Use of Tamoxifen as well as other agents in breast cancer Chemoprevention
Breast cancer Chemoprevention with Tamoxifen
The idea of designing an endocrine treatment to prevent breast cancer is not new. In 1936, Professor Lacassagne argued that it was necessary to find a therapy capable of preventing estrogen congestion in the breast. Professor Lacassagne was a visionary because at that time there wasn’t a genuine understanding about the mechanisms and actions of estrogen.
However in 1958, Professor H. Jensen made a historic discovery when he described the estrogenic receptor. He also suggested that breast cancers that contain these should be evaluated. Thus, in 1958 researchers had a target, the estrogen receptor, to work with in order to prevent breast cancer.
The Theory for developing anti-estrogen drugs emerged in the early 60’s. But it was not until Tamoxifen emerged (which was used in some countries to induce ovulation) when it was found to be a potential drug against cancer. Therefore, in the mid-1960’s, researchers had the two main components – target and drug.
The major effect of tumor suppression by Tamoxifen in cancerous rodent models
Tamoxifen has modest effects to control or suppress breast cancers clinically established in women. Studies suggests the following hypothesis about the development of the malignant mammary processes:-
… it is possible that tumors commence as Estrogen Receptors ER + breast cell clones, which during replication, give rise to daughter RE- cells.
If estrogen is needed for these cell divisions then the use of Tamoxifen at an earlier stage in the development of these clones could have a greater impact on tumor onset. This result would be greater than Tamoxifen applied to suppress the growth of already established clones, composed by ER + and ER – cells.
However, problems arose in the 1980’s. It was found that Tamoxifen used in healthy women, to prevent breast cancer, also increases the risk of Osteoporosis. In addition, Tamoxifen has been associated with Coronary Artery Disease. Furthermore, Tamoxifen stimulated the development of Endometrial Cancer in rats whose breast tumor growth was inhibited.
Mechanism and actions of Tamoxifen
Tamoxifen is a synthetic derivative of triphenylethylene with estrogenic and anti-estrogenic properties. In 1970 Tamoxifen was used in Britain for inducing ovulation. In 1960, scientists from Zeneca laboratory began to test the impact of anti-estrogen drugs for the treatment of advanced breast cancer. Indeed, Tamoxifen is found to be superior to other anti-estrogens in advanced breast cancer.
Tamoxifen Citrate was approved for breast cancer treatment in 1973 in England and in 1977 for the United States.
We can divide the mechanisms of Tamoxifen into three groups:
According to V.C. Jordan, one of the foremost experts on this subject, it is considered that Tamoxifen primarily acts by binding with the estrogen receptor in the cytoplasm of breast cancer cells. Breast cancer cells treated with Tamoxifen are blocked at the cell cycle G1 phase after mitosis is produced. The cells are blocked before entering S phase, with the consequent growth inhibition.
Thus, Tamoxifen is considered more tumorstatic than tumoricidal. It is thought that when the drug binds to the receptor this initiates cell death or inhibit the growth. A tumor may decrease in size by the death of some cells or because it can not replace the cells needed for the growth.
Peripheral Effects of Tamoxifen:
This drug has the ability to reduce metastatic spread because it:-
- Decreases the secretion of stimulating growth factors, such as transforming growth factor alpha (TGF-a). In addition, Tamoxifen stimulates the secretion of inhibitory factors such as transforming growth factor beta (TGF-b). The latter is known to inhibit growth of ER positive cells. It is also thought that through this mechanism acts on tumors with poor receptor expression. TGF-b not only controls growth in the same cells that synthesize it, but also exerts a paracrine function, which inhibits growth of adjacent cells.
- it also produces a decrease in circulating levels of growth stimulating factor, Insulin-like Growth Factor 1 (IGF-1). This growth factor has the ability to stimulate growth for both ER positive as well as ER negative cells.
- Tamoxifen reduces circulating free estrogen levels in postmenopausal women. This action is made by increasing the level of the principal hormone binding globulin, sex hormone binding globulin. (SHBG).
This protein is synthesized by the liver. It is also the main transporter of estrogenic steroids in the blood. Thus, an increase in its binding capacity may decrease concentration of plasma free steroids. Accordingly, an increase of this protein produces fewer steroids available for mammary tumor cells.
- Tamoxifen also decreases tumor invasion and metastatic spread by inhibiting angiogenesis.
- Finally, other actions not mediated by RE could be inhibition of protein kinase C, phospholipase C and calmodulin, as well as a blockade of histamine receptors.
The above mechanisms were observed in laboratory tests but it is not yet known if they singularly or jointly contribute to the effectiveness of Tamoxifen.
The drug produces estrogenic effects in some places as well as anti-estrogenic effects in others. The reason why each effect is exerted on a specific organ is still unknown. We will analyze separately each of these actions.
Cardiovascular effects of Tamoxifen
In the USA, as well as Europe, mortality from myocardial infarction in women has begun to exceed that of breast cancer in the sixth decade of life.
From the ages of 55 to 65 and mortality rates increase very dramatically. It is estimated that from 50 years of age, a white woman has a 46% chance of developing coronary heart disease. In addition, a white woman has a 31% chance of dying from cardiovascular disease.
When Tamoxifen emerged as an approved therapy for breast cancer, the concern about treating women with an anti-estrogen drug increased. The risk of affecting the lipid profile, as well as increasing the risk of cardiovascular disease is a worry. Since then, many studies have shown the estrogenic effects in lipids.
An analysis of nine different studies reveals an average decrease of 13% in total cholesterol and an average of 19% decrease in low-density protein, LDL. Unlike estrogen therapy, no changes were found in high density protein, HDL. It was also found that an increase in VLDL synthesis would result in a triglycerides increase.
Effects on bone
Bone fractures are a major cause of morbidity in postmenopausal women. Around 250,000 new cases present each year in the US alone. Bone fractures account for many hours of hospital care that triple those for breast cancer patients. It has been estimated that a woman may lose 35% of their cortical bone mass and 50% of trabecular bone throughout a lifetime.
US estimations suggest that risk of vertebral and hip fractures in postmenopausal white women are 16% and 32% respectively.
Initially, it was feared that Tamoxifen anti-estrogenic effects would accelerate bone resorption or could increase the risk of developing osteoporosis. However, studies in vitro and in vivo showed the opposite. Studies in vitro and in animals showed how Tamoxifen actually lowers the rates of resorption of trabecular bone which results in a net preservation of bone density.
In humans, nine studies were conducted to examine the effect of Tamoxifen on bone resorption. Fornander et al. were the first to observe that there was no increase in bone loss in patients taking Tamoxifen over 2 to 5 years.
The conclusion of these studies is that in both premenopausal as well as postmenopausal women taking Tamoxifen; bone density is maintained or even increased in relation to control groups.
- The mechanism by which Tamoxifen exerts a promoting effect of endometrial growth in some patients as well as a growth inhibitory effect in others is still unknown. However, there is evidence that Tamoxifen therapy increases the detection rate of endometrial malignant pathology. Some authors suggest that Tamoxifen may be an inducer or promoter of this type of neoplasia.
- It was found that the type of endometrial cancer is low grade malignancy presenting in women older than 50 years and produces symptoms in early stages. The study concludes that the risk of endometrial carcinoma associated with Tamoxifen is 2/1000 women/year vs 1/1000 in the general population. However, the dose of Tamoxifen did not seem to play any role.
- Clearly the benefits of Tamoxifen in treating breast cancer far exceeds any adverse effects. Thus, the risk of dying from endometrial carcinoma is much lower than dying from a breast cancer recurrence.
- The World Health Organizations (WHO) established Tamoxifen as an essential drug in treating breast cancer. However, in 1996, The International Agency for research on Cancer (IARC) cited Tamoxiefen treatment as carcinogenic. This finding was based on studies in rats and humans where endometrial carcinoma was detected in correlation with Tamoxifen use. The IARC states however, that no woman should be deprived of the beneficial effects of Tamoxifen, based on the risks of endometrial carcinoma.
Major symptoms observed in treatment with Tamoxifen are of four types:
Although Tamoxifen is a widely accepted treatment for women with breast cancer, around 4% of patients have to suspend treatment due to side effects.
Vasomotor symptoms are:
- Hot flashes
- Palm-sweating episodes
Side effects are found with increased frequency and intensity in some postmenopausal women treated with Tamoxifen.
Gynecological symptoms include increased vaginal secretions, vaginal irritation, and vaginal bleeding. About 4% of postmenopausal women complain of such symptoms, with moderate or more than moderate intensity, after 6 months of treatment.
Episodes of depression are observed in 1% or more of postmenopausal women treated.
It has been noted that nausea is an occasional side effect of Tamoxifen treatment
Some minor side effects are gastrointestinal intolerance, fluid retention, anorexia, headache and dizziness. The above side effects were observed in a small percentage of women, around 2-4%. However, the same effects were also observed in similar numbers in patients treated with a placebo in the NSABP-14 study.
A few cases of thromboembolism were observed during Tamoxifen treatment. Incidence of deep vein thrombosis in the NSABP-14 protocol was 0.8% in the Tamoxifen taking group compared to 0.3% in the placebo group. Previous history of thrombophlebitis can be a decisive factor in increasing the risk. Therefore exclusion of such patients in studies of chemoprevention could drastically reduce the incidence of thrombophlebitis.
Tamoxifen and Hormone Replacement Therapy
From the late 1970’s there has been a progressive increase in the use of hormone replacement therapy; HRT. HRT has a scientific basis in the benefits it provides to women during menopause, such as the prevention of osteoporosis and cardiovascular disease.
The symptoms that are characteristic of the menopause, may persist for more than five years in 20% of women. These menopausal problems can be prevented with HRT.
Studies made in both Italy and England highlight the beneficial effect of using Tamoxifen with HRT. This point will be analysed in more detail later. To summarize, both medical studies suggest that Tamoxifen exerts a protective effect in women using HRT. However, further studies to investigate this association are needed.