Update on Tamoxifen- Associated Endometrial Cancer in Breast Cancer Patients
January 1, 2000 5 minutes read
Special Feature
Update on Tamoxifen- Associated Endometrial Cancer in Breast Cancer Patients
By David M. Gershenson, MD
My last discussion of the relationship between tamoxifen and endometrial cancer in breast cancer patients was more than five years ago, and it is probably reasonable to review the topic again briefly since there is some new information. Tamoxifen is a nonsteroidal antiestrogen compound that was first approved by the FDA for the treatment of patients with breast cancer in 1978. Approximately 80,000 of the 182,000 women diagnosed annually with breast cancer in the United States will receive tamoxifen. Tamoxifen reduces the risk of subsequent contralateral breast cancer as well as breast cancer recurrences and deaths. Several reports have implicated tamoxifen in the development of endometrial polyps and hyperplasia. In the mid-1980s, reports of the association of tamoxifen with the development of endometrial cancer began to emerge. Early reports of endometrial cancer in tamoxifen users included small numbers of women and had no controls. Then two prospective, randomized trials—the Stockholm Adjuvant Tamoxifen Trial and the National Surgical Adjuvant Breast and Bowel Project (NSABP)—revealed an increased risk of endometrial cancer in the tamoxifen-treated women. In the NSABP trial, the relative risk (RR) of endometrial cancer was 7.5.
Because of its efficacy in the treatment of breast cancer, clinical trials were begun in the United States, the United Kingdom, and Italy to assess the primary prevention of breast cancer in the disease-free women. The NSABP Breast Cancer Prevention Trial randomized women with a breast cancer risk at least as great as that of a 60-year-old woman to either tamoxifen or placebo. Although women on the tamoxifen arm had a substantially reduced risk of invasive breast cancer, they also had a 2.5-fold greater incidence of endometrial cancer. The follow-up NSABP phase III trial is called the STAR trial. This trial will enroll 22,000 postmenopausal women and will randomize women between tamoxifen and the SERM raloxifene. The hope is that raloxifene will have a higher therapeutic index because of a lower risk of endometrial cancer.
In my opinion, a controversy still exists regarding the nature of the endometrial cancers observed in tamoxifen users. Some studies, such as the one from Yale1, have suggested that tamoxifen-associated endometrial cancers are much more likely to be high-grade with an unfavorable prognosis than endometrial cancers occurring in nonusers. Other reports, notably the studies from the NSABP and Memorial Sloan-Kettering Cancer Center, have found no such poor-prognosis characteristics associated with endometrial cancers developing in tamoxifen users.2,3 As additional information becomes available, this issue should be resolved.
A recent multi-institutional epidemiological study has provided additional data on endometrial cancer risk.4 Bernstein and colleagues conducted a case-control study of endometrial cancer nested within a population-based cohort of patients with breast cancer diagnosed from 1978-1992 within four regions of the United States. Endometrial cancer risk was associated with tamoxifen therapy for breast cancer (OR = 1.52). Risk increased with duration of tamoxifen use. Women with more than five years of exposure to tamoxifen had 4.06-fold greater odds of developing endometrial cancer than nonusers. Prior use of estrogen replacement therapy (ERT) increased risk associated with tamoxifen use. Furthermore, risk associated with tamoxifen use was stronger among heavier women than among thinner women, although trends did not differ statistically. Tamoxifen dose-response effects were more pronounced among women with both previous ERT exposure and higher body mass index than among women in other risk groups. Bernstein et al concluded that women with positive ERT histories and those who are obese, when prescribed tamoxifen, might warrant closer surveillance for endometrial cancer than women without such histories.
A major unresolved issue is appropriate surveillance of women taking tamoxifen.5 Love and colleagues conducted a study to evaluate whether screening with transvaginal ultrasound (TVUS) with or without hysteroscopy is worthwhile. A total of 487 women with breast cancer, 357 treated with tamoxifen and 130 controls, were screened with TVUS, and endometrial thickness was measured. Women with thickened endometrium underwent outpatient hysteroscopy. Length of time on tamoxifen ranged from five to 191 months (mean, 66 months), and endometrial thickness ranged from 1 mm to 38 mm (mean, 7.3 mm). Women treated with tamoxifen had significantly thicker endometrium than did controls. There was a statistically significant positive correlation between length of time on tamoxifen and endometrial thickness. One hundred forty-five women had endometrium greater than 5 mm on US, 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 US findings. Love et al conclude that TVUS is a poor screening tool because of the high false-positive rate, and that the low frequency of significant findings suggests that endometrial screening in asymptomatic women is not worthwhile. My personal clinical experience with TVUS in breast cancer patients receiving tamoxifen is consistent with the observations of Love et al.
Another potential method of endometrial screening in women receiving tamoxifen is office endometrial biopsy. In a study reported at the 1999 annual meeting of the American Society of Clinical Oncology, Barakat et al revealed the findings of a prospective trial in which breast cancer patients on tamoxifen underwent endometrial biopsies every six months for two years and then annually for an additional three years.6 Endometrial biopsy could not be performed in 5% of patients because of cervical stenosis. Screening resulted in an increase in operative procedures, with 14 patients (12.6%) requiring D&C for abnormal biopsy findings. Although three patients in the study underwent hysterectomy, only one had endometrial pathology detected by biopsy. Barakat et al conclude that the use of office endometrial biopsy for cancer screening in women receiving tamoxifen is limited. Based on available information, it appears that endometrial biopsy with or without TVUS should be reserved for patients with abnormal vaginal bleeding.
References
1. Magriples U, et al. J Clin Oncol 1993;11:485-490.
2. Fisher B, et al. J Natl Cancer Inst 1994;86:527-537.
3. Barakat RR, et al. Clin Obstet Gynecol 1996;39: 629-640.
4. Bernstein L, et al. J Natl Cancer Inst 1999;91: 1654-1662.
5. Love CD, et al. J Clin Oncol 1999;17:2050.
6. Barakat RR, et al. Proc Am Soc Clin Oncol 1999; 18:358a.
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