Comparison of uterine malignancies that develop during and following tamoxifen therapy
Introduction
It has been well established that the adjuvant use of tamoxifen for women with breast cancer decreases the recurrence rate and improves survival [1], [2], [3]. Associated with this benefit, however, is greater than 7-fold increase in the risk of endometrial cancer in women treated with tamoxifen [4], [5]. Recently, it has been determined that there is a 17-fold increase in the risk of sarcoma of the uterine corpus in this population, with the majority of the remaining cases being carcinosarcomas [6]. Several studies have reported that the increased risk of uterine cancer continues for years after tamoxifen therapy is discontinued [7], [8], [9], [10].
Two classes of endometrial cancer can generally be distinguished by standard clinical and pathologic criteria classified as type I and II tumors [11]. Type I tumors are associated with well-established risk factors for endometrial cancer, such as unopposed estrogen, low histologic grade, and endometrioid histologic subtype, and with a good overall prognosis [11]. In contrast, type II tumors are high-grade, non-endometrioid histologies, and have a worse overall prognosis [11]. There has been continued debate in the literature whether type II tumors are over-represented in tamoxifen-associated compared to sporadic uterine cancers [6], [8], [12].
The risk of uterine cancer after tamoxifen continues to be elevated after cessation of treatment [8], [9], [10]. The Stockholm Breast Cancer Study Group reported the results of long-term follow-up of breast cancer patients who participated in a randomized controlled trial looking at the efficacy of tamoxifen in the adjuvant setting [10]. They reported a continued increase in the cumulative incidence of endometrial cancer in women treated with tamoxifen compared with placebo, with a median follow-up time of 9 years. There is a growing body of data that suggests tamoxifen exposure may increase the risk of developing uterine cancer with unfavorable histologic features [6], [9], [13]. However, it is not known if the types of tumors that develop differ depending on the temporal relationship of tamoxifen exposure. The objective of this study was to test the hypothesis that women with breast cancer treated with adjuvant tamoxifen who developed uterine cancer more than 12 months after discontinuing tamoxifen therapy (past users) have more histologically unfavorable tumors compared with women who developed uterine cancer while taking tamoxifen or within 12 months of stopping therapy (recent users).
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Methods
A retrospective review was performed of all patients with a previous history of breast cancer who were treated with tamoxifen and subsequently developed uterine cancer at Memorial Sloan-Kettering Cancer Center (MSKCC) between January 1980 and June 2004. There were approximately 2900 cases of uterine cancer treated at MSKCC during this time period. This study was approved by the Institutional Review Board at MSKCC. Cases were included if a patient was diagnosed with breast cancer more than 12
Results
There were 106 women identified with a history of breast cancer treated with tamoxifen preceding their diagnosis of uterine cancer between January 1980 and June 2004. Sixty-seven women (63%) met the criteria for recent users, and 39 (37%) met the criteria for past users of tamoxifen. There was no significant difference in the duration of tamoxifen use for recent and past users with the mean duration being 58 and 62 months, respectively (Table 1; P = 0.45). The median time until developing
Discussion
Our study revealed an increase in aggressive histologic subtypes and poorly differentiated tumors in women who had discontinued tamoxifen therapy for more than 12 months compared with women who were diagnosed with uterine cancer while taking tamoxifen or within 12 months of stopping therapy. It appears that the likelihood of developing a type I or type II tumor after tamoxifen therapy depends on the temporal relationship of the tamoxifen exposure. Past prospective randomized studies did not
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