ArticlesRisk and prognosis of endometrial cancer after tamoxifen for breast cancer
Introduction
For nearly 20 years tamoxifen has been the endocrine treatment of choice for early and metastatic breast cancer.1 Despite this good reputation, tamoxifen users have a twofold to seven-fold increased risk of endometrial cancer,1, 2, 3, 4, 5, 6, 7, 8, 9 and the risk seems to be highest after long-term use.6, 7, 9, 10 In breast-cancer patients, this adverse effect is far outweighed by improved survival and lower incidence of contralateral breast cancer.1 In healthy women, however, the net benefit from tamoxifen as a preventive therapy against breast cancer is unclear.
Preliminary results of the Breast Cancer Prevention Trial (BCPT) showed a 45% reduction in breast-cancer incidence among tamoxifen users.11 However, neither of the two European chemoprevention trials with tamoxifen confirmed the BCPT's findings.12, 13 This fact, and the occurrence of life-threatening side-effects in BCPT (including pulmonary embolism, deep-vein thrombosis, and endometrial cancer), has emphasised the need for more extensive assessment of tamoxifen's adverse effects.
Clinicians often assume that tamoxifen-related endometrial cancers are early-stage and prognostically favourable tumours. However, this opinion is based on several small studies.4, 14, 15, 16 The clinicopathological characteristics and prognosis of endometrial cancer after tamoxifen have not been assessed in large studies.
Our nationwide case-control study is an expansion of our previous study6 and now includes 309 cases of endometrial cancer after breast cancer. We assessed the independent effects of duration and daily dose of tamoxifen on the risk of endometrial cancer, the evolution of risk after cessation of tamoxifen use, and possible interactions between tamoxifen and other risk factors for endometrial cancer. We address whether the clinicopathological and immunohistochemical characteristics and the ultimate prognosis of endometrial cancers in tamoxifen-treated women are different from those in patients not treated with tamoxifen.
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Patients
Eligibility criteria for selection of cases and controls have been described elsewhere.6 Cases were patients with a histologically confirmed diagnosis of endometrial cancer at least 3 months after a diagnosis of breast cancer. The breast-cancer diagnosis should have been made after Jan 1, 1976 (Jan 1, 1972, in two cancer hospitals where tamoxifen was used earlier). Cases should not have had other neoplastic diseases between the diagnoses of breast cancer and endometrial cancer, except for
Results
The median time between the diagnoses of breast cancer and endometrial cancer was 40 months (range 4–235, table 1). Most women were older than 55 years and were postmenopausal when breast cancer was diagnosed. Age at breast-cancer diagnosis was matched within 1 year for 84% of controls and within 2 years for 95%. Most of the endometrial cancers occurred in women whose breast cancer had been diagnosed after the mid-1980s. Calendar year of breast cancer was matched within 1 year for 92% of
Discussion
The risk of endometrial cancer in breast-cancer patients taking tamoxifen increased with duration of use, irrespective of daily dose. However, the risk did not decrease after cessation of treatment and was not modified by other risk factors for endometrial cancer. Endometrial cancers that developed after long-term tamoxifen treatment were more often MMMT or sarcomas of the endometrium, of high FIGO stage, p53 positive, and oestrogen-receptor negative than those in non-users. As a result,
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