Tamoxifen (‘Nolvadex’): a review: Antitumour treatment

doi:10.1016/S0305-7372(02)00036-1

Cancer Treatment Reviews

Volume 28, Issue 4, August 2002, Pages 165-180

https://doi.org/10.1016/S0305-7372(02)00036-1 Get rights and content

Abstract

Tamoxifen has been used in the management of breast cancer for over 30 years. Since its introduction for the treatment of advanced breast cancer, its indications have increased to include the treatment of early breast cancer, ductal carcinoma in situ, and more recently for breast cancer chemoprevention. Tamoxifen has a good tolerability profile and moreover, unlike many other endocrine therapies, it is efficacious in both pre- and postmenopausal women.

It is the combination of efficacy and tolerability that allows tamoxifen to maintain its position as the hormonal treatment of choice for most patients with oestrogen-receptor positive breast cancer. Ongoing studies will provide further information about the optimal duration of tamoxifen therapy and how it compares with the newer aromatase inhibitors.

Introduction

The introduction of the anti-oestrogen tamoxifen in the early 1970s represented a landmark in the treatment of breast cancer. Over 30 years later, tamoxifen has been shown to be effective not only for early and advanced breast cancer, but also for ductal carcinoma in situ (DCIS) and the chemoprevention of breast cancer in high risk pre- and postmenopausal women. Indeed, tamoxifen is the benchmark against which newer endocrine therapies continue to be measured. This paper will review the history of tamoxifen and summarize the key clinical data that have led to its common use in women with breast cancer. It will also discuss the pharmacology of, and resistance to, tamoxifen, and possible future indications.

Section snippets

History of tamoxifen

In the late nineteenth century, Beatson found that advanced breast tumours in premenopausal women were sometimes responsive to oophorectomy (1). It was therefore reasoned that the growth of oestrogen-dependent tumours could be curtailed by blocking the action of oestrogen. During the twentieth century endocrine therapies such as adrenalectomy and hypophysectomy were used in the treatment of advanced breast cancer, but there was a clear need for a non-surgical approach to the management of this

Tamoxifen in advanced breast cancer

The first clinical study with tamoxifen in patients with advanced breast cancer began in 1969 (9). Forty-six postmenopausal patients were treated with 10–20 mg tamoxifen daily for a minimum of 3 months. A remission rate of 22% was achieved, which was comparable to that seen with stilboestrol (which was in common use at that time), but with reduced toxicity. Subsequent studies have confirmed an overall objective response rate (complete plus partial responses) to tamoxifen of 34%. If patients with

Early breast cancer

Based on the efficacy and safety of tamoxifen in the treatment of advanced breast cancer, a number of studies have been conducted to determine its effect as adjuvant therapy in women who have undergone surgery for early breast cancer. These studies have compared tamoxifen alone with controls, or tamoxifen plus cytotoxic agents with cytotoxic agents alone. The results of the most important of these studies are shown in T, T.

The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)

Contralateral breast cancer

A significant reduction in the incidence of contralateral breast cancer was noted (114) 3 years into a study investigating the efficacy of 2 years’ versus 5 years’ adjuvant tamoxifen therapy in early breast cancer (110). Similar results have been reported in a number of other randomized clinical studies [70], [76], [87], [92]. The most recent EBCTCG meta-analysis suggests that 5 years’ treatment with adjuvant tamoxifen can reduce the risk of contralateral breast cancer by almost half (107). The

Prevention studies

The reduced incidence of contralateral breast cancer in women receiving tamoxifen provided the rationale for studies to assess tamoxifen in the prevention of breast cancer (107). A pilot study involving healthy women at increased risk of developing breast cancer began in the Royal Marsden Hospital, UK, in 1986 (116). National multicentre studies in Italy (117), the USA (National Surgical Adjuvant Breast and Bowel Project P1 (NSABP P1) study (118)), and the UK (International Breast Cancer

Tamoxifen resistance

Although tamoxifen has been shown to be effective in the treatment of breast cancer, some tumours do not respond, and those that do eventually acquire tamoxifen resistance, or their growth becomes stimulated by tamoxifen. There are many possible mechanisms to explain this resistance including the down-regulation, mutation, or loss of oestrogen receptors, impaired co-activator signalling, and altered tamoxifen pharmacology (125). These mechanisms have been reviewed recently (126).

Mechanism of action of tamoxifen

The anti-tumour effect of tamoxifen is thought to be mediated by its anti-oestrogenic effects. In a target cell oestrogen (E) binds to ER, which initiates a sequence of events (Figure 5) (129). The oestrogen–ER complex homodimerizes and binds to discrete DNA sequences, known as oestrogen response elements (ERE), in the regulatory regions of oestrogen-sensitive genes. The two transcriptional activation functions of the oestrogen–ER complex, AF1 and AF2, interact with other proteins

Adverse effects

Tamoxifen is generally well tolerated: short-term side-effects are similar to the symptoms of menopause and include hot flushes, irregular menses, vaginal bleeding or discharge, pruritus vulvae, and oedema.

Table 6 shows the adverse events observed in the NSABP P1 study, which investigated the use of tamoxifen to prevent breast cancer in women at high risk—only those events that were more common in the tamoxifen group than the placebo group are shown. In this study, 15 and 10% of those patients

Conclusion

Tamoxifen has been described as ‘the most important drug to be developed in the history of breast cancer’ (152). Certainly, its introduction heralded a new approach to the treatment of this condition. Its proven efficacy, combined with its good tolerability profile, makes tamoxifen the endocrine therapy of choice for all stages of breast cancer in women with ER-positive disease.

Since the first clinical trial of tamoxifen in the late 1960s over 50% of patients with advanced oestrogen receptor

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Tamoxifen (‘Nolvadex’): a review: Antitumour treatment

Abstract

Introduction

Section snippets

History of tamoxifen

Tamoxifen in advanced breast cancer

Early breast cancer

Contralateral breast cancer

Prevention studies

Tamoxifen resistance

Mechanism of action of tamoxifen

Adverse effects

Conclusion

Lancet

Toxicol Appl Pharmacol

Ann Oncol

Ann Oncol

Eur J Cancer Clin Oncol

Ann Oncol

Lancet

Ann Oncol

A nonsteroidal estrogen antagonist 1-(p-2-diethylaminoethoxyphenyl)-1-phenyl-2-(p-methoxyphenyl)-ethanol

Endocrinology

Gonadotrophin inhibiting and antifecundity effects of chloramiphene

Proc Soc Exp Biol Med

Induction of ovulation with clomiphene citrate (Clomid)

Obstet Gynecol Surv

A new derivative of triphenylethylene: effect on implantation and mode of action in rats

J Reprod Fertil

New synthetic agent for the induction of ovulation: preliminary trials in women

Br Med J

Contrasting endocrine activities of cis and trans isomers in a series of substituted triphenylethylenes

Nature

A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI 46474

Br J Cancer

Antioestrogens in the management of hormone-dependent cancer

Cancer Treat Rev

Clinical evaluation of tamoxifen in breast cancer (primary and recurrent)—double blind study

Clin Eval

Tamoxifen and fluoxymesterone in advanced breast cancer: a controlled clinical trial

Cancer Treat Rep

Clinical studies of tamoxifen in advanced breast cancer (Japan)—multi-centre open trial and double blind trial

Rev. Endocrine-Relat Cancer

A Phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer

Breast Cancer Res Treat

A clinical trial to compare the use of tamoxifen vs stilboestrol in the treatment of post-menopausal women with advanced breast cancer

Rev. Endocrine-Relat Cancer

Tamoxifen versus ethinyl estradiol in the treatment of postmenopausal women in advanced breast cancer

Cancer Treat Rep

Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer

N Engl J Med

Comparison of tamoxifen and diethylstilbestrol (DES) in advanced breast cancer

Clin Res

Edinburgh study on ‘Nolvadex’ (tamoxifen) against oestrogens

Rev. Endocrine-Relat Cancer

Hormonal therapy of advanced breast cancer: efficacy and toxicity of diethylstilbestrol (DES) vs. tamoxifen (TAM)

Proc Am Assoc Cancer Res

Randomized trial of estrogen vs. tamoxifen therapy for advanced breast cancer

Am J Clin Oncol

Primary endocrine therapy of advanced local breast cancer. (‘Nolvadex’, stilboestrol)

Rev Endocrine-Relat Cancer

Randomized comparison of tamoxifen versus diethylstilbestrol in estrogen-receptor or—unknown metastatic breast cancer: a Southeastern Cancer Study Group trial

Cancer Treat Rep

Third-line therapy for pretreated progressive postmenopausal breast carcinoma

Current Chemotherapy and Immunotherapy

Randomized clinical trial of megestrol acetate versus tamoxifen in paramenopausal or castrated women with advanced breast cancer

Am J Clin Oncol

Tamoxifen versus megestrol acetate in breast cancer

Rev Endocrine-Relat Cancer

Comparative study between TX and MAP in advanced breast cancer

J Steroid Biochem

Megestrol acetate vs tamoxifen in advanced breast cancer: a phase III trial of the Piedmont Oncology Association (POA)

Semin Oncol

Sequential treatment of metastatic breast cancer with tamoxifen after megestrol acetate therapy and vice versa (a retrospective study)

Med Oncol Tumor Pharmacother

Megestrol acetate versus tamoxifen in advanced breast cancer: correlation of hormone receptors and response

Semin Oncol

A phase III trial of treatment of tamoxifen versus treatment with high-dose medroxyprogesterone acetate in advanced postmenopausal breast cancer

Progr Cancer Res Therapy

Hormonotherapy of advanced breast carcinoma: comparative evaluation of tamoxifen citrate versus medroxyprogesterone acetate