Approximately 30% of individuals with breast cancer have some family history of cancer (generally breast and/or ovarian cancer).[1,2] However, the majority of women who present with a family history of cancer will not have a history that is suggestive of an autosomal dominantly inherited disorder (cancer in multiple generations). It is estimated that only 5% to 10% of breast and ovarian cancers are associated with a strong family history of cancer and are, therefore, likely to be attributed to inheritance of a mutation in a known cancer-causing gene. Current information suggests that these genes may be grouped into high-, moderate-, and low-risk genes. Genes that confer the greatest lifetime cancer risk can be thought of as high-risk genes.
In this article, we will focus on BRCA1, BRCA2, and TP53 (aka p53) as high-risk genes. Moderate-risk genes are inherited in an autosomal dominant fashion with lower penetrance and therefore less cancer risk. Low-risk genes can be associated with the smallest cancer risk. These genes and their risk for cancer are less well understood, and the associated cancer risks are controversial. Likely, cancer attributable to low-risk genes develops later in life and is linked to significant environmental exposure.[5,6]
The commercial availability of genetic testing for cancer risk introduces a new dimension in the assessment of breast and ovarian cancer risk. Genetic testing for cancer risk is a complex process. Appropriate individuals for testing should have the highest likelihood, within a family, of carrying a cancer-causing gene mutation. Before undergoing genetic testing, individuals must understand the risks, benefits, and limitations of genetic testing. This includes understanding the psychological and ethical issues that surround genetic testing.
The first steps in this process are gathering an accurate family history and recognizing the features of hereditary breast and ovarian cancer. It is also important to understand the options that are available for individuals who are at high risk of cancer (those with a family history or found to be gene mutation carriers).
High-risk cancer screening is available; however, these screening recommendations are based on expert opinions and are largely unproven. Options for cancer prevention include prophylactic surgery (oophorectomies, mastectomy) and chemoprevention. The ability to counsel and provide an accurate assessment of risk and appropriate screening recommendations for these individuals is critical for the provider. We present guidelines for risk assessment in individuals with a family history of breast and ovarian cancer and review the management issues involved in caring for this group of women.
Even in this era of microchip technology, an accurate family history continues to be the most informative tool for assessing cancer risk. Despite its importance in assessing risk, obtaining a family history is rapidly becoming a lost skill. Significant deficits exist in the documentation of family history in the primary care setting. This may stem from a diminution of the time that is available for physician and patient interactions, as well as a lack of emphasis during physician training. In one cross-sectional study, a family history was obtained in only 50% of new patient visits and was updated in 22% of established patient visits.
The first step in obtaining an accurate cancer family history involves gathering information to generate a pedigree that spans at least three generations. The history should include all types of cancer in both the paternal and maternal lineage, since breast and ovarian cancer risks can be transmitted through the father. For each affected relative, it is important to try to ascertain the site of the primary tumor, laterality of disease, age at diagnosis, treatment, and age at death. Eliciting information about unaffected family members is key to interpreting the family history and should include cause of and age at death. If the total number of female relatives is small, significant expression of an inherited gene may not be apparent. Gathering information about the presence of other chronic diseases in the family, such as osteoporosis and coronary artery disease, is important since this information may influence management recommendations (eg, recommendations for hormone replacement therapy).
Studies have shown that family history information that identifies breast or colon cancer as a primary cancer site in first-degree relatives may be accurate in 89% to 91% of cases. However, the accuracy rate for such information decreases in the case of second- and third-degree relatives. Often, the diagnosis of premalignant conditions may be confused with cancer, and sites of recurrence can be misidentified as second primary tumors. Hence, procuring pathology reports or medical records to verify a family history of cancer is strongly recommended. Ascertaining ancestry is an integral component of the process. The existence of specific mutations (eg, BRCA1/BRCA2) in certain populations makes ethnicity-based testing an important option to consider.
Current advances in technology may incorporate new tools such as computer programs to record genetic information, but physicians will continue to play an important role in the interpretation of this information and the definition of risk. Future developments in genetic research will only serve to increase the importance of an accurate family history. All physicians should develop methods to capture family history at the time of an initial patient visit and then periodically update this information.
Certain features of an individual’s personal or family history may lead the clinician to suspect an inherited predisposition to breast and/or ovarian cancer. A personal history of early breast cancer (onset at age < 50 years) or bilateral breast cancer may be a clue to a genetic predisposition. Additionally, breast and ovarian cancer in the same individual may herald the presence of hereditary malignancies. As we will discuss later, a history of ovarian cancer or early breast cancer plus Ashkenazi Jewish ancestry carries a significant risk of an inherited form of the diseases.
Inherited factors may play a role when the above personal history coexists with early-onset breast cancer, bilateral breast cancer, male breast cancer, or ovarian cancer in more than one generation. The presence of other cancers in the family, such as cancers occurring at early ages (eg, colon cancer at age < 50 years) or cancers without the usual risk factors (such as lung cancer in a nonsmoker) may be clues to an inherited form of cancer. See Table 1 for a list of other cancers that can be associated with hereditary breast or ovarian cancer.
Families vary in size, and it is important to take into account the number of individuals within a family, as well as the number of women at risk. For example, a small family with few women over age 40 diagnosed with one early breast cancer and ovarian cancer can be significant, whereas a very large family with several women over age 60 affected with breast cancer may be less likely to carry a genetic alteration in BRCA1/2.
Breast and ovarian cancer are features of several hereditary syndromes. Families with clear autosomal dominant patterns of inheritance are in the minority (5% to 10% of all individuals with either breast or ovarian cancer). More than 70% percent of such families will be found to carry mutations in BRCA1 or BRCA2. Individuals with BRCA mutations have high lifetime cancer risks and will be discussed below as high-risk genes. Other syndromes, such as Cowden’s disease, hereditary nonpolyposis colorectal cancer (HNPCC), Muir-Torre syndrome, and Peutz-Jeghers syndrome also display autosomal dominant patterns of inheritance. However, these carry a lower penetrance and, therefore, a lesser lifetime risk of cancer. These syndromes have a moderate lifetime cancer risk, and the genes associated with the syndromes have often been termed moderate-risk genes.
Low-risk genes carry the lowest risk of cancer (relative risks of 2.0 to 7.0) but are likely to be more prevalent than either high- or moderate-risk genes. Therefore, they contribute more to the overall development of cancer. To date, low-risk genes have not been associated with ovarian cancer, and consequently, only low-risk genes associated with the risk of breast cancer will be discussed in this article. See Table 2 for a list of high-, moderate-, and low-risk genes, their associated syndromes, and lifetime risk of breast and/or ovarian cancer.