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Tamoxifen Treatment for Breast Cancer: Concept to Gold Standard

Tamoxifen Treatment for Breast Cancer: Concept to Gold Standard

ABSTRACT: Tamoxifen is currently the endocrine treatment of choice for all stages of breast cancer and is the gold standard for antiestrogen treatment. Over the last 25 years, the drug has revolutionized breast cancer therapy. The extension of the use of this agent has occurred because of open dialogue between the laboratory and the clinic, in which laboratory findings led to extension of clinical use. Tamoxifen was originally discovered as part of a contraceptive research program at ICI Pharmaceuticals (now Zeneca). On the basis of the estrogen dependence of many breast cancers, tamoxifen, a potent antiestrogen, was predicted to have anticancer activity. Laboratory and animal studies demonstrated efficacy in breast cancer and an ability to block binding of estradiol to the estrogen receptor of human breast cancer. Preclinical studies showed the benefit of long-term vs short-term tamoxifen treatment, a finding duplicated in the clinic. [ONCOLOGY 11(Suppl 1):7-13, 1997]

Introduction

Tamoxifen (Nolvadex) was originally used as a palliative treatment of
advanced breast cancer. Laboratory studies demonstrating that 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 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]

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