Chemoprevention in breast cancer

Introduction

 
Chemoprevention is a new chapter in breast encology. Indeed, the roots of chemoprevention are based in epidemiology. This science will use chemoprevention on the women who have the highest risk factors of developing breast cancer.

The epidemiology arises from infectious and contagious diseases.  After a while, the categories of chronic diseases were also included. These chronic diseases include cancer, and especially breast cancer.  In this way, analytic epidemiology is currently geared to cancer prevention in the three variables: primary, secondary and tertiary.

Traditionally in medicine, most emphasis was on tertiary prevention. Thus, tertiary prevention focuses on trying to cure the disease or alleviate the symptoms. Tertiary prevention is a simplified scheme that led to some discredit due to lack of identifying risk factors. This method could not distinguish, with sufficient clarity, the women most exposed to the disease.
 

Studies on Women with Breast Cancer

 
Interestingly, of all women diagnosed with breast cancer less than one third present with risk factors. Indeed, over the years, there has been an endless list of risk factors, that have now been reduced to a few.

It is important to note that risk factors need to to be differentiated from forecast. The latter refers to the most exposed population, whilst the former refers to the evolutionary form. However, it is important that the data related to risk factors should be handled with caution. For some, risk factor data can promote cancerophobia, that alters the quality of life for some women.

 

In general terms there is a global increase in the incidence of breast cancer. This increase in incidence is related to age, i.e. breast cancer rates increase with older age.

Some of the general increase in breast cancer incidence may be associated with more intense screening campaigns. However, it does appear that breast cancer is on the increase in general.

The reasons for these increases are largely unknown

 
Some risk factors for breast cancer include:-

• Diet choices
• The use of oral contraceptives
• Alcohol consumption
• Older age, with longer exposure time of the breast tissue to the action of estrogen
• Family history of breast cancer: Particularly in first degree relatives
• Incidence of atypical hyperplasia

However, breast cancer risk factors only offer a limited explanation to the problem. Furthermore, between 70 % and 80 % of women with breast cancer do NOT have any of the known risk factors. If the most significant factors for breast cancer could be identified, the removal of these, or the use of chemoprevention, could be proposed as a preventive strategy.

Breast cancer screening (mammography screening), reduces mortality rates by approximately 30%. According to the 1992 consensus of St. Gallen, adjunctive therapies reduce the risk of recurrence or death by about 30% – 40%, in both positive and negative axilla biopsise.

However, even with reduced mortality rates due to screening, and the use of adjunctive therapies, the incidence of breast cancer is still increasing.

Consequently, a new branch of oncology, chemoprevention may play an important role in the fight against breast cancer.

Breast cancer epidemiology

 
Breast cancer accounts for around 32 % of all cancers in the United States. Breast cancer is the most common female cancer and the second cause of death by cancer.

Currently, the risk of breast cancer over the course of a woman’s life is 12.2%, or 1 in 8 women. The risk of death by breast cancer overall is 3.6%, or 1 in 282 women.

Age is a major risk factor and most breast cancers occur in women over 55 years. In the absence of other major risk factors, a woman between 35 and 55 years has only a 2.5% chance of developing breast cancer.

Let’s take a look at some of the figures over the years. In 1970, 5,120 women under 40 years reported breast cancer in the Surveillance Epidemiology and End Results (SEER) program. This number had increased to 7,800 by 1980, and again to 10,050 in 1990.

Thus, it is clear how the incidence for breast cancer is increasing but mortality for breast cancer remains constant. This is encouraging and demonstrates the real impact of the implemented therapeutic techniques.

Breast cancer is multifactorial

 
Breast cancer etiology seems to be multifactorial. Both endogenous and exogenous factors increase the incidence.

Risk factors

 

Family history

 
There are two very different levels of risk in women with a family history of breast cancer. Firstly, are the women with inherited genetic predisposition. Secondly, are the women who have an increased familial incidence of breast cancer.

Nowadays, mutations on the p53, BRCA-1 and BRCA-2 genes have been associated with a genetic predisposition to breast cancer. Genetic breast cancer is rare accounting for only 5-10% of all breast cancers in USA. The characteristics that suggest a genetic predisposition are:

• Over 3 relatives with breast cancer.
• History of breast and ovarian cancer.
• Breast cancer at an early age.
• Bilateral breast cancer.

In a woman with breast cancer, the probability of having an inherited gene mutation is directly related to the age of onset of cancer. It is estimated that 12% of women under 30 with breast cancer have this genetic mutation. This is in comparison to a 3 % probability in women who develop breast cancer between the ages of 40 and 49 years. In addition, the most studied genes to date are BRCA-1 and BRCA-2.

The BRCA-1 is located on chromosome 17q21

 
BRCA-1 mutations are associated with an increased risk for both breast and ovarian cancer. It is estimated that carriers of this mutation have a 50 % risk of developing breast cancer before 50 years. This risk increases to 85 % by the age of 65.

To date, 300 different mutations for this gene have been identified. The level of cancer risk associated with each mutation is still unknown. Furthermore, many more family studies are needed into this area.

The BRCA-2 is located on chromosome 13, and its mutations seem to have the same risk level of BRCA-1. Furthermore, BRCA-2 mutations are associated with an increased incidence of breast cancer in men.

Unlike women with a genetic predisposition for developing breast cancer, those with a higher family incidence of breast cancer have a much lower risk.

This familial risk varies according to the degree of closeness of the affected relatives.

In women under 50 years the risk is 13-21 % if a first degree relative has breast cancer. In women over 50 years the breast cancer risk is 9-11 %. In general, the risk of a woman with a family history of breast cancer rarely exceeds 30 %.

However, there is still a lot to learn about these genetic markers. Furthermore, the rates of false positives and false negatives are still unknown. In addition, there is no general consensus on which treatment option should be offered to women who carry these mutations. Many women would not want a prophylactic mastectomy and the role of tamoxifen remains uncertain.

Hormonal factors

A increased breast cancer risk is associated to a higher uninterrupted period of menstrual cycles. It seems that exists a 20% decrease in risk for each year; on which menarche is delayed. Historically, it was established as higher risk to women who experienced menarche before 12 years old. In addition, age of menopause influences the risk of developing breast cancer. Women who enter menopause before the age of 45 have half the risk that those that start after 55.

The age of first childbirth also influences the risk. Nulliparous women have a relative risk (RR) = 1.4; as well as those whose first childbirth occurs before age 30; have 2-5 times a greater risk than those with a gestation before 18-19 years.

The implication of breastfeeding has not been established. Some studies suggest that breastfeeding for prolonged periods of time would exert a protective effect in premenopausal women; while would have a little impact on breast cancer in postmenopausal women.

Regarding the intake of exogenous hormones, there is no convincing evidence indicating that oral contraceptives increase risk. Two meta-analysis suggest a small. But statistically significant increased risk in women with HRT (RR = 1.3 versus 1.6). However, in most women; the benefit of HRT reducing risk of cardiovascular diseases; as well as osteoporosis decreases the impact of this small risk increase.

Dietary and environmental factors

Epidemiological studies on the consumption of dietary fat and breast cancer risk have been inconclusive. The most important prospective study was conducted in 89,538 nurses with ages between 34 and 59; where no relation was found, between intake of saturated fat, total fat, cholesterol and linoleic acid and an increased risk of breast carcinoma. However, other studies did not exclude the possibility that a poor intake of fat during childhood; can alter the risk.

Evidence suggests a relationship between alcohol intake and breast cancer. A meta-analysis demonstrates a RR = 1.4 for every 24 grams of alcohol per day; equivalent to two glasses.

A moderate exposure to high radiation doses increases breast cancer risk. The risk level depends on the age; at which exposure occurred; with a minimum risk increase if it occurs after 40 years old. However, is estimated that less than 1% of breast cancers are results of exposure to diagnostic radiological procedures.

Other environmental factors; such as electromagnetic fields; occupational exposures and organochlorine pesticides have been suggested as possible risk factors for breast cancer. However there are no data to support these relationships.

Benign breast diseases

Proliferative breast diseases are associated with a small increase of breast cancer risk (RR = 1.5 vs 2), while atypical hyperplasia has the highest risk (RR = 4-5). Another lesion strongly associated with to an increased risk is lobular carcinoma in situ (according to Haagensen, RR= 6.9).

Most women have a combination of factors that increases and protects the breast carcinoma risk; which complicates the assignment of an individual risk level for each woman. Also is not clear if the risk conferred by combining multiple factors is additive, multiplicative or unchanged. An example of this, is the discovery of Dupont and Page; who observed that the combination of atypical hyperplasia with a history of an affected first-degree relative; increased the breast cancer RR 11 times compared to a RR= 4.4 for an individual factor of atypia.

Nor is there a consensus that asserts how much is the increased risk level needed to define a woman in high risk. One should be cautious at this point, because a woman labeled with a high risk may suffer herself from anxiety attacks without having clear therapeutic strategies. It is also important to mention, that about 50% of women who develop breast cancer have no more risk factors than age.

Breast cancer genetics

In the beginning of this decade, molecular biology acquired significance in the study of tumoral pathology. Geneticists, immunologists, biochemists and epidemiologists, have given prevalence to the breast cancer problem.

Carcinogenesis can be divided into two stages: initiation, an event occurred at genoma level; on which act physical, chemical and viral agents; and promotion related with tissue growth in tumoral formation. In this latter stage, growth factors and growth receptors are involved. The initiators factors generate a failure at the genetic material, although the cell can still repair its damage.

Factors are needed in order to stimulate those failures until they become irreversible, transforming the cell. These are known as promoter factors; useful because epidemiology was responsible of highlight them and it is from these; that researchers are trying to modify the obstacle of breast cancer.

In chemoprevention we found then, antimitogenic agents within; which the main ones are tamoxifen and anti-mutagenic agents.

Antimutagenic agents

• Xenobiotic detoxification enzymes
• Glutathione-s-transferase
• Cytochrome P-540 isoenzyme inhibition
• Prostaglandin-h-synthase inhibitor

Antimitogenic agents

• Tamoxifen
• AIC (aminoimidazole carboxamide)
• Quercetin (protein kinase level)
• A-difluoromethylomithine-ornithine decarboxylase
• Finasteride (testosterone-5a-reductase)

Is posed that the promoting agents, make possible the clinical expression of cancer. By discovering which are these; will imply their annulment. This is a powerful tool for preventive medicine; which opens a way to a new molecular epidemiology, that will allow us to advance to a concept of primary breast cancer prevention; by detecting molecular alterations previous to a neoplastic lesion.

But it is already proven that another group of genes are also involved in the breast cancer genesis. These are known as suppressor genes or anti-oncogenes; whose deterioration or inactivity would be a major factor for production of cancer. Within this group, the most important are the P53 suppressor gene and BRCA-1. Both mutation or inactivity of these genes would be the main responsible factor of an uncontrolled proliferation of breast cells; in cases with cancer family history.

We can state that, with all these new knowledge in genetics and molecular biology two challenges arise: first, look for immunological mechanisms capable of counteract the disease development and second; predict the risks that may have certain populations with a genetic predisposition to breast cancer; in order to perform chemoprevention in this specific group.

For all this, a multidisciplinary management is imperative who takes into account at all times, social, ethical and legal variables. It cannot be ignored that in many cases for this risk population; it is possible that a malignant tumor never appears and these individuals may be unnecessarily exposed to psychological traumas that could affect their personal, family and social life.

Tumor chemoprevention

What is chemoprevention?

The term chemoprevention, was first used in 1976 by Michael Sporn with this definition: “… is the inhibition or reversal of carcinogenesis through the use of non-cytotoxic drugs or nutrients that protect against the development; as well as progression of clones mutants of malignant cells”. In other word; it is the use of substances that allows to inhibit the development of invasive cancers, impeding a DNA molecular damage. Or if this has already occurred, reverse the progression of these pre-malignant cells to a final malignant differentiation.

There are two types of chemoprevention: primary chemoprevention; which fundamentally involves a large population of healthy women with moderate risk; with non-penetrating genetic factors and eventually first-degree relatives with breast cancer. You can also do primary prevention in a more limited population; but with high risk by increase of genetic predisposition, mainly due to the presence of genes BRCA-1 and BRCA-2. Also, there exists secondary chemoprevention, that would be done to subjects; who already have pre-malignant lesions; eg. atypical hyperplasia or in situ cancer.

But chemoprevention faces the problem of prolonged administration of potentially active pharmacological agents in groups of people of apparent good health. Therefore, both acute and chronic toxicity of such substances should be low. The composite must be easy to administer; preventive intervention should not be too expensive. Also, a monitoring program should not be too laborious.

Chemopreventive agents

They have been identified to date, over 600 compounds with potential chemopreventive action, about 30; of which are being studied in humans.

Chemopreventive agents can be divided into two main categories:

1. Compounds which inhibit the action of carcinogens.
2. Compounds that interfere with the factors that promote carcinogenesis.

Below will be enumerated the mechanism of action of some of them:

1. Retinoids

This term includes all vitamin A analogues; natural and synthetic. Various studies on retinoids proved its effectiveness as inhibitor of chemical carcinogenesis in skin, mammary glands, esophagus, respiratory tract, pancreas and bladder of experimental animals. Particularly when administered at a short distance of a carcinogenic activation process.

The modification of basic chemical structure of retinoids allows to produce new molecules with high organotropism. Along with the consequent increase of inhibitory activity and a systemic toxicity reduction. These agents are primarily differentiators. In these we have retinamide, fenretinide and 9-cis retinoic acid.

2. Protease inhibitors

Individuals who eats foods rich in protease inhibitors; rice, corn, bread, cereals; demonstrate a significant reduction in breast, colon, prostate, oral cavity and pharynx tumors.

3. Hormones and antihormones

Since 1960, based on knowledge of estrogen receptor; arises the idea of looking for substances capable of interacting with this “target”. Then, in 1970, it is started to suggest the chemopreventive activity of tamoxifen as an origin and development inhibitor of mammary tumors. Within this group are also found toremifene, hydroxyphenyl and droloxifene known as triphenylethylene.

These are pure antiestrogens; of which the most known commercially is Faslodex; so far known as 182780. In addition, since recently a new chapter is been opened about selective estrogen receptor modulators (SERMs); which have agonist and antagonist properties according; with which organ, these interact.

4. Phytoestrogens

They are chemical compounds produced by some plants and constitute the group of isoflavones. They are similes to estrogen substances that behave like non-steroidal estrogen; with agonist or antagonist actions. They have the characteristics of inhibiting enzymes; such as topoisomerase; which is related to DNA replication and acts at transcriptional level.

It has an antioxidant effect and inhibitor of cellular tyrosine kinase; which produce a down regulation of epidermal growth factor; insulin growth factor and platelet degrading factors. In summary, they have an anti-estrogenic and anti-proliferative activity. Some of them are equol, quercetin, coumestrol. Some vegetables high in phytoestrogens are; soy, barley, wheat, ginseng; among others.

5. Ascorbic acid (vitamin C)

Inhibits the formation of nitroso compounds. With protective action on gastric carcinoma.

6. Phenols

Some antioxidant phenolic compounds (hidroxianisol butoxide) are proven to be effective inhibitors of carcinogenesis; in lungs, colon, skin, liver as well as mammary glands of animals in experimentation.

7. Indoles (Cabbage – Cauliflower)

Capable of inhibiting tumors in several experimental models.