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Vol. 42. Núm. 90.
Páginas 9060-9064 (Mayo 1999)
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Vol. 42. Núm. 90.
Páginas 9060-9064 (Mayo 1999)
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Strategies for the modification of risk factors in gynecological cancers
J L. Benedet
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Strategies for the modification of risk factors in gynecological cancers

J. L. Benedet MD. FRCSC

Division of Gynecologic Oncology

BC Cancer Agency

Professor & Head, Department of Obstetrics & Gynecology

University of British Columbia


Dr. J. L. Benedet

Division of Gynecology Oncology

B. C. Cancer Agency

600 West 10th Avenue

Vancouver, B.C.

V5Z 4E6


The ultimate goal of any effective strategy for cancer control is to prevent individuals from dying from this disease. Strategies by necessity will vary with our knowledge of a particular cancer and the better we understand its epidemiology, etiology and the specific molecular mechanisms for each individual cancer, the better we will be able to effect a productive strategy for cancer control. Appropriate resources must also be available if the strategies are to achieve their goal.

The purpose of this paper is to review some of our knowledge regarding the risk factors for certain gynecological cancers and to see how this knowledge may then be used to achieve a reduction in cancer deaths.

Cancer prevention strategies have generally been divided into primary and secondary prevention. Primary prevention usually employs strategies directed toward the known risk or causative factors for a disease. Secondary prevention usually uses screening programs, either for specific subsets of the population or for all populations, in order to help identify a disease in a preclinical phase where intervention will beneficially impact mortality.


In order for primary prevention to be effective what is needed is a clear understanding of the epidemiology and etiology of a disease so that the identified risk factors can then be modified or ideally omitted from ones environment. Primary prevention strategies are founded on research and education. The focus is to try and educate the population regarding risk factors and then try to modify lifestyle practices.

The classic lifestyle modification has to do with lung cancer.


Few would argue that cigarette smoking or tobacco use in general is the major factor in the causation and mortality from lung cancer. Indeed in many parts of the world lung cancer has rapidly become one of the most common forms of cancer in women and these changes have been largely attributed to increased use of cigarettes(1,2,3). There is a substantial body of evidence(2,3) from both epidemiologic and toxicology studies indicating the carcinogenicity of smoking tobacco. Cigarette smoking has aIso been shown to increase the risk, not only of lung cancer, but also the risk of cancer of the oral cavity, larynx, esophagus, bladder, pancreas and kidney. It should be remembered, however, that the effect of cigarette smoking and cancer rates only manifests itself some 20-30 years after exposure first begins. Obviously women are not immune to the adverse health effects of tobacco smoking with all indications that in several countries lung cancer rates in women will continue to increase for the foreseeable futute and in some countries such as Canada lung cancer deaths(3) have already overtaken breast cancer as the most common cause of mortality for malignant disease. What is even more worrisome is that the real effect will not be obseved for another 20 or more years.

The message is clear; that the most effective strategy that can be initiated against lung a cancer deaths in women must be based on education and promotion centred around primary prevention. Governments and public health authorities should encourage the banning of advenising for tobacco and tobacco products, particularly when they are coupled with advertisements suggesting that it is fashionable for young people, in particular, to be smokers.


Probably the second major determinant of cancer risk is associated with complex exposures coming from diet, nutrition and dietary practices. It is difficult to quantify the exact mechanisms of carcinogenesis caused by human dietary exposures or practices but as the epidemiological studies of diet and cancer become more sophisticated associations will become clearer and the mechanisms better understood. Some estimates have suggested that as many as 35% of human cancers may be associated with dietary practices.

Much of this research focus with regard to dietary factors(4,5) in cancer has focuse on fat intake as well as the dietary intake of vitamins as well as meats and vegetables. Obviously, promotion of healthy dietary practices should be encouraged but realistically, in many parts of the world, the ability to effect specific dietary changes will be impacted by economic and cultural factors. Primary prevention, although understood in this regard, may be difficult to effect.


There is increasing recognition that infective agents and processes are one of the three major identifiable groups of cancer causes. Good evidence(6) is present to show that infection with certain hepatitis viruses is related to hepatocellular carcinoma as well as striking associations have been demonstrated between Epstein-Barr virus (EBV), nasopharyngeal cancer as well as EBV infection in Hodgkin''s disease in certain countries. Most importantly, from a gynecological point of view however, is the overwhelming amount of evidence(7) implicating infection with certain subtypes of human papillomavirus (HPV) as one of the rnajor causal factors in cervix cancer.


Occupational exposure to carcinogens, pollution, food additives, medicines and medical procedures such as radiation therapy, and geographical factors certainly account for some, but definitely only a small proportion,of the local cancer burden in women. Identification of such factors will also help in planning useful primary prevention strategies.


1. Cancer of the Breast

Breast cancer is the most frequent occurring malignancy amongst women worldwide and in developed countries it is by far the most common. There is no region in the world with a truly low rate of breast cancer.

The etiology of breast cancer, in spite of many detailed studies, has remained elusive. Hereditary breast cancer is important and probably accounts for 5% of all breast cancers. Much work has been done in identifying gene mutations of the BRCA-1 and BRCA-2 genes in certain ethnic and familial situations.

Another change in the risk of breast cancer has been noted in migrant women(8,9), particularly in studies form Hawaii, San Francisco and Japan, where women who reside in Hawaii or San Francisco have double th rate of breast cancer than of their Japanese forebearers. These findings strongly suggest environmental factors as playing a role in the causation of breast cancer.

The fact that the rate is higher amongst blacks as compared to white members of the same community in many locations in the United States also suggests that a large proportion of breast cancer is related to environmental or lifestyle factors and therefore would theoretically be ovoidable if we could identify these specific factors.

a) Risk Factors for Breast Cancer and Preventative Strategies

The risk for breast cancer is increased about 50% in nulliparous compared to parous women. The risk increases with advancing age of first birth(10-12), until a first birth occurring after the age of 35 years carries a higher risk than nulliparity, indicating that first child-birth after this age is no longer protective against breast cancer. The association with parity is less clear but in general it appears that there may be some independent contribution of high parity to reducing breast cancer risk. Risk also appears elevated with a late menopause and conversely early menopause, whether natural of artificial, contributes to reducing risk. Early age at menarche as well as breast-feeding may have some associations but studies(13) are not clear with conflicting results. Several studies(14-16) have also been done trying to quantify the risk of abortion to breast cancer with certain studies showing that an interrupted pregnancy does not impart the long-term protective effect that a full-term pregnancy does against breast cancer development. In terms of possible preventative strategies, this is important given the large number of induced abortions that are done worldwide and the common nature of breast cancer itself. Other identified risks for breast cancer have included dietary factors such as increasing body mass index in post menopausal women, as well as studies(17-21) trying to link risk to dietary fat intake have produced conflicting evidence. Not all fat should be considered in a similar manner as higher consumption of olive oil as seen in studies(19-21) from Spain, Greece and Italy, may be associated with lower risk of breast cancer. A large number of studies(22-26) have been carried out trying to better identify the relationship between hormone use in the either oral contraceptives and hormone replacement therapy and the risk for breast cancer. In summary, women who are using combined oral contraceptive medication or who have used them in the past ten years are generally thought to be at a slightly increased risk of breast cancer, with the relative risk disapperaing therapy in perimenopausal and postmenopausal women, the overall risk is also slightly elevated.

Primary prevention strategies in trying to identify risk factors for breast cancer can be utilized in attempt to produce alterations that ultimately will affect mortality. Secondary prevention, through earlier diagnosis, should increase survival and is the basic principle inherent in mammography screening programs. Their use is however limited mainly to developed countries with sufficient economic resources to carry out such programs. In the women with BRCA-1 and BRCA-2 gene abnormalities, either through a familial history of breast cancer or because of belonging to a specific ethnic group, may benefit from widespread introduction of programs to identify the aberrant gene in young women so that possible intervention strategies can be introduced at an age before one would normally expect to see the cancer develop. Finally, several studies have now shown that women treated with tamoxifen have approximately a 1/3 reduction in breast cancer risk in the contralateral breast.

2. Cervical cancer

Cervical cancer is the second most common form of malignancy worldwide as approximately 450,000 cases would be reported annually. It is also the leading cause of death from malignancy in developing countries. Generally the highest recorded rates in the world are in sub-Saharan Africa as well as Central and South America and some regions of Southeast Asia. Cervical cancer has been one of the most studied of human malignancies and the vast literature(27-30) exists on its epidemiology. This literature has consistently demonstrated a clear association between a woman''s risk of developing cervical cancer and the number of sexual partners she or her partner have had. This association strongly suggests that a sexually transmitted agent is involved in the etiology of cervical cancer and viruses have been considered amongst the most likely candidates. Human papillomavirus infection (HPV) has long been suspected as having a possible role in the causation of cervical cancer. We currently udnerstand that there are over 70 different types of HPV''s identified to date with 20 or so having been shown to have oncogenic potential. HPV-16 and HPV-18 are the subtypes most commonly associated with advanced cervical intraepithelial neoplasia and invasive cervical cancer.

The knowledge that cervical cancer resembles a sexually transmitted disease as it is related inversely to the age at first intercourse and directly to the number of partners and independently related to multiparity, are all factors that could be used in primary prevention strategies for this disease. Education amongst young people as to the association with sexual practices, i.e. early age at onset and multiple partners and how such practices can effect their relative risk in developing this disease in the future, can and should be introduced.

Most importantly, a long history of secondary prevention(31) through cervical cancer screening programs in populations have clearly demonstrated the benefits of this approach. Simply utilizing a system whereby women would be screened every thrree years between the ages of 35 and 65 has been estimated to produce a reduction in the incidence of cervical cancer by over 90%.

3. Endometrial cancer

The epidemiology of endometrial cancer is not unlike that of breast cancer in several respects. Incidence rates are generally reported to be higher in developed countries of North America and Europe while those in Japan are relatively low. Endometrial cancer is predominantly a disease of older post-or perimenopausal women with a known association with hormone use and body mass index. It is strongly related to elevated levels or availability of exogenous or endogenous estrogens(32-34) and correspondingly low levels of progesting. Thus it appears related to anovulation in many women, where estrogen replacement treatment in the menopause and obesity are all factors which increase endogenous estrogen levels and are all factors that can be modified in an attempt to reduce relative risks of this disease. Combined estrogen and progestin medication seerns to confer effect leading to a reduced relative risk for this disease. Estrogen treatment may also protect against colon cancer(35).

The obvious preventive strategies that would seem to hold the most prominence at this time is optimizing body weight for individuals and avoiding obesity and hormone replacement therapy is needed and progestin supplementation should be part of the regimen.

4. Ovarian cancer

Ovarian cancer is an important gynecological cancer, particularly in the western world where it usually ranks sixth amongst the most frequent forms of cancer in women. The importance of epithelial ovarian cancer in most countries is that is the leading cause of death from pelvic malignancy in women excluding colon and rectal cancers. It is also a disease with no early warning signs or symptoms and the vast majority of cases are diagnosed with stage 3 o 4 disease, where the chances of cure are much less.

The etiology of ovarian cancer is unknown. The risk of ovarian cancer appears to increase with age and is approximately twice as common in nulliparous women as compared to parous women. An increased risk has also been suggested for late age at first birth, early menarche and late menopause with some protection being suggested by higher parity. The concept of «incessant ovulation» was put forth by Fatahalla in the 1970''s and has been the basic mechanism invoked to explain these observations. It is throught that the repeated ovulations produced tears in the surface epithelium and the ultimate repair and regeneration process may subject the cells to influences that ultimately lead to incorporation of surface epithelium into subsurface areas of the ovary encystation and ultimately transformation into malignant epithelium. Several studies(36) have indicated that oral contraceptive use is protective against ovarian cancer with the incidence being reduced by approximately 40% in users and to an even greater extent in individuals who have been long-term users of these medications. Thus on a population scale, the use of combined oral contraceptive tablets has probably been the major determinant of the favorable decrease in ovarian cancer rates observed in many western countries.

Currently cancer of the lung, breast, skin, cervix and endometrium are all common cancers that could be impacted in a significant fashion with existing knowledgeand.


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