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Obstetrics & Gynecology 2004;104:255-260
© 2004 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Does Tamoxifen Use Affect Prognosis in Breast Cancer Patients Who Develop Endometrial Cancer?

Brian M. Slomovitz, MD, Charlotte C. Sun, DrPH, Pedro T. Ramirez, MD, Diane C. Bodurka, MD, Paul Diaz and Karen H. Lu, MD

From the Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

Address reprint requests to: Karen H. Lu, MD, Department of Gynecologic Oncology, Unit 440, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009; e-mail: khlu{at}mdanderson.org.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: The use of tamoxifen to prevent breast cancer and decrease recurrence is not controversial. However, the effect that tamoxifen may have in women with a history of breast cancer in whom endometrial cancer develops is unclear. The purpose of this study was to estimate whether a history of tamoxifen use is a prognostic factor for such patients.

METHODS: Between 1990 and 2002, patients seen at The University of Texas M. D. Anderson Cancer Center with a history of breast cancer who developed endometrial cancer were identified. Medical records were reviewed to identify clinical, pathologic, and outcome information.

RESULTS: Eighty-nine patients with a history of breast cancer in whom endometrial carcinoma developed were identified. Fifty-two percent (46/89) had a history of tamoxifen use (median duration 48 months; range 2–120 months). There were no significant differences in the clinical or pathologic features between tamoxifen users and nonusers. A history of tamoxifen use was associated with a shorter interval from breast cancer to endometrial cancer diagnosis (77.2 versus 121.3 months for nonusers; P = .01). There was no significant difference in overall survival between tamoxifen users and nonusers (39.2 months versus 48.3 months, P = .27), and there was no difference in endometrial cancer-specific survival duration between tamoxifen users and nonusers (55.7 versus 51.0 months, P = .92).

CONCLUSION: Among tamoxifen users, the interval from breast cancer to endometrial cancer diagnosis was significantly shorter than that in nonusers. In this cohort, a history of tamoxifen use was not associated with a worse overall or disease-specific survival.

LEVEL OF EVIDENCE: II-2

Several population-based studies have demonstrated that patients with breast cancer are at increased risk for endometrial cancer.1–3 In particular, the Breast Cancer Detection Demonstration Project3 reported a relative risk (RR) of endometrial cancer of 1.3 in women with a history of breast cancer. Although not well established, factors involved in the association between breast and endometrial cancer may be linked with reproductive factors (eg, hyperestrogenic states and nulliparity) and genetic predispositions.

Currently, tamoxifen is the most widely prescribed selective estrogen receptor modulator, because it is used by as many as 1 million women.4 In the breast, tamoxifen inhibits the potent proliferative effects of estrogen. Large prospective clinical trials have demonstrated improved recurrence-free and overall survival in both premenopausal and postmenopausal women with breast cancer who take tamoxifen (20 mg/d for 5 years).5 In women with estrogen receptor (ER)-positive breast cancer, tamoxifen is highly effective as an adjunct to other primary chemotherapeutic agents and significantly improves outcome and 5-year survival.5 More recently, the indications for tamoxifen use have broadened to include long-term adjuvant therapy as well as preventive therapy in selected women with a high risk of developing breast cancer. For women at increased risk for breast cancer (Gail index ≥ 1.66% at 5 years), tamoxifen reduces the incidence of breast cancer by 50%.6 Consequently, a large number of women, including healthy young patients with no history of cancer, will be subjected to the effects of tamoxifen, making it crucial to understand the possible effects of this agent at other organ sites.

In contrast to its antiestrogenic effect in the breast, tamoxifen is an ER agonist in the uterus. A report by Killackey et al7 in 1985 provided some of the earliest data highlighting this relationship. Also, in a study of the Swedish Cancer Registry, there was a 6.4-fold increase in the RR of endometrial cancer in 931 patients receiving tamoxifen when compared with a placebo group (Fornander T, Rutqvist LE. Adjuvant tamoxifen and second cancers [letter]. Lancet 1989;1:616). The greatest risk of cancer was in those who took tamoxifen for at least 5 years. National Surgical Adjuvant Breast and Bowel Project protocol B-14, which was published in 1994, also highlighted the increased risk of endometrial cancer with adjuvant tamoxifen therapy.8 This randomized trial of tamoxifen versus a placebo in women with ER-positive breast cancer revealed a 7.5-fold increase in the risk of tamoxifen-related endometrial cancer. Additionally, in a case-controlled study in The Netherlands, women using tamoxifen for more than 2 years had a 2.3 times greater risk of endometrial cancer than did nonusers.9 This study showed an increase in risk with an increase in the duration of tamoxifen use and cumulative dose. Although not evaluating patients with a personal history of breast cancer, results of the National Surgical Adjuvant Breast and Bowel Project protocol P-1 Breast Cancer Prevention trial have also demonstrated an increased risk of endometrial cancer in patients receiving tamoxifen (RR 2.53).10 This increased risk was found predominantly in women aged 50 years or older. In all of these studies, the benefit of tamoxifen in preventing recurrent or primary breast cancer outweighed the risk of endometrial cancer.

The role of tamoxifen in decreasing breast cancer recurrence is not controversial. As obstetricians and gynecologists, we must determine whether a history of tamoxifen use affects the clinical course of endometrial cancer in patients with a history of breast cancer. Therefore, the purpose of the present study was to estimate whether a history of tamoxifen use is a prognostic factor in these patients. Specifically, we sought to determine the affect that tamoxifen use had on the interval between breast cancer and endometrial cancer diagnosis and its affect on overall and endometrial cancer–specific survival.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Upon Institutional Review Board approval, a retrospective review of patients with endometrial carcinoma seen at the Gynecologic Oncology Outpatient Clinic at The University of Texas M. D. Anderson Cancer Center between 1990 and 2002 was performed. In addition, the Tumor Registry database maintained by the Department of Medical Informatics at our university was used to confirm that no cases were missed. Patients with uterine sarcomas were excluded from this study. Eighty-nine patients with endometrial cancer who had a history of breast cancer were identified. Patients were not required to have undergone treatment of their breast cancer at M. D. Anderson Cancer Center to be included in this study.

Clinical and demographic information were obtained from the patients’ medical records, as were their history and duration of tamoxifen use. Treatment and follow-up information were also collected.

The {chi}2 test (or Fisher exact test, when appropriate) and the independent t test were used to compare clinical and demographic information. Overall survival and endometrial cancer–specific survival curves were generated using the Kaplan-Meier method. Survival was calculated from the time of endometrial cancer diagnosis. The log rank test was used to compare survival curves based upon several prognostic factors. The SPSS 11. 5 software program (SPSS Inc, Chicago, IL) was used for all of the analyses.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
We identified 89 patients with a history of breast cancer in whom endometrial cancer developed. Fifty-four percent (48/89) of these women had endometrioid endometrial cancer, 29% (26/89) had uterine papillary serous carcinoma, 14% (12/89) had malignant mixed mullerian tumors, and 3% (3/89) had clear cell carcinoma. Fifty-two percent of the patients (46/89) had a history of tamoxifen use. The median duration of tamoxifen use was 48 months (range 2–120 months). Patients in whom endometrial cancer developed while taking tamoxifen (defined as taking tamoxifen at the time of diagnosis or stopped within 2 months of diagnosis, n = 29) were most likely to have endometrioid endometrial cancer than women with a history of tamoxifen use who had stopped taking tamoxifen for other reasons (62% versus 20%; P = .02).

Demographic information comparing tamoxifen users with nonusers is listed in Table 1. There were no significant differences in their clinical features (ie, age at time of cancer diagnosis, medical or family history, presenting symptoms). Although not statistically significant, women taking tamoxifen weighed less than the nonusers did (P = .07). The most common presenting symptom was abnormal vaginal bleeding.


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  		Table 1. Clinical Information

 

Table 2 lists pathologic features of the tamoxifen users and nonusers. Fifty percent (23/46) of the tamoxifen users had a high-risk histologic subtype (uterine papillary serous carcinoma, clear cell carcinoma, or malignant mixed mullerian tumors) compared with 42% (18/43) of the nonusers (P = .59). There were no significant differences in the stage or grade of endometrial cancer between tamoxifen users and nonusers.


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  		Table 2. Pathologic Information

 

Table 3 compares the interval from diagnosis of breast cancer to that of endometrial cancer. Compared with women who did not take tamoxifen, the time to diagnosis of endometrial cancer was shorter for women with a history of tamoxifen use (121.3 months versus 77.2 months, respectively, P = .01). In the subgroup of patients who had endometrioid endometrial cancer (23 tamoxifen users, 25 nonusers), tamoxifen use was associated with a decreased interval when compared with no tamoxifen use (67.3 months versus 129.3 months; P = .01). This difference was not seen in patients who had uterine papillary serous carcinoma, clear cell carcinoma, or malignant mixed mullerian tumors.


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  		Table 3. Interval From Breast to Endometrial Cancer Diagnosis

 

In our study population, 37% (17/46) of the tamoxifen users and 37% (16/43) of the nonusers had progressive or recurrent endometrial cancer. Patients with uterine papillary serous carcinoma, clear cell carcinoma, or malignant mixed mullerian tumor histologic subtypes were more likely to have a recurrence than were those with endometrioid endometrial cancer, regardless of tamoxifen use (54% versus 23%; P = .01).

Table 4 compares the median overall survival and endometrial cancer–specific survival between tamoxifen users and nonusers. There was a significant difference in overall survival in those women who developed endometrioid endometrial cancer (37.3 months for tamoxifen users versus 84.0 months for nonusers, P = .01). Otherwise, we did not find any difference in overall survival or endometrial cancer–specific survival between tamoxifen users and nonusers.


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  		Table 4. Median Overall Survival and Endometrial Cancer–Specific Survival

 


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, tamoxifen use was associated with a shorter interval between diagnosis of breast and endometrial cancer than that in patients who did not use tamoxifen. This association was highlighted in the subgroup of women who had endometrioid endometrial cancer. Specifically, in women with a history of breast cancer who had endometrioid endometrial cancer, the interval from diagnosis of breast cancer to that of endometrial cancer was approximately 5 years in tamoxifen users and more than 10 years in nonusers (P = .01). In addition, endometrial cancer developed in 68% of the tamoxifen users while they were taking tamoxifen; most of these patients had endometrioid endometrial cancer.

In this cohort of patients, tamoxifen use was not a prognostic factor for overall survival or endometrial cancer–specific survival. There was a significant difference in overall survival between the tamoxifen users and nonusers for the patients who developed endometrioid endometrial cancer. The reasons for this difference are not known. Because of the limited sample size in this study, we had insufficient power to conclude that tamoxifen by itself affects overall survival and endometrial cancer–specific survival. Large prospective, population-based studies would better determine the effect of tamoxifen use on survival in patients who have endometrial cancer.

Most reports have not shown an adverse prognosis for uterine cancers arising as a result of tamoxifen therapy. In one study, 17 uterine cancers developed in a group of 931 patients taking tamoxifen: 94% were grade 1 or 2, and 82% were stage I (Fornander and Rutqvist, Lancet 1989). Also, in the National Surgical Adjuvant Breast and Bowel Project B-14 study, endometrial cancer developed in 23 patients; 78% of the cases were grade 1 or 2.8 Furthermore, in the National Surgical Adjuvant Breast and Bowel Project P-1 trial, all 36 uterine cancers that developed in patients receiving tamoxifen were stage I.10 Barakat et al11 demonstrated no histologic differences in the uterine cancers that arose in 23 patients with breast cancer who took tamoxifen for at least 1 year when compared with a control group.

Other studies, however, have shown a more adverse prognosis for endometrial cancers in patients with a history of tamoxifen use. In a retrospective review of tamoxifen-associated endometrial carcinoma, Magriples et al12 found that cases associated with tamoxifen use were more aggressive histologically and of a higher grade than those not associated with tamoxifen use. In this study, all of the patients received higher than standard doses of tamoxifen. In addition, Silva et al13 reported a higher incidence of uterine papillary serous carcinoma in patients with breast cancer who received tamoxifen when compared with patients who did not take tamoxifen. More recently, tamoxifen treatment was associated with an increased risk for the development of sarcomas and malignant mixed mullerian tumors of the uterus.14,15

Similar to findings in women who do not have a history of breast cancer, the most common presenting symptom in our patient population was abnormal bleeding. We recommend endometrial sampling in all women (premenopausal or postmenopausal) who have abnormal vaginal bleeding while taking tamoxifen. The American College of Obstetricians and Gynecologists has not advocated routine endometrial biopsies in asymptomatic women taking tamoxifen because of the low risk of endometrial cancer (2–3/1,000 patients) and absence of a cost-benefit analysis for any of the screening methods.16 Transvaginal ultrasonography has been used to assess the thickness and characteristics of the endometrial stripe. In postmenopausal women not taking tamoxifen, endometrial pathology is unlikely if the endometrial stripe is less than 5 mm thick.17 However, postmenopausal women taking tamoxifen have a thicker endometrial stripe, larger endometrial volume, and greater incidence of endometrial polyps than do control patients. Another study warned about the interpretation of ultrasound findings in tamoxifen users.18 This study reported that sonographic thickening of the endometrium was due to subendometrial thickening. The low specificity of ultrasonography prevents it from being an effective screening test in patients taking tamoxifen.19

The results of this study suggest that tamoxifen use may play a greater role in the development of the endometrioid histologic subtype of endometrial cancer and are consistent with the findings of the National Surgical Adjuvant Breast and Bowel Project B-14 and P-1 trials.8,10

Although it is presumed that tamoxifen causes endometrial cancer by acting as an estrogenic analogue, the specific mechanism of this process is unclear. There have been few studies examining the molecular effects of tamoxifen in endometrial cancer.20–25 Most recently, Ferguson and colleagues26 performed microarray-based expression profiling of tamoxifen-associated endometrial cancers and found that the molecular profile of these tumors was not different from those not associated with tamoxifen use. Wilder and colleagues27 found more frequent expression of ER-ß and lower expression of ER-{alpha} in tamoxifen-associated tumor. Further studies are needed to better evaluate the ER pathway and its role in the tumorigenesis of tamoxifen-related cancers. Steroid coactivators (eg, src-1, AIB1, cdc25-B) may be up-regulated by tamoxifen and thus may play a role in this pathway.

Weaknesses of this study include its retrospective design, small sample size, exclusion of uterine sarcomas, limited patient follow-up, and incomplete information available from the medical records. In particular, information about the hormone status (eg, ER-positive or -negative), the histologic subtype, and the stage of the breast cancer would be useful.

In conclusion, we found that the interval between breast and endometrial cancer diagnosis was significantly shorter in patients with a history of tamoxifen use. In this cohort of patients, tamoxifen use did not affect disease-specific survival in patients with breast cancer in whom endometrial cancer developed. Larger prospective studies are needed to determine whether tamoxifen use affects overall survival. Molecular studies are needed to determine the specific effects of tamoxifen on the endometrium. These studies may also help identify biomarkers of the risk of endometrial cancer.


   Footnotes
 
Received February 13, 2004. Received in revised form April 1, 2004. Accepted April 15, 2004.

Presented at the 35th Annual Meeting of the Society of Gynecologic Oncology, San Diego, CA, February 7–11, 2004.

10.1097/01.AOG.0000131620.67911.03


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Adami HO, Krusemo UB, Bergkvist L, Persson I, Pettersson B. On the age-dependent association between cancer of the breast and of the endometrium: a nationwide cohort study. Br J Cancer 1987;55:77–80.[Medline]

2. Harvey EB, Brinton LA. Second cancer following cancer of the breast in Connecticut, 1935–82. Natl Cancer Inst Monogr 1985;68:99–112.

3. Kazerouni N, Schairer C, Friedman HB, Lacey JV Jr, Greene MH. Family history of breast cancer as a determinant of the risk of developing endometrial cancer: a nationwide cohort study. J Med Genet 2002;39:826–32.[Free Full Text]

4. Shapiro CL, Recht A. Side effects of adjuvant treatment of breast cancer. N Engl J Med 2001;344:1997–2008.[Free Full Text]

5. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists’ Collaborative Group. Lancet 1992;339:1–15.[Medline]

6. Levine M, Moutquin JM, Walton R, Feightner J. Chemoprevention of breast cancer: a joint guideline from the Canadian Task Force on Preventive Health Care and the Canadian Breast Cancer Initiative's Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. CMAJ 2001;164:1681–90.[Abstract/Free Full Text]

7. Killackey MA, Hakes TB, Pierce VK. Endometrial adenocarcinoma in breast cancer patients receiving antiestrogens. Cancer Treat Rep 1985;69:237–8.[Medline]

8. Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM. 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 1994;86:527–37.[Abstract/Free Full Text]

9. Bergman L, Beelen ML, Gallee MP, Hollema H, Benraadt J, van Leeuwen FE. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres’ ALERT Group. Assessment of Liver and Endometrial cancer Risk following Tamoxifen. Lancet 2000;356:881–7.[Medline]

10. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, 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 1998;90:1371–88.[Abstract/Free Full Text]

11. Barakat RR, Wong G, Curtin JP, Vlamis V, Hoskins WJ. Tamoxifen use in breast cancer patients who subsequently develop corpus cancer is not associated with a higher incidence of adverse histologic features. Gynecol Oncol 1994;55:164–8.[Medline]

12. Magriples U, Naftolin F, Schwartz PE, Carcangiu ML. High-grade endometrial carcinoma in tamoxifen-treated breast cancer patients. J Clin Oncol 1993;11:485–90.[Abstract/Free Full Text]

13. 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 1994;13:248–58.[Medline]

14. Wickerham DL, Fisher B, Wolmark N, Bryant J, Costantino J, Bernstein L, et al. Association of tamoxifen and uterine sarcoma. J Clin Oncol 2002;20:2758–60.[Free Full Text]

15. Curtis RE, Freedman DM, Sherman ME, Fraumeni JF Jr. Risk of malignant mixed mullerian tumors after tamoxifen therapy for breast cancer. J Natl Cancer Inst 2004;96:70–4.[Abstract/Free Full Text]

16. American College of Obstetricians and Gynecologists. Tamoxifen and endometrial cancer. ACOG Committee Opinion 169. Washington, DC: ACOG; 1996.

17. Nasri MN, Coast GJ. Correlation of ultrasound findings and endometrial histopathology in postmenopausal women. Br J Obstet Gynaecol 1989;96:1333–8.[Medline]

18. Goldstein SR. Unusual ultrasonographic appearance of the uterus in patients receiving tamoxifen. Am J Obstet Gynecol 1994;170:447–51.[Medline]

19. Gardner FJ, Konje JC, Brown L, Khanna S, Bell SC, Taylor DJ, et al. Uterine surveillance of asymptomatic postmenopausal women taking tamoxifen. Climacteric 1998;1:180–7.[Medline]

20. Mourits MJ, Ten Hoor KA, van der Zee AG, Willemse PH, de Vries EG, Hollema H. The effects of tamoxifen on proliferation and steroid receptor expression in postmenopausal endometrium. J Clin Pathol 2002;55:514–9.[Abstract/Free Full Text]

21. Mourits MJ, Hollema H, De Vries EG, Ten Hoor KA, Willemse PH, Van Der Zee AG. Apoptosis and apoptosis-associated parameters in relation to tamoxifen exposure in postmenopausal endometrium. Hum Pathol 2002;33:341–6.[Medline]

22. Hague S, Manek S, Oehler MK, MacKenzie IZ, Bicknell R, Rees MC. Tamoxifen induction of angiogenic factor expression in endometrium. Br J Cancer 2002;86:761–7.[Medline]

23. Anzai Y, Holinka CF, Kuramoto H, Gurpide E. Stimulatory effects of 4-hydroxytamoxifen on proliferation of human endometrial adenocarcinoma cells (Ishikawa line). Cancer Res 1989;49:2362–5.[Abstract/Free Full Text]

24. Barsalou A, Gao W, Anghel SI, Carriere J, Mader S. Estrogen response elements can mediate agonist activity of anti-estrogens in human endometrial Ishikawa cells. J Biol Chem 1998;273:17138–46.[Abstract/Free Full Text]

25. Sakamoto T, Eguchi H, Omoto Y, Ayabe T, Mori H, Hayashi S. Estrogen receptor-mediated effects of tamoxifen on human endometrial cancer cells. Mol Cell Endocrinol 2002;192:93–104.[Medline]

26. Ferguson SE, Olshen AB, Viale A, Awtrey CS, Barakat RR, Boyd J. Gene expression profiling of tamoxifen-associated uterine cancers: evidence for two molecular classes of endometrial carcinoma. Gynecol Oncol 2004;92:719–25.[Medline]

27. Wilder JL, Shajahan S, Khattar NH, Wilder DM, Yin J, Rushing RS, et al. Tamoxifen-associated malignant endometrial tumors: pathologic features and expression of hormone receptors estrogen-alpha, estrogen-beta and progesterone; a case controlled study. Gynecol Oncol 2004;92:553–8.[Medline]




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