and dilatation and curettage. Thereafter, 171 patients were randomized in a phase III study to continue TAM treatment (88 patients) or switch to 1 mg of ANA (83 patients). The mean endometrial thickness at entry to the study was comparable in the ANA and TAM groups [12.4 ± 5.8 and 12.9 ± 5.6 mm, respectively; P = 0.59]. Six months after randomization, endometrial thickness was significant lower in patients switched to ANA therapy [3.3 ± 1.2 mm] compared to those who continued TAM treatment [6.7 ± 2.4 mm; P < 0.0001]. This significant difference between the 2 groups was maintained throughout the entire treatment period. In the ANA group, no patients presented with an endometrial thickness >10 mm, while in the TAM group 30 (34.1%) presented with an endometrial thickness of >10 mm [range 11–24 mm; P < 0.0001] [27]. Four patients in the ANA group had a second endometrial biopsy (due to vaginal bleeding). All had endometrial atrophy. Of the 29 patients in the TAM group undergoing a second hysteroscopy and endometrial biopsy, polyps were recovered in 14 (48.3%), hyperplasia in 8 (27.6%) [2 having atypical hyperplasia] and atrophy in 7 (24.1%). There was no significant difference in recurrent vaginal bleeding between the 2 groups [27]. In a recent prospective, open-label, randomized study, 979 postmenopausal breast cancer women were randomized, following 2 years of TAM treatment, to continue 20 mg of TAM (452 patients) or to switch to 1 mg of ANA (445 patients) for an additional 2 years. Patients were monitored every 6 months during 1–3 years and annually thereafter. There were no significant statistical differences in different types of endometrial pathologies recovered in the TAM group as compared to the ANA group [endometrial cancer: 2 (0.4%) vs. 0 (0%), respectively; endometrial hyperplasia: 39 (8.6%) vs. 8 (1.8%), respectively; endometrial polyps: 15 (3.3%) vs. 4 (0.9%)]. There was also no significant difference between the 2 groups with regard to vaginal bleeding [TAM group 9 (2.0%) vs. ANA group 7 (1.6%)] [23].
P value
I. Cohen / Maturitas 59 (2008) 285–292 Table 1 Distribution of endometrial thickness in postmenopausal breast cancer patients who completed adjuvant tamoxifen and who were randomized to receive anastrozole or tamoxifen
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Table 2 Distribution of endometrial thickness in postmenopausal breast cancer patients whose tamoxifen treatment was replaced by aromatase inhibitors Reference
No. of patients
Duration of tamoxifen treatment (months)
Endometrial thickness before discontinuation of TAM (mm)
Duration of aromatase inhibitor treatment (Months)
Endometrial thickness (mm)
P value
[28] [29]
36 27
24.9 ± 9.8 24.1 ± 20.8
11.4 ± 4.6 8.2 ± 5.0
6.1 ± 2.8 36 ± 48
4.8 ± 2.9 3.0 ± 1.2
0.001 –
A prospective TVS evaluation of the dynamics of endometrial thickness performed in 36 postmenopausal breast cancer patients whose TAM treatment was replaced with AIs, revealed a significant decrement of endometrial thickness following 24.9 ± 9.8 months of TAM treatment, from a value of 11.4 ± 4.6 mm, measured at the last ultrasonographic measurement performed before discontinuation of TAM treatment, down to a value of 6.1 ± 2.8 mm, measured following 4.8 ± 2.9 months of AI therapy (P = 0.001). In 12 patients (80%), endometrial thickness was reduced following the administration of AIs, one patient (6.7%) had no change and 2 (13.3%) patients demonstrated a light increase of endometrial thickness [28]. All study patients, except one, were free of endometrial pathologies, following the switching to AI treatment. In one patient, whose endometrial thickness increased from 7.6 to 12 mm, hysteroscopy revealed benign endometrial polyp [28]. Similar results were also recorded by Garuti et al. [29], showing gradual decrease in endometrial thickness in 27 patients switched from TAM to AI therapy (8.2 ± 5.0 mm at baseline, 4.3 ± 1.6 mm at 12 months, 3.3 ± 1.3 mm at 24 months and 3.0 ± 1.2 mm at 36–48 months). Simple endometrial hyperplasia was detected only in 1 (3.7%) patient, following 12 month of AI therapy [29].
3. Endometrial thickness Endometrial thickness was found to be significantly lower in patients switched from TAM treatment to ANA therapy compared to those who continued TAM treatment [26–29]. This significant difference between the 2 groups was maintained throughout the entire treatment [27]. Endometrial thickness was also higher in patients treated with a combination of TAM and AI [26]. Thus, replacement of TAM treatment by AI in postmenopausal breast cancer patients, resulted in a significant decrease of endometrial thickness [26–29] (Tables 1 and 2).
4. Vaginal bleeding In most studies, vaginal bleeding was reported in significantly more patients who continued TAM therapy compared to those switched to AIs [19–21]. However, in one study a similar amount of patients suffered from vaginal bleeding in both groups [22] (Table 3).
5. Benign endometrial pathologies Replacement of TAM treatment by AI in postmenopausal breast cancer patients resulted in the
Table 3 Distribution of vaginal bleeding in postmenopausal breast cancer patients whose tamoxifen treatment was replaced by aromatase inhibitors Reference
TAM-treated patients (no.)
ANA-treated patients (no.)
Vaginal bleeding in TAM-treated patients (no.)
Vaginal bleeding in ANA-treated patients (no.)
OR
P value
[19] [20] [21] [22]
3157 225 3094 1117
3089 223 3092 1120
263 (6.6%) 12 (8.0%) 317 (10.2%) 195 (17%)
132 (3.3%) 15 (7.4%) 167 (5.4%) 198 (18%)
– – – 1.02
<0.001 0.5 <0.0001 –
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Table 4 Distribution of endometrial pathologies in postmenopausal breast cancer patients who completed adjuvant tamoxifen and who were randomized to receive anastrozole or tamoxifen Reference No. of tamoxifen patients No. of anastrozole patients Endometrial atrophy with tamoxifen (no.) Endometrial atrophy with anastrozole (no.) Endometrial polyp with tamoxifen (no.) Endometrial polyp with anastrozole (no.) Endometrial hyperplasia with tamoxifen (no.) Endometrial hyperplasia with anastrozole (no.)
23 452 445
27 88 83 7 (8.0%) 4 (4.2%) 14 (16.0%) 0 (0.0%) 8 (9.1%) 0 (0.0%)
15 (3.3%) 4 (0.9%) 39 (8.6%) 8 (1.8%)
Table 5 Distribution of endometrial cancer in postmenopausal breast cancer patients who completed adjuvant tamoxifen and who were randomized to receive anastrozole or tamoxifen Reference
TAM-treated patients (no.)
ANA-treated patients (no.)
Endometrial cancer in TAM-treated patients (no.)
Endometrial cancer in ANA-treated patients (no.)
OR
P value
[19] [20] [21] [22] [23]
3157 225 3094 1117 452
3089 223 3092 1120 445
10 (0.3%) 17 (11.3%)a 17 (0.8%) 7 (<1%) 2 (0.4%)
4 (0.1%) 2 (1.0%)a 5 (0.2%) 1 (<1%) 0 (0.0%)
– – – 1.14 –
0.18 0.0002 0.02 – –
a
Overall endometrial pathologies (including endometrial cancer).
appearance of only few, benign endometrial pathologies [23,26–29]. In some studies different endometrial pathologies were more common in patients who continued TAM therapy as compared to patients switched to AIs [23,27]. However, in other study there were no significant statistical differences in different types of endometrial pathologies recovered in the TAM group as compared to the ANA group [26] (Table 4).
6. Endometrial cancer Endometrial cancer was recovered in significantly more patients who continued TAM therapy as compared to those switched to AIs [19–21]. However, in other studies there were no significant statistical differences in the frequency of endometrial cancer diagnosed in the TAM group as compared to the ANA group [22,23] (Table 5).
7. Conclusions and discussion The data reported in this review may hint on the possibility that AIs may provide a potential protective effect on the endometrium in postmenopausal breast cancer patients previously treated with TAM. However, the changes in endometrial thickness, reported following the administration of AIs, should be regarded with caution, as it may well be that the decrement of the endometrial thickness was mainly due to the discontinuation of TAM treatment, regardless of the administration of AIs, as it has been shown that median endometrial thickness significantly decreases within 6 months following TAM discontinuation [14,17], and remains constantly low thereafter [14]. Patients switched from TAM treatment to AIs should be continuously monitored by TVS, as detecting TVS endometrial echo thicker than that recorded before discontinuation of TAM, or detecting a thickening of endometrium following the administration of AIs, should alert the clinician to the possible existence of endometrial pathology.
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These potential changes in endometrial thickness following discontinuation of TAM treatment may have extreme importance, as it has been reported that more than one third of past users of TAM developed uterine and endometrial cancer with worse prognosis and with more invasive histologic features than current TAM users [6,7]. Moreover, in several studies endometrial cancer was diagnosed in breast cancer patients following replacement of TAM by AIs [19–23]. Therefore, until we shall have enough data on the severity of endometrial cancer developed in patients switched from TAM to AIs, it is reasonable to continue monitoring these patients by TVS.
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[28] Markovitch O, Tepper, Fishman A, Aviram R, Cohen I. Aromatase inhibitors reverse tamoxifen induced endometrial ultrasonographic changes in postmenopausal breast cancer patients. Breast Cancer Res Treat 2007;101: 185–90. [29] Garuti G, Cellani F, Centinaio G, Montanari G, Nalli G, Luerti M. Prospective endometrial assessment of breast cancer patients treated with third generation aromatase inhibitors. Gynecol Oncol 2006;103:599–603.