Cancer Therapy: Clinical

Anastrozole versus Treatment in Postmenopausal Women with Endocrine-Responsive and Tamoxifen-Induced Endometrial Pathology Bernd Gerber,1, 2 Annette Krause,1, 2 Toralf Reimer,2 Ionas Mylonas,1, 2 Josef Makovitzky,3 Gu« nther Kundt,4 and Wolfgang Janni1

Abstract Purpose:Toinvestigate the effect of switching from adjuvant tamoxifen to anastrozole (Arimidex) treatment in postmenopausal women with endocrine-responsive breast cancer and histologically proven tamoxifen-induced benign endometrial pathology. Experimental Design: Two hundred twenty-six postmenopausal women who had received adjuvant tamoxifen 20 mg/d (z12 months , V48 months) and developed abnormal vaginal bleed- ing and/or an asymptomatic endometrial thickness >10 mm [measured by transvaginal ultrasound (TVUS)] were subjected to hysteroscopy and dilation and curettage (D&C). Thereafter, 171 patients were randomized in a phase III study to continue tamoxifen treatment (n = 88) or switch to anastrozole1mg/d (n = 83).Patients were monitored for V42 months usingTVUS at 6-monthly intervals. Results: At study entry, there were no significant differences in vaginal bleeding, endometrial thickness, and histologic findings between the two treatment groups. Throughout the treatment period, there was no significant difference in recurrent vaginal bleeding between groups [anastro- zole, 4 of 83 (4.8%); tamoxifen, 9 of 88 (10.2%); P = 0.18]. Six months after randomization, the mean endometrial thickness for patients who switched to anastrozole was significantly reduced compared with those who continued tamoxifen treatment (P < 0.0001). Significantly fewer anas- trozole patients required a repeat hysteroscopy and D&C compared with those on tamoxifen [4of83(4.8%)and29of88(33.0%),respectively;P < 0.0001]. Repeat hysteroscopy and D&C revealed endometrial atrophy in all 4 cases in the anastrozole group and14 polyps, 8 hyper- plasias, and 7 atrophies in the tamoxifen group. Conclusions: Switching from tamoxifen to anastrozole treatment significantly reduced the need for a second hysteroscopy and D&C due to recurrent vaginal bleeding or thickening of the endometrium in postmenopausal breast cancer patients with tamoxifen-induced endometrial abnormalities.

Breast cancer is a major cause of morbidity and mortality, with such as the endometrium. This agonist effect in the endometri- more than 1 million new cases and 410,000 deaths reported um can stimulate proliferation, which increases the risk of worldwide each year (1). For many years, the selective polyps, hyperplasia, and by 2- to 4-fold receptor modulator tamoxifen has been the standard treatment compared with patients not receiving tamoxifen (2–10). It has for postmenopausal women with hormone-sensitive breast been reported that 10% of tamoxifen-treated patients will cancer. Although tamoxifen is an antagonist develop tamoxifen-induced endometrial pathology within 5 in breast tissue, it also acts as an estrogen agonist in other tissues years, leading to operative intention (11). Although the American Society of Clinical Oncology Technology Assessment (12) has recently recommended that the optimal hormonal therapy for postmenopausal women Authors’ Affiliations: 1Department of Obstetrics and Gynecology, Klinikum Innenstadt, Ludwig-Maximilians University, Munich, Germany and Departments of with hormone-sensitive early breast cancer should now include 2Obstetrics and Gynecology and 3Pathology, and 4Institute of Medical Informatics an inhibitor, the 9th St. Gallen International and Biometry, University of Rostock, Rostock, Germany Consensus Conference did not reach a consensus on the Received 2/10/05; revised 8/4/05; accepted 10/14/05. optimal use of aromatase inhibitors on the treatment of Grant support: FORUN project nos. 995076 and 995568. The costs of publication of this article were defrayed in part by the payment of page primary breast cancer (13). The American Society of Clinical charges. This article must therefore be hereby marked advertisement in accordance Oncology recommendations stated that the incidences of life- with 18 U.S.C. Section 1734 solely to indicate this fact. threatening adverse events, such as endometrial cancer, with Requests for reprints: Bernd Gerber, Department of Obstetrics and Gynecology, an are significantly reduced compared with Suedring 81,18059 Rostock, Germany. Phone: 49-381-4401-4500; Fax: 49-381- tamoxifen. This has been shown in the Arimidex, Tamoxifen, 4401-4599; E-mail: [email protected]. F 2006 American Association for Cancer Research. Alone or in Combination (ATAC) trial, where initiating doi:10.1158/1078-0432.CCR-05-0225 treatment with anastrozole (Arimidex) in postmenopausal

www.aacrjournals.org 124 5 Clin Cancer Res 2006;12(4) February15, 2006 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2006 American Association for Cancer Research. Cancer Therapy: Clinical women with early breast cancer has been shown to significantly Oncology Group V2, Charlson V3) were included in the trial. Patients had reduce the incidence of endometrial cancer, vaginal bleeding, to be accessible for treatment and follow-up. There were no age limitations and discharge compared with initiating treatment with tamox- in this trial. Glandulocystic atrophy was defined as an apparent increase in ifen (14). Moreover, subprotocols of the Arimidex, Tamoxifen, endometrial thickness detected by transvaginal ultrasound (TVUS), which may be a result of tamoxifen-induced of cystically dilated Alone or in Combination trial have also indicated a reduced endometrial glands with periglandular stromal and myometrial conden- incidence of endometrial abnormalities and medical interven- sation whereas the overlying epithelium remains atrophic (20). tions in the anastrozole group compared with the tamoxifen Patients were excluded from the study if they had histopathologically group (15–18), suggesting that anastrozole may have a proven endometrial carcinoma or atypical hyperplasia, if they were protective effect against endometrial cancer (19). receiving concurrent treatment with other hormonal agents, or if no There are currently no published prospective data that detail written consent had been obtained (Fig. 1). the effect of anastrozole in patients with tamoxifen-induced Trial design. In this open-label phase III trial, 173 patients were endometrial pathology. Therefore, the aim of this study was prospectively randomized to either continued treatment with tamoxifen to evaluate the effect of switching from adjuvant tamoxifen 20 mg/d or switch to anastrozole 1 mg/d. Patients were randomized by ‘‘complete randomization’’ (synonymous simple randomization), to anastrozole on recurrent vaginal bleedings (primary end which is a simple coin-tossing procedure, and ‘‘random number point) and endometrial thickening (secondary end point) in generation’’ was used to prepare the randomization sequence (21). postmenopausal breast cancer patients with histologically The study was conducted in accordance with the Declaration of verified tamoxifen-induced endometrial changes. Helsinki and informed consent was obtained from each patient. The primary end point of the study was the incidence of renewed Patients and Methods vaginal bleeding. The secondary end point was change in endometrial thickness (defined as the width of the combined thickness of the Eligibility criteria. Between January 1998 and January 2003, 226 anterior and posterior sides of the endometrium) as detected by TVUS. eligible postmenopausal women with endocrine-responsive, invasive For the 171 patients included in the analysis, a normal endometrial breast cancer, who were receiving adjuvant tamoxifen treatment and thickness (<5 mm) had been confirmed by TVUS in 67% of patients had suspected endometrial changes (abnormal vaginal bleeding and/or before the initiation of adjuvant tamoxifen. The endometrial thickness thickened endometrium), were referred to our hospital for invasive in the remaining 33% asymptomatic patients was not known at the diagnostic measures (Fig. 1). time of beginning with adjuvant tamoxifen treatment. The postmenopausal state was defined as no regular menstruation Follow-up. Assessments for patients receiving randomized treatment within 1 year of primary treatment of breast cancer or after a bilateral were made at 6-monthly intervals by the same gynecologist for up to a salpingoovarectomy. After immunohistochemical assessment, patients maximum of 42 months. Endometrial thickness and morphology were defined as ‘‘endocrine responsive’’ if the estimated estrogen and were measured using TVUS in the longitudinal plane with a 5.0-MHz progesterone receptor content of the primary tumor was z20% and transvaginal probe. Data on other adverse events were not collected and z10%, respectively; ‘‘uncertain endocrine responsive’’ if receptor evaluated as part of the study. content was 1% to 19% and 1% to 9%, respectively; and ‘‘endocrine Patients with renewed abnormal vaginal bleeding following treat- nonresponsive’’ if the estrogen and progesterone receptor content at the ment were subjected to a repeat hysteroscopy and D&C immediately. primary tumor was undetectable. Patients with an endometrial thickness >10 mm and nonsuspicious A hysteroscopy, in addition to dilation and curettage (D&C), was done morphology required repeated TVUS after 3 months. In the event of any in all patients and polyps were resected by operative hysteroscopy. further increase in endometrial thickness, or if the endometrium showed Postmenopausal women with histopathologically confirmed endometrial any suspicious morphology (nonhomogeneous endometrium with polyps, hyperplasia, or glandulocystic atrophy, an estimated life different density, cysts, no clear boundary between endometrium and expectancy of z5 years (irrespective of breast cancer diagnosis), and no myometrium), hysteroscopy and D&C were done. Further treatment severe or relevant comorbidity (performance status Eastern Cooperative in such cases was decided on an individual basis; patients stopped

Fig. 1. Flow chart outlining the procedures and number of randomized patients. *, one patient in each group was withdrawn due to breast cancer recurrence and missing ultrasound data; neither received study medication.

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Ta b l e 1. Patient demographics, treatment duration, and baseline tumor characteristics

Anastrozole 1 mg/d (n = 83) Tamoxifen 20 mg/d (n =88) P Mean age (range), y 57.9 (46-78) 58.9 (46-83) 0.34* Mean BMI (range), kg/m2 28.5 (16-52) 27.7 (19-52) 0.35* Mean duration of tamoxifen before endometrial pathology, mo (SD) 25.4 (11.2) 27.2 (9.8) 0.18* Mean duration of endocrine treatment after randomization, mo (SD) 32.2 (9.7) 30.3 (8.9) 0.18* Tu m o r s i z e ( % ), m m c V20 35 (42.2) 45 (51.1) 0.24 >20 48 (57.8) 43 (48.9) Nodal status (%) c 0 42 (50.6) 53 (60.2) 0.21 1 41 (49.4) 35 (39.8) AmericanJoint Committee on Cancer stage (%)b c Stage I 19 (22.9) 31 (35.2) 0.20 Stage IIA/B 41 (49.4) 38 (43.2) StageIIIA/B 23(27.7) 19(21.6) Endocrine responsivenessx c Responsive 63 (75.9) 66 (75.0) 0.45 Uncertain 15(18.1) 18(20.5) Nonresponsive 0 0 Unknown 5 (6.0) 4 (4.5) Surgical therapy (%) c Breast-conserving therapy 22 (26.5) 34 (38.6) 0.09 Mastectomy 61 (73.5) 54 (61.4) Adjuvant systemic therapy (%) c Tamoxifen 48 (57.8) 60 (68.2) 0.16 Chemotherapy followed by tamoxifen 35 (42.2) 28 (31.8)

*Two-sided t test. cPearson’s m2 test. bSee ref. 35. xPatients were defined as endocrine responsive if the immunohistochemically estimated estrogen and progesterone receptor content at the primary tumor was >20% and >10%, respectively; uncertain endocrine responsive if 1% to 19% and 1% to 9%, respectively; and endocrine nonresponsive if the estrogen and progesterone receptor content was undetected.

endocrine treatment, persisted with the assigned study treatment, or breast cancer recurrence and another one was withdrawn due to switched treatment. missing ultrasound data; neither received study medication. A It was recommended that randomized treatment should continue up total of 83 patients were randomized to switch to anastrozole to a maximum of 5 years or until tumor recurrence, loss of follow-up, or and 88 patients were randomized to continue tamoxifen troubling adverse events. treatment. The two treatment groups were well balanced in Statistical methods. Using a two-tailed m2 test with a significance level of a = 0.05 and a power of 0.80, a total of 170 patients were terms of baseline patient and tumor characteristics (Table 1). required to show a significant decrease of recurrent vaginal bleeding At the time of study entry, there was no significant difference from f33% to 15%. Determination of sample size was achieved by in the incidence of vaginal bleeding and an endometrial using the software nQuery (22). thickness >10 mm between the anastrozole and tamoxifen Statistical analysis was done on a per protocol basis. A two-tailed t groups (P = 0.64; Table 2). Of the 48 patients (57.8%) within the test was used to calculate the differences between the means of anastrozole group and 55 patients (62.5%) within the tamoxifen independent samples that had continuous variables and, depending on group who presented with an endometrial thickness >10 mm, m2 the number of cases, the test or Fisher’s exact test was used to 27 and 26 patients, respectively, presented with vaginal bleeding. compare categorical variables. All statistical tests were two sided. A total of 53 patients were followed for a maximum period of The body mass index(BMI) of each patient was calculated by dividing weight (kg) by height2 (m). Mean TVUS measurements (SD) 42 months. The mean duration of tamoxifen treatment before were calculated in each patient group for all the examination dates. the first endometrial pathology was observed was similar between the two treatment arms (Table 1). The duration of Results endocrine treatment after randomization, and overall, was longer in the anastrozole group [32.2 (F9.7) and 58.6 (F6.6) Patients. Of the 226 postmenopausal breast cancer patients months, respectively; P = 0.18] compared with the tamoxifen who had previously received tamoxifen 20 mg/d for z12 and group [30.3 (F8.9) and 57.8 (F6.7) months, respectively; V48 months, 173 (76.5%) were included in the study (Fig. 1). P = 0.26]. However, this difference did not reach statistical Following randomization, one patient was withdrawn due to significance.

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Ta b l e 2 . Endometrial pathology at randomization

Anastrozole 1 mg/d (n = 83) Tamoxifen 20 mg/d (n =88) P Endometrial pathology at randomization (%) Vaginal bleeding 35 (42.2) 33 (37.5) 0.64* Endometrial thickness >10 mm, no bleeding 21 (25.3) 29 (33.0) Vaginal bleeding + endometrial thickness >10 mm 27 (32.5) 26 (29.5) Histologic findings of first hysteroscopy and D&C (%) Endometrial polyps 37 (44.6) 40 (45.5) 0.98* Hyperplasia 16 (19.3) 16 (18.2) Glandulocysticatrophy 30(36.1) 32(36.4)

*Pearson’s m2 test.

Primary end point (renewed vaginal bleeding). Throughout underwent a repeat hysteroscopy and D&C due to recurrent the treatment period, there was no significant difference in the vaginal bleeding or thickening of the endometrium compared number of patients experiencing renewed vaginal bleeding with those who continued tamoxifen treatment [4 (4.8%) between the anastrozole and tamoxifen groups [4 (4.8%) and 9 versus 29 (33.0%) patients; P < 0.0001]. (10.2%) patients, respectively; P = 0.18]. Of the 62 patients Histopathologic findings. Of the four patients in the with histologically confirmed atrophy, 23 (37.1%) reported anastrozole group who required repeat D&C due to vaginal vaginal bleeding before randomization and 11 (17.7%) bleeding, endometrial atrophy was found in all four cases. Of reported vaginal bleeding after. the 29 patients in the tamoxifen group undergoing second Secondary end point (endometrial thickness). The mean hysteroscopy and D&C, polyps were found in 14 cases (48.3%), endometrial thickness at time of admittance study entry hyperplasia in 8 cases (27.6%), and atrophy in 7 cases (24.1%). was comparable in the anastrozole and tamoxifen groups Two of the eight patients with hyperplasia had atypical [12.4 (F5.8) and 12.9 (F5.6) mm, respectively; P = 0.59]. Six hyperplasia and underwent hysterectomy. The results of the months after randomization, the endometrial thickness was first and second gynecologic investigations were consistent in significantly lower in those patients who switched to anas- 21 of the 33 patients (63.6%) assessed (P = 0.003). trozole [3.3 (F1.2) mm] compared with those continuing Additional findings. There was no significant difference in tamoxifen treatment [6.7 (F2.4) mm; P < 0.0001]. A significant the frequency of breast cancer recurrences during endocrine difference between the two groups could be found throughout treatment between the two treatment groups (7.2% in the the entire treatment period (Fig. 2). In the anastrozole group, anastrozole group and 9.1% in the tamoxifen group; P = 0.66). no patients presented with an endometrial thickness >10 mm. Examination of a possible influence of BMI, age, and duration In contrast, 30 patients (34.1%) within the tamoxifen group of endocrine treatment on the occurrence of first and second presented with an endometrial thickness >10 mm (range 11-24 endometrial pathology revealed no significant correlation. mm; P < 0.0001); 8 of these patients reported vaginal bleeding. Twenty-sixof these 30 patients (86.7%) required a second D&C. Significantly fewer patients in the anastrozole group Discussion This open-label randomized trial was designed to evaluate the effects of switching to anastrozole following adjuvant tamoxifen treatment (z12 months, V48 months) compared with remaining on tamoxifen in postmenopausal patients with breast cancer and histologically confirmed tamoxifen-induced endometrial pathology (polyps, hyperplasia, and glandulocys- tic atrophy). The rationale behind switching to anastrozole was to avoid invasive procedures necessitated by recurrent abnor- mal vaginal bleeding and/or thickened endometrium in tamoxifen-treated patients. Although there was no significant difference in recurrent vaginal bleeding between the two treatment arms throughout the treatment period, significantly fewer patients receiving anastrozole required repeat hysteroscopy and D&C compared with those who continued tamoxifen treatment. Additionally, the analyses show a significant reduction in mean endometrial thickness in patients who switched to anastrozole compared with those who continued on tamoxifen treatment. These data Fig. 2. Comparison of endometrial thickness in patients receiving anastrozole treatment following tamoxifen with those continuing tamoxifen treatment.Vertical are in line with our earlier study investigating the effects of lines, SD. *, P < 0.0001. c, before hysteroscopy and D&C. tamoxifen on the endometrium in postmenopausal women

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It is findings, a retrospective analysis of the Arimidex, Tamoxifen, now known that this is not the best method for assessing Alone or in Combination trial (n = 9,366) shows that initiating tamoxifen-induced endometrial changes due to the high false- treatment with anastrozole rather than tamoxifen can reduce positive rate (11, 28). However, it has recently been reported the risk of gynecologic adverse events, including vaginal that TVUS is appropriate for screening the endometrium for bleeding, vaginal discharge, and endometrial cancer (14). intrauterine pathology before endocrine treatment in women Further analyses of the Arimidex, Tamoxifen, Alone or in with breast cancer (with an endometrial thickness of 3 mm as a Combination trial have also indicated a protective effect of cutoff for needing further investigations with hysteroscopy and anastrozole against endometrial cancer compared with expected endometrial biopsy; refs. 29, 30). rates in an untreated, age-matched population. In contrast to this Avoiding invasive procedures is one of the potential benefits protective effect of anastrozole, tamoxifen treatment resulted in of switching from tamoxifen to anastrozole treatment for an increase in relative risk for endometrial cancer to 2.68 (95% postmenopausal breast cancer patients. Although efficacy was confidence interval, 1.34-4.80; ref. 19). not an end point of the current study, the Italian Tamoxifen A study by Berliere et al. (23) evaluated the effects of Arimidextrial, which has recruited 446 postmenopausal aromatase inhibitors (anastrozole or ) on the endome- women who have undergone surgery for node-positive trium of 31 breast cancer patients who had developed local endocrine-responsive tumors, has shown that patients who recurrence or pernicious metastatic evolution of their breast switch to anastrozole show a reduction in the risk of relapse tissue during tamoxifen treatment. The authors concluded that and death compared with those who continue tamoxifen aromatase inhibitor treatment did not reduce endometrial treatment (median follow-up, 36 months; ref. 31). These data thickness. Patients were grouped into those who have never are further supported by combined analyses of the Austrian been treated for endometrial pathology before or during Breast and Colorectal cancer Study Group Trial 8 and Arimidex- tamoxifen therapy (n = 27) and those who had been treated Nolvadex95 Trial, in which 3,224 postmenopausal women are for endometrial polyps before initiation of tamoxifen therapy being evaluated to assess whether switching to anastrozole after (n = 4). The mean endometrial thickness evaluated by TVUS 2 years of tamoxifen is more effective than continuing tamo- before and 2 years after initiation of aromatase inhibitor xifen treatment (32). In this combined analysis, the hazard treatment was found to be 9.2 and 8.5 mm, respectively, in the ratio for recurrence-free survival with anastrozole compared untreated group, and 7.5 and 7.2 mm, respectively, in the treated with tamoxifen treatment was 0.59 (95% confidence interval, group. During follow-up, one case of polyps was observed in 0.42-0.82; P < 0.0018) regardless of the nodal status. Thus, the each group. In the present study, the mean endometrial thickness inclusion of a third-generation aromatase inhibitor in the decreased to within reference ranges (3-4 mm) in patients endocrine treatment sequence for postmenopausal breast receiving anastrozole but not in those receiving tamoxifen cancer patients significantly improves outcomes compared (7-9 mm). The greater decrease in endometrial thickness with tamoxifen treatment alone. observed in this study following treatment with anastrozole The American Society of Clinical Oncology Technology could possibly be explained by a higher endometrial thickness Assessment states that postmenopausal women with endocrine- before randomization (12.4 mm with anastrozole and 12.9 mm responsive breast cancer may consider switching to an aromatase with tamoxifen). It is also important to consider that hystero- inhibitor after 2 to 3 years of treatment with tamoxifen to reduce scopy and D&C may have contributed to the reduction in the risk of tumor recurrence (12). In addition, the report states endometrial thickening by removing the pathologic cause that treatment with an aromatase inhibitor significantly reduces (e.g., polyps and hyperplasia). Preliminary results the incidence of life-threatening adverse events, including have shown that switching to an aromatase inhibitor signifi- endometrial cancer, compared with tamoxifen treatment (12). cantly reduces tamoxifen-induced endometrial thickening Indeed, recent clinical trial data have shown that patients who (measured by TVUS) after 6 months (P =0.021; ref. 24). In initiate treatment with anastrozole have a significantly lower addition, 12 months of anastrozole treatment in 11 obese post- risk of developing endometrial cancer and other gynecologic menopausal women with endometrial hyperplasia resulted in an disorders (vaginal bleeding and discharge) than those who atrophic endometrium in all cases (25). initiate treatment with tamoxifen (14, 16, 18, 33, 34). Although It has been hypothesized that the increased incidence of there was no significant difference between groups in renewed endometrial pathology with adjuvant treatment may be vaginal bleeding throughout the treatment period in this study, associated with patient age and BMI. In postmenopausal our results show that switching from tamoxifen to anastrozole women, endometrial thickness before and during adjuvant significantly reduces the need for a second hysteroscopy and treatment has been shown to be negatively correlated with age D&C due to renewed vaginal bleeding or endometrial thickening and positively correlated with BMI, possibly as a result of in postmenopausal breast cancer patients with tamoxifen- increased aromatase activity in fatty tissues (11, 26, 27). induced endometrial abnormalities. However, the analyses in the present study showed that BMI, age, and duration of endocrine treatment showed no significant Acknowledgments correlation with the occurrence of primary and secondary endometrial pathologies. We thank JulieTorode and Sarah Goodger, Ph.D., for their editorial support.

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