Elsevier

The Lancet

Volume 356, Issue 9233, 9 September 2000, Pages 881-887
The Lancet

Articles
Risk and prognosis of endometrial cancer after tamoxifen for breast cancer

https://doi.org/10.1016/S0140-6736(00)02677-5Get rights and content

Summary

Background

Tamoxifen increases the risk of endometrial cancer. However, few studies have produced reliable risk estimates by duration, dose, and recency of use, or addressed the prognosis of endometrial cancers in tamoxifen-treated women.

Methods

We did a nationwide case-control study on the risk and prognosis of endometrial cancer after tamoxifen use for breast cancer. Information on tamoxifen use and other risk factors for endometrial cancer was obtained from 309 women with endometrial cancer after breast cancer (cases), and 860 matched controls with breast cancer but without endometrial cancer. For 276 cases, we obtained tissue blocks of endometrial cancer to review the diagnosis, and used immunohistochemistry to examine hormone-receptor status and overexpression of p53.

Findings

Tamoxifen had been used by 108 (36·1%) of 299 cases and 245 (28·5%) controls (relative risk 1·5 [95% Cl 1·1–2·0]). Risk of endometrial cancer increased with longer duration of tamoxifen use (p<0·001), with relative risks of 2·0 (1·2–3·2) for 2–5 years and 6·9 (2·4–19·4) for at least 5 years compared with non-users. Endometrial cancers of stage III and IV occurred more frequently in long-term tamoxifen users (≥2 years) than in non-users (17·4% vs 5·4%, p=0·006). Long-term users were more likely than non-users to have had malignant mixed mesodermal tumours or sarcomas of the endometrium (15·4% vs 2·9%, p≤0·02), p53-positive tumours (31·4% vs 18·2%, p=0·05), and negative oestrogen-receptor concentrations (60·8% vs 26·2%, p=≤0·001). 3-year endometrial-cancer-specific survival was significantly worse for long-term tamoxifen users than for non-users (76% for ≥5 years, 85% for 2–5 years vs 94% for non-users, p=0·02).

Interpretation

Long-term tamoxifen users have a worse prognosis of endometrial cancers, which seems to be due to less favourable histology and higher stage. However, the benefit of tamoxifen on breast-cancer survival far outweighs the increased mortality from endometrial cancer. Nevertheless, we seriously question widespread use of tamoxifen as a preventive agent against breast cancer in healthy women.

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.

Section snippets

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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