Elsevier

The Lancet

Volume 352, Issue 9122, 11 July 1998, Pages 93-97
The Lancet

Articles
Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women

https://doi.org/10.1016/S0140-6736(98)85011-3Get rights and content

Summary

Background

Tamoxifen is a candidate chemopreventive agent in breast cancer, although the drug may be associated with the development of endometrial cancer. Therefore we did a trial in hysterectomised women of tamoxifen as a chemopreventive.

Methods

In October, 1992, we started a double-blind placebo-controlled, randomised trial of tamoxifen in women (mainly in Italy) who did not have breast cancer and who had had a hysterectomy. Women were randomised to receive tamoxifen 20 mg per day or placebo, both orally for 5 years. The original plan was to follow the intervention phase by 5 years' follow-up. In June, 1997, the trialists and the data-monitoring committee decided to end recruitment primarily because of the number of women dropping out of the study. Recruitment ended on July 11, 1997, and the study will continue as planned. The primary endpoints are the occurrence of and deaths from breast cancer. This preliminary interim analysis is based on intention-to-treat.

Findings

5408 women were randomised; participating women have a median follow-up of 46 months for major endpoints. 41 cases of breast cancer occurred so far; there have been no deaths from breast cancer. There is no difference in breast-cancer frequency between the placebo (22 cases) and tamoxifen (19) arms. There is a statistically significant reduction of breast cancer among women receiving tamoxifen who also used hormone-replacement therapy during the trial: among 390 women on such therapy and allocated to placebo, we found eight cases of breast cancer compared with one case among 362 women allocated to tamoxifen. Compared with the placebo group, there was a significantly increased risk of vascular events and hypertriglyceridaemia among women on tamoxifen.

Interpretation

Although this preliminary analysis has low power, in this cohort of women at low-to-normal risk of breast cancer, the postulated protective effects of tamoxifen are not yet apparent. Women using hormone-replacement therapy appear to have benefited from use of tamoxifen. There were no deaths from breast cancer recorded in women in the study. It is essential to continue follow-up to quantify the long-term risks and benefits of tamoxifen therapy.

Introduction

The idea of interfering with the initiation and promotion ofbreast cancer by means of pharmaceutical compounds (chemoprevention) arose about a decade ago. There are many experimental and epidemiological data to support the use of tamoxifen as a chemopreventive. This drug has both oestrogenic and antioestrogenic properties.1, 2 These properties, including reduction of circulating insulin-like growth factor 1, inhibition of angiogenesis, and induction of apoptosis, help explain the otherwise unexpected response to tamoxifen seen in oestrogen-receptor-negative, postmenopausal women.3 Women with breast cancer have a 2–3-fold increased risk of contralateral breast cancer. In the randomised trials with adjuvant tamoxifen of breast cancer, the incidence of contralateral breast cancer decreased by around one-third.3, 4, 5, 6, 7, 8, 9, 10 This result, and the good safety profile in cancer patients based on large numbers of women with long follow-up, put tamoxifen among the front runners for evaluation as a chemopreventive in breast cancer.

However, side-effects of tamoxifen include an increased occurrence of endometrial cancer.8, 9. In view of this potential adverse event, we undertook a randomised trial in women who had had a hysterectomy. Such women have a reduced risk of breast cancer when there has been an associated bilateral oophorectomy.10

Section snippets

Participants and inclusion and exclusion criteria

The Italian Tamoxifen Prevention Study includes healthy women aged 35–70 who had had a total hysterectomy for reasons other than neoplasm. Women were recruited via national advertising and also from direct contact with gynaecologists throughout Italy (with a minority of cases recruited from abroad). Women with severe concurrent illness or history of cardiac disease were excluded from randomisation. Endometriosis and suspected or certain previous deep-vein thrombosis were also exclusion

Results

The study involves 55 participating centres, of which 51 were in Italy, three in South America (Brazil two, Argentina one), and one in Greece. Most patients (5230, 96·7%) were recruited in Italian centres.

5408 women were randomised (figure 1), with a median age of 51 years (table 1). 3837 women are still on treatment. The overall median time on study intervention is 30·5 months. 1422 women dropped out of the study, and 149 have completed 5 years of treatment. For deaths, cancer diagnosis, and

Discussion

The principal investigators were concerned about the large numbers of women withdrawing from the study, the unexpected finding with hypertriglyceridaemia, the findings about vascular events, and the number of well women complaining about the side-effects of tamoxifen. In agreement with the data-monitoring committee, we ended recruitment in June, 1997. The study investigators were informed during the 6-monthly meeting (held on July 11, 1997), of the decision to end recruitment to the trial

References (20)

  • CuzickJ et al.

    Tamoxifen and contralateral breast cancer

    Lancet

    (1985)
  • VeronesiU et al.

    et al

    Prevention of breast cancer with tamoxifen: the Italian study in hysterectomized women. Breast

    (1995)
  • JordanVC et al.

    Anti-oestrogen action in experimental breast cancer

    Recent Results Cancer Res

    (1980)
  • CollettaAA et al.

    Alternative mechanisms of action of anti-oestrogens

    Breast Cancer Res Treat

    (1994)
  • Tamoxifen for early breast cancer: an overview of the randomised trials

    Lancet

    (1998)
  • Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer

    Br J Cancer

    (1988)
  • BonadonnaG et al.

    Adjuvant and neoadjuvant treatment of breast cancers with chemotherapy and/or endocrine therapy

    Semin Oncol

    (1991)
  • FisherB et al.

    New perspective on cancer of the contralateral breast: a marker for assessing tamoxifen as a preventing agent

    J Natl Cancer Inst

    (1991)
  • CreasemanWT

    Endometrial cancer: incidence, prognostic factors, diagnosis and treatment

    Semin Oncol

    (1997)
  • MacMahonB

    Overview of studies on endometrial cancer and other types of cancer in humans: perspectives of an epidemiologist

    Semin Oncol

    (1997)
There are more references available in the full text version of this article.

Cited by (804)

  • Adenocarcinoma of the uterine corpus and sarcomas of the uterus

    2023, DiSaia and Creasman Clinical Gynecologic Oncology
  • Breast diseases

    2023, DiSaia and Creasman Clinical Gynecologic Oncology
  • Breast Cancer Risk Assessment and Management of the High-Risk Patient

    2022, Obstetrics and Gynecology Clinics of North America
  • Endocrine prevention of breast cancer

    2021, Molecular and Cellular Endocrinology
View all citing articles on Scopus
View full text