Tamoxifen Treatment for Breast Cancer: Concept to Gold Standard

Introduction

Tamoxifen (Nolvadex) was originally used as a palliative treatment of advanced breast cancer. Laboratory studies demonstrating that tamoxifen(Drug information on tamoxifen) could prevent progression of cancer led to studies as adjuvant treatment. The results of these studies demonstrated that tamoxifen could produce survival advantages in appropriate patients. Tamoxifen was subsequently shown to prevent contralateral breast cancer with a low incidence of side effects. The efficacy of tamoxifen in breast cancer has prompted investigations of it as a preventive agent in women who are at high risk of developing breast cancer.

As with any drug, tamoxifen has benefits and risks associated with its use. In addition to its benefits as an effective cancer treatment, tamoxifen has been shown to have additional benefits in relation to bone and lipids. The risk of development of endometrial cancer in tamoxifen-treated patients has been a concern. However, clinical studies have shown that the absolute risk is low, and may be due to methodologic biases in the studies and to the increased risk of endometrial cancer documented in untreated breast cancer patients.

The broad laboratory and clinical database on tamoxifen compiled over the last 25 years allows for a reasoned evaluation of the benefits and risks of tamoxifen treatment and indicates that the benefits of tamoxifen for breast cancer patients far outweigh the risks.

Twenty-five years ago, tamoxifen was only an experimental antiestrogen with the code ICI 46,474. Since the approval of tamoxifen for the treatment of advanced breast cancer in postmenopausal women, first in the United Kingdom in 1973 and then in the United States in 1978, the drug has revolutionized the approach to breast cancer therapy.

Today, tamoxifen is the endocrine treatment of choice for all stages of breast cancer and, remarkably, it is the only single agent proven to provide survival advantages in patients with both node-positive and node-negative disease.[1,2]

The success and efficacy of the treatment is demonstrated by the fact that the World Health Organization has declared that tamoxifen is an essential drug for breast cancer therapy. Over the last quarter century, the shift of antiestrogens from the bench to the bedside has dramatically altered clinical practice as well as demonstrated the value of these agents.

Tamoxifen was originally discovered in the laboratories of ICI Pharmaceuticals in Cheshire, England. Ironically, the scientists (Drs. Harper, Richardson, and Walpole, Figure 1) were primarily interested in new drugs to regulate fertility and they set up their screening tests accordingly. Compound ICI 46,474 was found to be a potent antiestrogen in the rat and had high potency as an antifertility agent.[3,4]

The head of the project, the late Dr. Arthur Walpole, was also passionately interested in developing drugs for cancer treatment, and earlier in his career he had focused on therapies that could be useful to treat breast cancer.[5] He was also aware that oophorectomy and adrenalectomy (antiestrogenic treatment modalities) were beneficial treatments for advanced breast cancer, and concluded that it would not be unreasonable to develop an antiestrogenic drug for breast cancer treatment.

Tamoxifen was evaluated in preliminary clinical studies for a variety of different indications. A small phase II study against historical controls demonstrated activity and virtually no side effects for the treatment of advanced breast cancer in postmenopausal women.[6] However, it was one thing to demonstrate clinical activity and entirely another thing to gain general acceptance by the medical community as a safe treatment and as the endocrine treatment of choice for all stages of breast cancer.

This process has taken 20 years and has moved forward because of open communication between the laboratory and the clinic. Ideas from the laboratory have pointed the way to clinical investigations that in turn have extended the utility of tamoxifen (Figure 2). Today there are eight million woman-years of experience with tamoxifen, and concerns that have been raised have been addressed and placed into a reasonable perspective of risks and benefits.

The aim of this historical overview is to provide a framework to understand the development of tamoxifen. A number of important laboratory observations have guided the clinical evaluation of antiestrogens and have provided the basis for the strategies used in the treatment of breast cancer and now the clinical testing of tamoxifen as a chemopreventive agent.

ICI 46,474 to Tamoxifen

The first systematic laboratory study of tamoxifen as an antitumor agent was conducted at the Worcester Foundation for Experimental Biology (now the Worcester Foundation for Biomedical Research) in Shrewsbury, Massachusetts (1972-1974). At a time when tamoxifen was being evaluated as a treatment for advanced breast cancer, the laboratory studies demonstrated that tamoxifen inhibits the growth of carcinogen-induced rat mammary carcinomas, preferentially controls growth of estrogen receptor (ER)-positive mammary tumors, and blocks the binding of [3H] estradiol(Drug information on estradiol) to the ER of human breast tumors. Overall, the results of the laboratory studies were used to encourage human studies by the Eastern Cooperative Oncology Group (ECOG), and an overview[7] of laboratory data introduced tamoxifen to the National Surgical Adjuvant Breast and Bowel Project (NSABP) in 1976.

Perhaps most important, studies were published that demonstrated tamoxifen could prevent the chemical induction of rat mammary carcinomas.[8,9] These data—with the subsequent findings that tamoxifen has a low incidence of side effects, high patient acceptability, and the unique ability to prevent the development of contralateral breast cancer—laid the foundation for the current prevention trials.[10]

Adjuvant Use

While tamoxifen was initially approved for the endocrine treatment of advanced disease, the primary conceptual breakthrough was the idea of using adjuvant therapy to destroy micrometastases throughout a patient's body. Chemotherapy was naturally the first choice because of its cytotoxicity.

The goal was to cure patients, so there was an initial reluctance to use an endocrine approach because these agents were considered only palliative therapy for advanced disease; complete remission did not seem possible with endocrine therapy alone. Nevertheless, several adjuvant trials were initiated with one year duration of tamoxifen administration.[11-14] Short-term therapy was chosen because of the expectation of drug resistance.

We first addressed the problem of the duration of adjuvant tamoxifen therapy in the laboratory by using a carcinogen-induced rat mammary tumor model, the only model available in the 1970s.[15-18] We reasoned that if the carcinogen was administered to susceptible strains of rats and then allowed to be promoted by ovarian hormones, the mammary glands would have microfoci of mammary tumor cells that would be similar to micrometastases. We asked the question of whether short-term tamoxifen could inhibit the appearance of tumors. The experiment (Figure 3) demonstrated that although short-term therapy reduced the number of tumors that developed, most animals developed at least one tumor. In contrast, continuous therapy with a clinically relevant dose of tamoxifen maintained the majority of animals in a tumor-free state.

These data, and the concept that long-term adjuvant tamoxifen therapy should be evaluated in clinical trials, were first presented at a symposium at Kings College, Cambridge in September 1977. [15] In 1977, a preliminary clinical evaluation of long-term adjuvant tamoxifen was conducted at the University of Wisconsin.

The results,[22,23] which showed that tamoxifen was safe and potentially effective, were used to establish ECOG protocols of long-term vs short-term tamoxifen with chemotherapy. However, with the routine use of long-term antiestrogen therapy in node-negative patients, of whom the majority could be cured by surgery alone, the concern in the mid-1980s became the potential physiological harm that could result from tamoxifen in postmenopausal women.

Professor Michael Baum and Dr. Helen Stewart, present at the Cambridge Symposium, later compared the efficacy of two years and five years of adjuvant tamoxifen therapy, respectively (Figure 4). In the 1980s, both clinical trial groups demonstrated for the first time that long-term adjuvant tamoxifen could produce a survival advantage in postmenopausal women with node-positive breast cancer.[19-20] It has recently been shown that five years is superior to two years of therapy.[21]