Breast cancer is the most common cancer and the second leading cause of cancer deaths in women in the United States.  In 2008, approximately 184,450 patients were estimated to be diagnosed with invasive breast cancer, and an estimated 40,930 were estimated to die of this disease.   Furthermore, over 50,000 female carcinoma in situ breast cases would have been diagnosed.  The etiology of breast cancer is poorly understood with multiple genetic and environmental factors involved in the initiation and progression of cancer. 

 

Scandinavian Twin Study:  For years, there has been a hot debate as to whether the cause of breast cancer is genetic or environmental.  Then in 2000, Lichtenstein and his colleagues at the Karolinska Institute in Sweden published their study of 44,788 pairs of twins from the Swedish, Danish, and Finnish twin registries.  In this study, they looked at cancer risk with 28 different types of cancers and did statistical modeling of genetic and hereditary contributions in eleven different cancer types.  For breast cancer, they clearly showed that only 27% of breast cancers were due to genetic factors.  This was an even lower hereditary component than other common cancers such as prostate and colorectal.  This study and others have confirmed the fact that over 70% of breast cancers are influenced by environmental factors.

 

BRCA genes:  Although much attention has been made about hereditary breast cancer, only two genes are commonly tested for breast cancer risk assessment.  These two genes are tumor suppressor genes named “BRCA1” and “BRCA2” that are involved with DNA repair.  These two genes only account for about 5% of all breast cancers.  Because of the Scandinavian twin study, most experts believed that there are other yet to be discovered genes involved with breast cancer.  Because the chance of having a BRCA mutation in the general population is so low, genetic testing is not indicated in most patients.  However, if a patient has a family history of breast cancer, then a mathematical model can be used to determine if BRCA testing is indicated.  The likelihood of being a BRCA carrier increases with the number of relatives who had cancer and if the cancers occurred earlier in life.  For example, in families with four or more cases of breast or ovarian cancer under the age of 60, over 80% are found to have a damaged version of BRCA1 or BRCA2.  If a patient is a carrier of one or both of the BRCA1 and BRCA2 genes, her risk of breast cancer dramatically increases.  According to estimates of lifetime risk, about 13.2% (132 out of 1,000 individuals) of women in the general population will develop breast cancer, compared with estimates of 36-85% (360-850 out of 1,000) of women with an altered BRCA1 or BRCA2 gene.  In other words, women with an altered BRCA1 and/or BRCA2 gene are up to eight times more likely to develop breast cancer than women without alterations in those genes.  The BRCA1 mutation confers a higher risk than a BRCA2 mutation.  Women who inherit a damaged BRCA1 gene have a 60-85% chance of developing breast cancer at some stage in their lives and a 20-40% chance of developing ovarian cancer.  For BRCA2, the risks are 40-60% and 10-20%, respectively.  

 

Family History and Breast Cancer:  Although the spotlight in hereditary breast cancer has been directed on the BRCA genes, the majority of patients with a family history of breast cancer are BRCA1 and BRCA2 negative.  Even in these BRCA negative patients, however, there is an increased risk of developing cancer with a family history of breast cancer.   Six factors (unrelated to BRCA genes) have been studied in patients with a family history of breast cancer.  They are as follows:

 

1.  Degree of relationship:  If the family member with a history of cancer is a first degree relative, the increased risk is much greater than for second degree relatives. 

2.  Number of relatives who have had breast cancer:  People with two or more family members who have had breast cancer are at higher risk than those with only one affected relative.

3.  Age of onset of cancer:  If the relative developed breast cancer at an early age (pre-menopausal), the risk is higher than if the relative developed post menopausal breast cancer.

4.  Bilateral breast cancer:  If the relative has a history of bilateral breast cancer, the risk is greater than having a relative with unilateral breast cancer.

5.  Gender of the relative:  If the family member with breast cancer is a man, the risk is higher.

6.  Other related early onset tumors:  If there is a family history of early onset ovarian cancer, this incurs an increased risk for a person.

 

How to decide whether you need the BRCA gene test

 

The following is an excerpt from the American Society of Breast Surgeons:

1.  Early onset breast cancer (diagnosed before age 50)

2.  Two primary breast cancers, either bilateral or ipsilateral
3.  A family history of early onset breast cancer
4.  Male breast cancer
5.  A personal or family history of ovarian cancer
6.  Ashkenazi (Eastern European) Jewish heritage
7.  A previously identified BRCA1 or BRCA2 mutation in the family

Any one of these features alone indicates a risk for harboring a BRCA1 or BRCA2 mutation.  The presence of more than one of these features raises that risk to greater than 10%, the traditional cutoff for recommending a BRCA test. Such patients should have access to BRCA testing.  A simple risk-calculation model based on the prevalence of mutations seen among women tested for BRCA mutations is available at http://www.brcacalculator.com.

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