TAMOXIFEN, A NONCORTICOSTEROIDAL partial

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1 Investigation of Endometrial Abnormalities in Asymptomatic Women Treated With Tamoxifen and an Evaluation of the Role of Endometrial Screening By C.D.B. Love, B.B. Muir, J.B. Scrimgeour, R.C.F. Leonard, P. Dillon, and J.M. Dixon Purpose: Tamoxifen is the most commonly prescribed adjuvant therapy for women with breast cancer. It has agonist activity on the endometrium and is associated with an increased risk of endometrial cancer. The aim of this study was to evaluate whether screening with transvaginal ultrasound (TV USS) with or without hysteroscopy is worthwhile. Patients and Methods: A total of 487 women with breast cancer, 357 treated with tamoxifen and 130 controls, were screened with TV USS, and endometrial thickness was measured. Women with thickened endometrium underwent outpatient hysteroscopy. Results: Length of time on tamoxifen ranged from 5 to 191 months (mean, 66 months), and endometrial thickness ranged from 1 to 38 mm (mean, 7.3 mm). Women treated with tamoxifen had significantly thicker endometrium than did controls (P F.0001). There was a statistically significant (P F.0001) positive correlation between length of time on tamoxifen and endometrial TAMOXIFEN, A NONCORTICOSTEROIDAL partial estrogen agonist, is the most commonly prescribed adjuvant therapy for women with breast cancer. Since its introduction in 1971, it has been used to treat millions of women worldwide. Recent studies have demonstrated a reduction in breast cancer incidence with prophylactic use of tamoxifen, 1 and it has a product license in the United States for prevention of breast cancer in high-risk women. It is a partial agonist because, although it antagonizes estrogen in the breast, it has agonist activity on the uterus and, in particular, on the endometrium. In 1985, Killackey et al 2 first reported an association between tamoxifen use and the development of endometrial cancer. Since then, there have been numerous reports confirming this association. 3-9 Overall, there seems to be a twofold to threefold increase in the incidence of endometrial cancer in women treated with From the Edinburgh Breast Unit, Western General Hospital, Edinburgh, United Kingdom. Submitted December 15, 1998; accepted March 16, Financial support to purchase the transvaginal probe was provided by the Sarah Percy Research Fund of the Edinburgh Breast Unit. Address reprint requests to C.D.B. Love, MBChB, Academic Offıce, Edinburgh Breast Unit, Western General Hospital, Edinburgh EH4 2XU, United Kingdom; jmd@wght.demon.co.uk by American Society of Clinical Oncology X/99/ thickness. One hundred forty-five women had endometrium greater than 5 mm on USS, and 134 underwent successful outpatient hysteroscopy, 61 of whom had atrophic endometrium, resulting in a 46% false-positive scan rate. The remaining women all had benign features to explain the USS findings. Conclusion: TV USS detects a high incidence (41%) of apparent endometrial thickening in women treated with tamoxifen, although 46% had atrophic endometrium on further assessment, and none of the remaining asymptomatic women had significant lesions. Length of time on tamoxifen relates to endometrial thickening as measured by TV USS. TV USS is a poor screening tool because of the high false-positive rate. The low frequency of significant findings suggests that endometrial screening in asymptomatic women is not worthwhile. J Clin Oncol 17: by American Society of Clinical Oncology. adjuvant tamoxifen. 6,10 In view of this, should women who receive tamoxifen either as adjuvant therapy or as breast cancer prevention be screened for endometrial abnormalities? Furthermore, if screening is advocated, what is the optimum screening protocol? The aim of this study was to assess the incidence of endometrial abnormalities in asymptomatic women with breast cancer treated with adjuvant tamoxifen and to evaluate the role of two possible screening tools: transvaginal ultrasound (TV USS) scanning and outpatient hysteroscopy. PATIENTS AND METHODS Between January 1996 and March 1997, 357 premenopausal and postmenopausal asymptomatic women who received tamoxifen 20 mg/d as adjuvant treatment for breast cancer (study group) were recruited from a regional breast cancer unit long-term follow-up clinic. All women were eligible if they had an intact uterus and were fit enough to have all procedures performed. The age range for women treated with tamoxifen was 29 to 75 years (median, 56 years). Forty-two women were premenopausal at the time of assessment, and 315 were postmenopausal. Postmenopausal women were defined as those who had been amenorrheic for more than 12 months. Duration of tamoxifen use ranged from 5 to 191 months (mean, 66 months; median, 62 months). Unit policy at the time of the study was to continue tamoxifen until the time of first recurrence. One hundred thirty controls (women with a diagnosis of breast cancer who had never received tamoxifen) were also recruited. The age range for controls was 29 to 69 years (median, 48 years). Twenty-three were premenopausal and 107 were postmenopausal at the time of recruitment Journal of Clinical Oncology, Vol 17, No 7 (July), 1999: pp

2 ENDOMETRIAL SCREENING IN WOMEN ON TAMOXIFEN 2051 The first 120 women treated with tamoxifen underwent both TV USS and outpatient hysteroscopy performed within 10 days (median, 6 days) of each other to evaluate each method of screening in terms of patient tolerance and detection of abnormalities. These 120 women were asked to evaluate the pain and discomfort of each procedure on a 10-point scale (1, not uncomfortable; 10, very uncomfortable/painful). TV USS was performed using an ATL Apogee 800 ultrasound machine (Advance Technology Laboratories, UK, Ltd, Letchworth, United Kingdom) with a 5- to 9-MHz vaginal probe. Maximum double endometrial thickness was measured in the longitudinal plane using the machine s electronic calipers. Outpatient hysteroscopy without paracervical block was performed using an Olympus 3.6-mm flexible hysteroscope (Keymed Ltd, Livingston, Scotland, United Kingdom). All hysteroscopies were performed by the same investigator and recorded on videotape. A second investigator reviewed all recorded material for validation and verification purposes. An endometrial thickness greater than 5 mm in postmenopausal women or a thickness greater than the accepted cycle limits in premenopausal women was defined as abnormal. Accepted cycle limits in premenopausal women are 4 to 8 mm in the follicular phase and 10 to 12 mm in the luteal phase. 11 The pilot study demonstrated that all abnormalities observed at hysteroscopy were identified on TV USS. Significantly less discomfort was experienced with TV USS (P.0001, Mann-Whitney U test; Fig 1). The remaining 237 women and the 130 controls underwent TV USS, and those with abnormal scan results then underwent hysteroscopy. Statistical analyses were conducted using the Instat software package (Graphpad Software Inc, San Diego, CA). RESULTS Endometrial thickness measured by TV USS in 357 women in the study group ranged from 1 to 38 mm, with a mean and median thickness of 7.3 mm and 5 mm, respectively. Table 1 shows the relationship between endometrial thickness and tamoxifen duration. Patients were divided into four groups based on duration of tamoxifen treatment (0 to 2 years, 2 to 5 years, 5 to 10 years, and 10 years); these cutoff points were deemed the most clinically relevant. There was a highly significant positive correlation between the length of time on tamoxifen and endometrial thickness (P.0001, Spearman correlation test). Twenty-five percent of patients who received tamoxifen for 5 years had endometrial thickening as assessed by TV USS. The endometrium of women who received tamoxifen was significantly thicker than that of controls (range, 1 to 10 mm; P.0001, Mann-Whitney U test; Table 1). The controls included 23 premenopausal women whose endometrial thickness was within accepted cycle limits. None of the control patients required hysteroscopy. Two hundred women, including those who had the procedure performed as part of the pilot study, underwent outpatient hysteroscopy. In 145 of the 357 women who Fig 1. Comparison of patient procedure scores.

3 2052 LOVE ET AL Table 1. Relationship Between Endometrial Thickness and Duration of Tamoxifen Treatment Duration of Tamoxifen Treatment (years) No. of Women Endometrial Thickness (mm) Thickened Endometrium* Mean SE No. % Whole group Controls *Thickened endometrium is 5 mm in postmenopausal women or greater than accepted cycle limits in premenopausal women. received tamoxifen (41%), hysteroscopy was performed because of an abnormally thickened endometrium observed on TV USS. Hysteroscopy was successful in 134 of 145 women. Hysteroscopy failure occurred in 11 women for the following reasons: cervical stenosis (n 8), a cervical polyp (n 2), and a previous pelvic floor repair such that opening the speculum to view the cervix was impossible (n 1). These 11 women subsequently underwent dilatation and curettage (D&C). Of the 134 women who underwent successful hysteroscopy, 61 had atrophic endometrium, resulting in a 46% false-positive rate of TV USS. Of the 73 remaining women, all had benign features that accounted for the thickened endometrium observed on TV USS. These benign features included cystic endometrium (n 23), edematous endometrium (n 23; descriptive terms for the appearance of the endometrium at hysteroscopy), polyps (n 21), and submucous fibroids (n 6). Numerous attempts were made to sample edematous endometrium in the outpatient setting using pipelle, Sharman curette (Dupae Health Care, Leeds, United Kingdom), and biopsy instruments; all were unsuccessful. The first 10 women with edematous endometrium proceeded to D&C; no tissue was obtained in seven, and three had cystically dilated glands only. This appearance was not investigated further. No cancers were detected in the study group of 357 asymptomatic women, and there were no endometrial abnormalities in the control group. During the study period, one simple hyperplasia and one carcinoma were found in two women who received tamoxifen as adjuvant treatment for breast cancer and who were referred for hysteroscopy for investigation of irregular vaginal bleeding. Both of these women had thickened endometrium on TV USS and subsequently underwent hysteroscopy and biopsy. Both then underwent D&C to confirm a diagnosis. DISCUSSION There is clear evidence of an increased risk of endometrial cancer in women treated with tamoxifen. 6,7,10,12-17 Even with this increased incidence, the benefits of tamoxifen in reducing the number of contralateral breast cancers is greater than the number of women who develop endometrial cancer. Because the risks do not warrant cessation of the use of tamoxifen, should these women have their endometrium screened? Some investigators have advocated such a policy and have also suggested an initial endometrial assessment before starting tamoxifen The present study aimed to establish the incidence of endometrial abnormalities in asymptomatic women on tamoxifen, to address whether screening is valuable, and, if so, to determine the optimal screening protocol. In a group of 357 asymptomatic women with breast cancer treated with adjuvant tamoxifen, 145 (41%) had apparent endometrial thickening on TV USS scan. However, on hysteroscopy, 61 of these women (46%) had atrophic endometrium. This 46% false-positive rate is unacceptable for a screening technique because it subjects large numbers of women to unnecessary investigations. No significant abnormalities were detected in any of the women screened, and several investigators have reported similar findings. 19,21 It would have been better had we been able to confirm our hysteroscopic findings with histology, especially having identified apparently edematous endometrium, which appeared as thickened endometrium with no specific features on TV USS. The appearance of apparently edematous or cystic endometrium at hysteroscopy was an observation rather than a diagnosis. As yet, there is no exact pathologic correlation for these findings. Other investigators have reported that it is difficult to perform biopsy on tamoxifentreated endometrium even in the presence of apparent hysteroscopic abnormalities, 22 and despite using various biopsy instruments, we were unsuccessful in obtaining material for histology at hysteroscopy. Therefore, D&C was performed in the first 10 women with this finding, but we again failed to obtain endometrial tissue in seven, and the other three had cystically dilated endometrial glands (referred to as glandulocystic atrophy by some investigators). Therefore, it was agreed that subjecting the other 13 asymptomatic women with the same appearance to further investigation was inappropriate. Had the aim of the study been to investigate a symptomatic population, ie, abnormal vaginal bleeding, then all nonatrophic findings would have required more aggressive investigations. However, histology was analyzed in all asymptomatic patients with a hysteroscopic abnormality initially by means of D&C, and

4 ENDOMETRIAL SCREENING IN WOMEN ON TAMOXIFEN 2053 only when it was evident that the correlation between hysteroscopy and pathology was excellent were the remainder of these women not investigated further. In the majority of women with thickened endometrium on TV USS, the scan showed cystic changes within the endometrium. This thickened, cystic appearance on TV USS has been well documented It has been suggested that it may be caused by endometrial serosa or myometrial edema, and that TV USS does not consistently identify true endometrial thickness. Although this could provide an explanation for the edematous hysteroscopic appearance, it was not possible to predict from the scan whether the women had edema or whether benign endometrial pathology was present. Neven et al 28 reported a similar difficulty in predicting polyps from a tamoxifen-related thickened cystic appearance on TV USS. It has been suggested that the normal endometrial cutoff point ( 5 mm in postmenopausal women) should be increased in women treated with tamoxifen, perhaps up to 8 mm, in view of the false-positive USS findings. However, until the histology/pathology of the USS findings are established, it seems appropriate to continue to use standard, accepted endometrial thickness cutoff points. The apparent endometrial thickness on TV USS seems directly related to duration of tamoxifen treatment and does not necessarily indicate serious endometrial pathology. Caution is therefore required when interpreting TV USS scans in women treated with tamoxifen, and in women with apparent endometrial thickening, it would seem appropriate to proceed to outpatient hysteroscopy as the second-line investigation rather than inpatient general anesthetic procedures (D&C). The high false-positive scan rate demonstrates that TV USS is a poor screening tool for the detection of endometrial cancer in women on tamoxifen. This is consistent with a low reported positive predictive value of endometrial thickening in women on hormone replacement therapy. 29 Although hysteroscopy was better tolerated than expected, it remains an uncomfortable and relatively invasive technique that requires specialized equipment, making it an inappropriate screening tool. There is no better tool available at the present time, and in view of the low frequency of significant findings, endometrial screening in asymptomatic women treated with tamoxifen does not seem to be useful, a conclusion also reached by Bertelli et al. 30 We no longer screen these women, but we advise them of the potential risks and suggest they report any abnormal discharge or bleeding immediately. In this way, rather than subjecting large numbers of women to unnecessary procedures, those who present with symptoms can be promptly and efficiently investigated. 1. 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5 2054 LOVE ET AL 20. Nasri M, Shephard J, Setchell M, et al: The role of vaginal scanning in the measurement of endometrial thickness in postmenopausal women. Br J Obstet Gynaecol 98: , Touraine P, Driguez P, Castier I, et al: Lack of induction of endometrial hyperplasia with tamoxifen. Lancet 345: , Ismail SI: Gynaecological effects of tamoxifen. J Clin Pathol 52:83-88, Cohen I, Altaras MM, Shapira J, et al: Time-dependent effect of tamoxifen therapy on endometrial pathology in asymptomatic postmenopausal breast cancer patients. Int J Gynecol Pathol 15: , Anteby E, Yagel S, Zacut D, et al: False sonographic appearance of endometrial neoplasia in postmenopausal women treated with tamoxifen. Lancet 340: , Goldstein SR, Unusual ultrasonographic appearance of the uterus in patients receiving tamoxifen. Am J Obstet Gynecol 170: , Hulka CA, Hall DA: Endometrial abnormalities associated with tamoxifen therapy for breast cancer: Sonographic and pathologic correlation. AJR Am J Roentgenol 160: , Ciatto S, Cecchini S, Bonardi R, et al: Ultrasonography surveillance of endometrium in breast cancer patients on adjuvant tamoxifen. Lancet 344:60, 1994 (letter) 28. Neven P, De Muylder X, Can Velle Y, et al: Longitudinal hysteroscopic follow-up during tamoxifen treatment. Lancet 351:36, 1998 (letter) 29. Langer RD, Pierce JJ, O Hanlon KA, et al: Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. N Engl J Med 337: , Bertelli G, Venturini M, Del Mastro L, et al: Tamoxifen and the endometrium: Findings of pelvic ultrasound examination and endometrial biopsy in asymptomatic breast cancer patients. Breast Cancer Res Treat 47:41-46, 1998