Among women, breast cancer is the most commonly diagnosed cancer after non-melanoma skin cancer, and is the second leading cause of cancer deaths after lung cancer. Many factors known to increase a woman's risk of breast cancer are known - and some may be modified to decrease a woman's risk of cancer. In a select group of cancer patients (7-10%) genetic factors may be the predominant determinant. In another group of patients cancer might develop because an inherited factor increased susceptibility to environmental carcinogens. The following are the most commonly known risk factors for susceptibility to breast cancer.
Age
The risk of breast cancer increases with age, with the majority of breast cancer diagnoses occurring after the age of 50. In women with a hereditary susceptibility, breast cancer tends to occur at an earlier age than sporadic cases. The mean age of breast cancer in women who carry a BRCA mutation is in the early to mid 40s.
Reproductive and Menstrual History
Early age at menarche (first menstrual cycle) and late age at menopause increase the risk of breast cancer. The risk of breast cancer may be decreased by early first-term pregnancy (usually defined as prior to the age of 30). These factors seem to be more significant in women who do not have a mother or sister with breast cancer, and have differing roles in women with a hereditary susceptibility to breast cancer - such as those who carry a mutation in the BRCA genes.
Sex
Women are far more likely to develop breast cancer than men. On average, a woman living in the United States has an approximate 11% risk of developing breast cancer over her lifetime. Breast cancer that develops in a man is much less common (accounts for less than 1% of all breast cancer) but is more common in men who have a hereditary predisposition.
Family History
Population studies demonstrate that 5% to 10% of women have a mother or a sister with breast cancer. About twice that number have a first- or second-degree relative with breast cancer. Analysis of the risk conferred by a first-degree relative suggests that these women are approximately two times more likely to develop breast cancer. This risk varies with the age at which the affected relative was diagnosed (the younger the age at diagnosis, the greater the risk), and is stronger for women under the age of 50 who have a first-degree relative who was diagnosed with breast cancer before the age of 50.
The number of relatives affected with breast cancer and how close they are in relation to an individual is important in determining risk. In general, the greater number of family members and the closer the biologic relationship, the greater the risk. Importantly, the number of female relatives in the family influences the usefulness and significance of the family history.
Breast cancer risk is also moderately increased in women who have a first-degree relative with ovarian cancer. The likelihood that a cancer predisposition gene is present is greater in those families in which breast and ovarian cancer is present. Familial cancer aggregations do not necessarily indicate a genetic basis, however, as they can also be caused by a shared environment. The ultimate proof of an inherited cancer syndrome is the demonstration of a germline mutation in the relevant gene.
Genetic Susceptibility
Approximately 5% to 10% of breast cancers demonstrate a pattern of inheritance. This is demonstrated by the finding of an increased incidence of cancer from generation to generation, with approximately 50% of those at risk demonstrating disease. In reviewing the family history it is important to remember that the susceptibility to breast cancer can be inherited through the mother's or the father's side of the family. If a hereditary pattern is suggested, genetic cancer risk assessment can assist in the determination of the risk of a particular cancer susceptibility syndrome. These syndromes include the hereditary breast and ovarian cancer syndrome associated with the BRCA genes, Cowden syndrome associated with PTEN mutations, the Li-Fraumeni syndrome due to TP53 mutations, ataxia telangiectasia associated with ATM mutations and the Peutz-Jeghers syndrome. Each of these syndromes has characteristic features that assist in their identification.
Hormonal Influences
Oral Contraceptives
Studies have demonstrated that oral contraceptives may play a slight role in increasing breast cancer risk in long-term users. Many of these studies evaluate the effects of oral contraceptives used prior to the advent of current low-dose oral contraceptives, and further studies are ongoing to determine the effects of current therapies.
Hormone Replacement Therapy
In 2002, the Women's Health Initiative released its findings on the risk of breast cancer in women taking combined estrogen plus progesterone. This study showed that after an average of 5.6 years, 245 of the 8,506 women taking estrogen/progesterone hormone replacement therapy and 185 of the 8102 women taking a placebo developed breast cancer. There were 349 cases of invasive breast cancer, a type that has a greater chance of spreading to other parts of the body. Tumors in women taking combination hormone replacement therapy tended to be larger and more advanced in stage. From this data we know that there is an increased risk of breast cancer in women who take combination estrogen plus progesterone hormone replacement therapy that amounts to eight additional cases of breast cancer for every 10,000 women over one year. Overall, there was a 24% increase in the risk of breast cancer.
It is important for women to discuss the risks and benefits of hormone replacement therapy with their health care provider. It is also important that women know that studies of the risk of breast cancer associated with taking formulations containing estrogen alone are still ongoing.
Radiation Exposure
Data from survivors of exposure in Hiroshima and Nagasaki as well as studies of women who have undergone radiation therapy to the chest and upper body for diseases such as Hodgkin's lymphoma, thyroid disease or acne have documented an increased risk of breast cancer. The history of radiation exposure plays an important role in decision-making regarding screening. Increased sensitivity to radiation has also been suggested as the source of increased breast cancer risk in carriers of mutations in the ataxia telangiectasia (ATM) gene and in the Li-Fraumeni Syndrome.
Benign Breast Disease
Certain benign breast diagnoses are independently associated with an increased risk of breast cancer. Women who have proliferative disease without atypia are at 1.6 to 1.9 times the risk for breast cancer in comparison to those with non-proliferative breast disease. A diagnosis of atypical ductal hyperplasia may increase the risk of breast cancer in a woman 2.5 to 5.3 times. A diagnosis of lobular carcinoma in situ (LCIS), often an incidental finding on breast biopsy, is associated with an approximately 30% lifetime risk of a subsequent breast cancer.
Previous Breast Cancer Diagnosis
Women with a previous diagnosis of breast cancer have an approximate risk of 20% (lifetime) risk for developing a second primary breast cancer, depending upon the age at diagnosis. Women with inherited BRCA mutations may have up to a 60% lifetime risk of a contralateral (opposite) breast cancer diagnosis.
Other Factors
There are many other factors including obesity, fat intake, and level of physical activity that have been linked to an increased risk of breast cancer. Increased density of breast tissue as seen on mammography is also associated with an increased risk of breast cancer.
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