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© 2000 American Society for Clinical Oncology Effect of Adjuvant Tamoxifen on the Endometrium in Women With Breast Cancer: A Prospective Study Using Office Endometrial BiopsyFrom the Gynecology Service, Department of Surgery; Breast Service, Department of Medicine; Department of Pathology; and Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Richard R. Barakat, MD, c/o Gynecology Service Academic Office, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Room MRI-1027, New York, NY 10021; email gynbreast{at}mskcc.org
PURPOSE: To determine the frequency of developing abnormal pathologic changes in the endometria of tamoxifen-treated women. To characterize the type of pathologic changes involved. PATIENTS AND METHODS: Between October 1991 and September 1998, 159 patients initiating tamoxifen therapy for breast cancer confined to the breast and axillary lymph nodes were entered in a prospective study. In this study, office endometrial biopsies (EMBs) were obtained during the initiation of tamoxifen and at 6-month intervals for a 2-year period. Three subsequent annual EMBs were recorded for each patient, amounting to a 5-year surveillance. RESULTS: One hundred fifty-nine patients with a median age of 50 years were entered onto study. Patients were assessable if EMBs were performed at least 1 year after the initiation of tamoxifen treatment. Nine patients (5.7%) were considered protocol violations. The remaining 111 assessable patients underwent a total of 635 EMBs (mean, 5.8 EMBs), with a median surveillance time of 36 months. Eighty-two (12.9%) of the 635 biopsies revealed tissue insufficient for diagnosis. Fourteen patients (12.6%) underwent dilation and curettage (D&C) for an abnormal EMB, persistent bleeding, or for evaluation of adnexal masses at the time of laparoscopy. Findings at D&C included complex hyperplasia (n = 1), abnormal histiocytes (n = 1), simple hyperplasia (n = 2), polyps (n = 4), endocervical polyp (n = 1), and decidualization (n = 2). Three D&Cs were negative. Three patients have undergone hysterectomy. CONCLUSION: EMB was used to monitor the endometrium in the majority (95%) of breast cancer patients on tamoxifen in this trial, but the utility of routine EMB for screening in tamoxifen-treated women seems limited.
TAMOXIFEN, A nonsteroidal antiestrogen, was first approved by the Food and Drug Administration for the treatment of patients with breast cancer in 1978. Large clinical trials involving over 75,000 patients have demonstrated an improved recurrence-free and overall survival benefit in both pre- and postmenopausal women.1 Long-term adjuvant tamoxifen is the endocrine treatment of choice for selected patients with breast cancer, and there are currently large-scale trials continuing to evaluate its role as a chemopreventative agent in healthy women at risk for breast cancer. One of the most significant complications of long-term tamoxifen use is the possible development of endometrial cancer. Although tamoxifen is believed to exert its main effect by blocking the binding of estrogen to the estrogen receptor (ER), it exhibits a wide range of biologic effects that may account for its activity in ER-negative tumors as well as some of its unwanted side effects. These include inhibition of calmodulin, stimulation of transforming growth factor beta secretion, induction of apoptosis, interaction with P-glycoprotein, inhibition of protein kinase and phospholipase C, and stimulation of phosphoinositide kinase activity.2 Although primarily an antiestrogen, tamoxifen may also exhibit some mild estrogenic effects. After an initial report by Killackey et al,3 which suggested a possible link between tamoxifen use and the development of endometrial carcinoma in three patients, numerous retrospective reports of tamoxifen-associated uterine cancer were published.4-15 The anecdotal nature of many of these small series, however, did not provide conclusive evidence to justify an association between long-term use and endometrial cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-1416 performed a randomized trial of tamoxifen versus placebo in women with ER-positive breast cancer confined to the breast with negative axillary nodes. Results from this trial of 4,063 patients revealed a 7.5-fold increase in the risk of developing endometrial cancer in the tamoxifen-treated group. The average annual hazard rate for endometrial cancer was 0.2 per 1,000 women in the placebo group and 1.6 per 1,000 women in the randomized tamoxifen-treated group. In a case-control study using Surveillance, Epidemiology, and End-Results data, Bernstein et al17 confirmed a four-fold increased risk of endometrial cancer in breast cancer patients with more than 5 years of tamoxifen use compared with nonusers. This effect was most pronounced, however, in those with known risk factors for endometrial cancer, including higher body mass index and prior use of estrogen replacement therapy. Indications for tamoxifen use have broadened to include long-term adjuvant therapy as well as preventative therapy for selected high-risk women. Consequently, a large number of women, including healthy, young patients with no history of cancer, will be subjected to the long-term effects of tamoxifen. In the NSABP P-1 trial, 13,338 women at increased risk for breast cancer were randomly assigned to tamoxifen versus placebo for 5 years.18 Tamoxifen reduced the risk of both invasive and noninvasive breast cancer by 49% and 50%, respectively. The authors reported 33 cases of endometrial cancers in the tamoxifen-treated group compared with 14 in the control group (relative risk = 2.53). The cancers in the tamoxifen-treated group occurred predominantly in women over the age of 50. These cancers were diagnosed at an early stage and, therefore, did not result in any deaths as a result of endometrial cancer. Currently, the NSABP is conducting the P-2 trial, which compares tamoxifen to raloxifene in a similar population. The question emerges, then, of what recommendations can be made at this point regarding endometrial cancer screening in breast cancer patients currently treated with tamoxifen. The best method for screening, if any, remains to be determined. The aim of the present study was to evaluate prospectively the role of EMB in monitoring the endometrium in women with breast cancer on tamoxifen.
Between October 1991 and September 1998, 159 patients initiating tamoxifen therapy (at a dose of 20 mg/d) for breast cancer confined to the breast with or without axillary lymph node involvement were entered in a prospective study. In this study, EMBs were obtained at initiation of tamoxifen and at 6-month intervals for a 2-year period. Three additional annual EMBs were performed subsequently, amounting to a surveillance of 5 years. The study included both pre- and postmenopausal women with T1-3, N0-1, M0 breast cancer. The surveyed group had a median age of 50 years (range, 33 to 75 years) and had to be enrolled within 10 weeks of initiating tamoxifen therapy. Ineligible patients included those with a history of having undergone a hysterectomy, those with a history of prior use of estrogen-replacement therapy, and patients who were unable to tolerate an EMB. The protocol schema included a baseline gynecologic exam along with a Papanicolaou smear and an EMB using a Pipelle endometrial biopsy device (Unimar, Wilmington, CT). These examinations were repeated every 6 months for 2 years, then annually for an additional 3 years, for a total of eight biopsies. A formal dilation and curettage (D&C) with hysteroscopy was performed for further evaluation of an abnormal EMB or for persistent bleeding. Patients who developed simple hyperplasia on study underwent more frequent biopsies (every 3 months) to monitor for progression to a more significant lesion. Criteria for removal from the study included the development of atypical hyperplasia or endometrial carcinoma.
One hundred fifty-nine patients were entered onto study. Patients were assessable if EMBs were performed for at least 1 year after initiation of tamoxifen. Forty-eight patients were not assessable (Table 1); eight patients (5%) could not undergo the first EMB procedure because of a stenotic cervix, six (3.8%) were too early at time of analysis, 13 (8%) were noncompliant with the follow-up schema, three (2%) had progression of breast cancer, six (3.8%) discontinued tamoxifen, two (1.3%) were unable to tolerate EMB, and one (0.6%) had tamoxifen discontinued secondary to phlebitis. In addition, nine patients (5.7%) were considered protocol violations; four had stage IV breast cancer, and five had a history of prior use of hormone replacement therapy. No patient was excluded based on the results of their initial biopsy. The remaining 111 assessable patients underwent a total of 635 EMBs (mean, 5.8 EMBs), with a median surveillance time of 36 months. Five hundred forty-four patients (86%) revealed benign endometria. Eighty-two of the biopsies (12.9%) revealed tissue insufficient for diagnosis. This was assumed to reflect atrophic endometrium if, in the investigators opinion, the pipelle had been successfully introduced into the endometrial cavity. No further evaluation was performed unless the patient developed abnormal bleeding. Nine biopsies (1.4%) were abnormal, which led to further evaluation, usually consisting of a D&C with hysteroscopy. In total, 14 (12.6%) of the 111 patients underwent a D&C for an abnormal EMB, persistent bleeding, or for evaluation of adnexal masses at the time of laparoscopy. Findings at D&C included complex hyperplasia (n = 1), abnormal histiocytes (n = 1), simple hyperplasia (n = 2), polyps (n = 4), endocervical polyp (n = 1), and decidualization secondary to progesterone (n = 2). In addition, there were three negative D&Cs, two at the time of laparoscopy for bilateral salpingo-oophorectomy for benign ovarian disease (Table 2).
Three patients have undergone hysterectomy (Table 3). The first patient was a 45-year-old woman who underwent a lumpectomy and axillary dissection for breast cancer. Postoperatively, she received radiation therapy to the breast, followed by six cycles of chemotherapy with CMF before initiating tamoxifen. An endometrial biopsy performed after 12 months of tamoxifen revealed endometrial hyperplasia with mucinous change. A D&C was performed for further evaluation, and this procedure revealed extensive mucinous change suspicious for a mucinous carcinoma. The patient, therefore, underwent a laparoscopically assisted vaginal hysterectomy, and this revealed complex hyperplasia with no evidence of carcinoma. The second patient was a 50-year-old woman who underwent a left-modified radical mastectomy followed by eight cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) and tamoxifen. Because of persistent abnormal vaginal bleeding, she underwent a D&C with benign findings after 9 months of tamoxifen. Tamoxifen was discontinued after 15 months of use, secondary to patient intolerance. Three months later, a computed tomography scan for surveillance revealed a large pelvic mass suspicious for an ovarian neoplasm. At the time of laparotomy, the mass was found to be uterine in origin. A hysterectomy was performed and final pathology revealed a high-grade leiomyosarcoma.
The third patient was also a 50-year-old woman who received CMF chemotherapy and tamoxifen after a left-modified radical mastectomy that revealed metastatic disease in one lymph node. After 48 months of tamoxifen, she underwent a laparoscopically assisted vaginal hysterectomy for persistent bleeding despite benign endometrial biopsies. This procedure revealed a large endometrial polyp. Although three of the sampled patients (2.7%) required hysterectomy, only one of these had pathology detected by endometrial biopsy.
Many patients with breast cancer who are taking tamoxifen worry a great deal about the possibility of developing a different cancer, specifically endometrial cancer. Clinicians who care for these patients sense this anxiety, and, in an effort to help, may attempt to screen for endometrial cancer. With an expected annual risk of endometrial cancer of approximately two per 1,000 women, as defined by the NSABP B-14 trial,16 the chance of detecting endometrial cancer is very low. The patient may, however, benefit from the reassurance that a negative test provides. The best method for screening for endometrial cancer, if any, remains to be determined. Transvaginal sonography may provide a noninvasive means of screening for endometrial pathology in tamoxifen-treated breast cancer patients. The definition of an abnormal endometrial stripe remains to be defined. As reported by Lahti et al,10 if a cutoff of  5 mm was used to define an abnormal endometrial echo, 22 patients (51.2%) had no abnormal endometrial pathology noted at the time of endometrial biopsy. Kedar et al18 reported a predictive value of 100% (16 of 16 patients) for atypical hyperplasia or polyps using an endometrial stripe of  8 mm. These findings suggest that premalignant changes can be detected with transvaginal sonography. Care must be taken, however, that the ultrasonographic findings of the endometrium in tamoxifen-treated patients are not overinterpreted. Goldstein19 reported on five postmenopausal tamoxifen-treated patients who, on routine surveillance with vaginal probe ultrasonography, were described as having heterogeneous, bizarre-appearing endometria with multiple sonolucent areas suggestive of a polyp. Because of concerns regarding tamoxifen use and endometrial neoplasia, the first patient was referred for a curettage and hysteroscopy. Minimal tissue was obtained, and hysteroscopic evaluation revealed a smooth atrophic endometrium. When the abnormal sonographic appearance persisted, the patient underwent a sonohysterogram, which involves the instillation of 3 to 10 mL of saline at the time of sonography. The fluid enhancement revealed that the changes originally interpreted as endometrial were actually subendometrial in origin. Four additional patients with similar abnormal sonographic findings were actually found to have subendometrial abnormalities on sonohysterogram. It is unclear what these abnormal areas represent as none of the patients have undergone hysterectomy, although it was speculated that they may represent adenomyomatous-like changes. Love et al20 reported on the sonographic endometrial characteristics of 357 asymptomatic patients treated with tamoxifen for a mean of 66 months compared with 130 control patients who did not use tamoxifen. Women receiving tamoxifen, compared with the controls, had a greater mean endometrial thickness (7.3 mm v 2.5 mm, respectively) that correlated with increasing duration of use. Using a cutoff of greater than 5 mm for abnormal endometrial thickness, 41% of the tamoxifen-treated group met this criteria compared with none of the controls. Office hysteroscopy was performed successfully in 134 out of 145 of these women, whereas the remaining 11 underwent a D&C. Atrophic endometrium was noted in 61 patients, giving a false-positive rate of 46%. The remaining patients all had benign features to account for the thickened endometrial stripe. This study confirmed the poor predictive value of transvaginal sonographic measurement of endometrial stripe thickness for detecting endometrial cancer. Perhaps most importantly, the study reported that no cancers were detected in this group of asymptomatic patients, whereas one case each of endometrial hyperplasia carcinoma was detected in women referred for abnormal bleeding. Some have proposed annual endometrial sampling, although this suggestion presents its own difficulties. For example, Gal et al21 were unable to perform EMBs with a Novak curette in 44% of 89 postmenopausal patients because of atrophic changes. The question then arises as to whether these patients should be subjected to the inherent morbidity of a fractional D&C, which usually requires general anesthesia. In a report by Gibson et al,22 all cases of endometrial carcinoma detected by D&C in tamoxifen-treated breast cancer patients presented with abnormal bleeding resulting in the early-stage detection of a majority of cases. In 1991, an emerging body of literature implicated tamoxifen use with an increased risk of developing endometrial cancer. With this in mind, we initiated a prospective endometrial screening trial to determine, using EMB, the feasibility of detecting pathologic changes in the endometria of women taking tamoxifen. With EMB we were able to successfully evaluate the endometrial cavity in 95% of patients. As is the case with any screening program, our protocol led to an increase in the number of operative procedures. Specifically, 14 patients (12.6%) required a D&C under general anesthesia. Despite performing a total of 635 biopsies, a mean of approximately six per patient, only one patient had significant pathology, complex hyperplasia, which led to a hysterectomy. Although this patient was asymptomatic, the value of early detection for this lesion is questionable, as the progression rate of untreated complex hyperplasia without atypia to endometrial cancer is reported to be only 3%.23 During the study period, two additional patients underwent a hysterectomy; neither of these, however, were performed for pathologic changes detected on endometrial biopsy. One patient had persistent vaginal bleeding because of a large endometrial polyp, and the other patient underwent a hysterectomy for a uterine leiomyosarcoma, despite having undergone a negative D&C for persistent abnormal bleeding 6 months earlier. Some reports have associated tamoxifen use with a higher incidence of uterine sarcomas and other high-risk histologic subtypes. A report from the Yale Tumor Registry by Magriples et al24 suggested that uterine cancers occurring in breast cancer patients on tamoxifen might behave more aggressively and carry a worse prognosis. Silva et al25 reviewed the M.D. Anderson Cancer Center experience with 72 breast cancer patients who subsequently developed malignant uterine neoplasms. Fifty-seven patients had not received tamoxifen as part of their treatment, whereas 15 patients had received tamoxifen. A high incidence of leiomyosarcomas was noted in both tamoxifen-treated and untreated patients (14% v 17%, respectively), which is much higher than the 1% to 2% incidence of sarcomas that one would expect to find. Other studies,13-15 however, have not been able to confirm that tamoxifen use is associated with the development of high-risk endometrial cancers. The ultimate goal of any cancer-screening program is to detect disease at the earliest stage, when it is most curable. To date, there is still no evidence that any form of screening for endometrial cancer in tamoxifen-treated patients will accomplish this. Because tamoxifen-associated endometrial cancers seem to have a similar stage, grade, and histology as endometrial cancers occurring in the general population,14 their prognosis is generally good, and early detection will probably not improve outcome significantly. Furthermore, a very small number of tamoxifen-treated breast cancer patients could be expected to benefit from screening for endometrial cancer. Because the annual risk of endometrial cancer is two per 1,000 women16 in this population and approximately 15% of these cancers will result in the patient’s death,26 annual screening could potentially decrease mortality in only 0.002 x 0.15 = 0.0003, or 0.03%, of all tamoxifen-treated patients.27 Because approximately 80,000 women begin tamoxifen treatment annually, the cost to undertake screening for endometrial cancer in this population may be prohibitively high. Breast cancer patients on tamoxifen are anxious about developing a second cancer. Although it may seem beneficial to order a battery of screening tests, if these screening tests do not have proven records of efficacy, then they might feed, rather than alleviate, these anxieties and lead to unnecessary procedures. Clinicians should attempt to allay patients’ fears by educating them about the actual risks and outcomes of endometrial cancers developing while on tamoxifen. Women with breast cancer, whether they are receiving tamoxifen or not, should undergo an annual gynecologic evaluation. They should be instructed to alert their physician about any sign of abnormal vaginal bleeding, including spotting or abnormal vaginal discharge. Prompt endometrial sampling should be initiated for patients with any sign of abnormal vaginal bleeding.
We thank the members of the Memorial Sloan-Kettering Cancer Center Breast Service who provided patients for this study.
1. Early Breast Cancer Trialists’ Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized clinical trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 339:1–15; 71–85, 1992 2. Friedman ZY: Recent advances in understanding the molecular mechanisms of tamoxifen action. Cancer Invest 16: 391-396, 1998[Medline] 3. Killackey MA, Hakes TB, Pierce VK: Endometrial adenocarcinoma in breast cancer patients receiving antiestrogens. Cancer Treat Rep 69: 237-238, 1985[Medline] 4. Hardell L: Tamoxifen as risk factor for carcinoma of corpus uteri. Lancet 3: 563, 1988 (letter) 5. Neven P, Muylder X, Van Belle Y, et al: Tamoxifen and the uterus and endometrium. Lancet 1: 375, 1989 (letter)[Medline] 6. Fornander T, Cedermark B, Mattsson A, et al: Adjuvant tamoxifen in early breast cancer: Occurrence of new primary cancers. Lancet 21: 117-120, 1989 7. Atlante G, Pozzi M, Vincenzoni C, et al: Four case reports presenting new acquisitions on the association of breast and endometrial cancer. Gynecol Oncol 37: 378-380, 1990[Medline] 8. Mathew A, Chabon AB, Kabakow B, et al: Endometrial carcinoma in five patients with breast cancer on tamoxifen therapy. NY State J Med 90: 207-208, 1990[Medline] 9. Malfetano JH: Tamoxifen-associated endometrial carcinoma in postmenopausal breast cancer patients. Gynecol Oncol 39: 82-84, 1990[Medline]
10.
Magriples U, Naftolin F, Schwartz PE, et al: High-grade endometrial carcinoma in tamoxifen-treated breast cancer patients. J Clin Oncol 11: 485-490, 1993 11. Lahti E, Blanco G, Kauppila A, et al: Endometrial changes in postmenopausal breast cancer patients receiving tamoxifen. Obstet Gynecol 81: 660-664, 1993[Medline]
12.
Seoud MA-F, Johnson J, Weed JC: Gynecologic tumors in tamoxifen-treated women with breast cancer. Obstet Gynecol 82: 165-169, 1993 13. Van Leeuwen FE, Benraadt J, Coebergh JWW, et al: Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet 343: 448-452, 1994[Medline] 14. Barakat RR, Wong G, Curtin JP, et al: Tamoxifen use in breast cancer patients who subsequently develop corpus cancer is not associated with a higher incidence of adverse histologic features. Gynecol Oncol 55: 164-168, 1994[Medline] 15. Assikis VJ, Jordan VC: Gynecologic effects of tamoxifen and the association with endometrial carcinoma. Int J Gynecol Obstet 49: 241-257, 1995[Medline]
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Fisher B, Costantino JP, Redmond CK, et al: Endometrial cancer in tamoxifen-treated breast cancer patients: Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 86: 527-537, 1994
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Bernstein L, Deapen D, Cerhan JR, et al: Tamoxifen therapy for breast cancer and endometrial cancer risk. J Natl Cancer Inst 91: 1654-1662, 1999
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Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371-1388, 1998 19. Kedar RP, Bourne TH, Powles TJ, et al: Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet 343: 1318-1321, 1994[Medline] 20. Goldstein SR: Unusual ultrasonographic appearance of the uterus in patients receiving tamoxifen. Am J Obstet Gynecol 170: 447-451, 1994[Medline]
21.
Love CDP, Muir BB, Scrimgeour JB, et al: Investigation of endometrial abnormalities in asymptomatic women treated with tamoxifen and an evaluation of the role of endometrial screening. J Clin Oncol 17: 2050-2054, 1999 22. Gal D, Kopel S, Bashevkin M, et al: Oncologic potential of tamoxifen on endometria of postmenopausal women with breast cancer: Preliminary report. Gynecol Oncol 42: 120-123, 1991[Medline] 23. Gibson LE, Barakat RR, Venkatraman ES, et al: Endometrial pathology at dilation and curettage in breast cancer patients: Comparison of tamoxifen users and nonusers. Cancer J Sci Am 2: 35-38, 1995 24. Kurman RJ, Kaminski PF, Norris HJ: The behavior of endometrial hyperplasia: A study of untreated endometrial hyperplasia in 170 women. CA Cancer J Clin 56: 403–412, 1985 25. Magriples U, Naftolin F, Schwartz PE, et al: High-grade endometrial carcinoma in tamoxifen-treated breast cancer patients. J Clin Oncol 11: 485-490, 1993 26. Silva EG, Tornos CS, Follen-Mitchell M: Malignant neoplasms of the uterine corpus in patients treated for breast carcinoma: The effects of tamoxifen. Int J Gynecol Pathol 13: 248-258, 1994[Medline] 27. Barakat RR: The effect of tamoxifen on the endometrium. Oncology 9: 129–134, 1995
28.
Barakat RR: Screening for endometrial cancer in the patient receiving tamoxifen for breast cancer. J Clin Oncol 17: 1967-1968, 1999 Submitted February 28, 2000; accepted June 16, 2000. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
