Genetic tests for breast and ovarian cancer
3-page executive summary
Breast cancer is the most commonly diagnosed cancer in women. In 2005, there were about 3000 incident cases of breast cancer in Norway. Ovarian cancer is less common, with about 400 cases each year. Although breast cancer is relatively common, only about 5-10 % of cases are due to inheritance of highly penetrant cancer susceptibility genes. The genes are also associated with an increased risk of ovarian cancer. The two main genes that confer susceptibility to breast and ovarian cancer are the BRCA1 gene and the BRCA2 gene. The mutations in these genes are associated with both the hereditary breast cancer and hereditary ovarian cancer. One characteristic of inherited breast and ovarian cancer is that cancer usually appears at younger age.
There is a question if genetic testing can reduce the incidence and morbidity of cancer more than the existing strategy based on documenting families with an inherited predisposition to cancer. The Directorate for Health and Social Affairs has asked the Norwegian Knowledge Centre for the Health Services to summarize the documentation of the genetic testing of BRCA1 and BRCA2 and the clinical outcome of the testing.
We have performed a search for systematic reviews in Cochrane Library and Health technology Assessment databases until September 2007.
Data has been gathered from four systematic reviews that have summarised published literature on genetic testing for BRCA1 and BRCA2 for breast and ovarian cancer. BRCA1 and BRCA2 are very large genes. Since the cloning of BRCA1 and BRCA2, more than a thousand mutations have been identified in these genes. From the published literature, there is no compelling evidence to suggest that one genetic test performs better than another. To ensure a full mutation screen more that one method need to be used. Different populations have different mutations. Hence, the type of mutation analysis required often depends on population or subpopulations. Individuals from families with known mutations can more easily be tested specifically for them. Population were specific BRCA mutations are clustered because of a common ancestors are so called founder population.
Cancer risk in family history risk groups are estimated by determining the prevalence of the mutation and its penetrance for breast and ovarian cancer. The prevalence of mutations varies according to the geographic and ethnic origin(s) of the population. Few direct measures of the prevalence of clinically important BRCA1 or BRCA2 mutations in a general population have been published. Models have estimated the prevalence to be about 1 in 397 in a general population. The systematic reviews find that many (up to 36 %) women with breast cancer who are mutation carriers report no family history of breast or ovarian cancer.
A small number of clinically significant BRCA1 and BRCA2 mutations have been found repeatedly in different families, such as the four founder mutations most common in the Norwegian population. The prevalence of each mutation differs according to different parts of the country.
The penetrance or cumulative lifetime risk of breast cancer in women who carry these inherited gene mutations is estimated to 65 % for BRCA1 and 45 % for BRCA2, and these cancers often occur at a younger age. The penetrance for ovarian cancer in women with BRCA1 mutations is estimated to be 39 % and is slightly lower, 11 %, in women who carry BRCA2 gene mutations.
The cumulative lifetime risk of breast or ovarian cancer in Norwegian women who carry one of the four BRCA1 founder mutations is approximately 58 % (51-66 %).
Increased surveillance, chemoprevention and prophylactic surgeries are standard options for the effective medical management of mutation carriers. Prophylactic surgery was associated with a reduced risk of breast and ovarian cancers in short term cohort studies. However, optimal management of female carriers who choose to undergo prophylactic surgeries is still poorly understood.
International guidelines recommend testing for mutations only when an individual has personal or family history features suggestive of inherited cancer susceptibility, the test can be adequately interpreted, and results will aid in management. Genetic counselling is recommended prior to testing.
There exist several genetics tests for BRCA gene mutations; no test can detect all mutations in BRCA1 or BRCA2 genes. Testing primarily benefits families in which a BRCA1/2 mutation has been discovered. Individuals from Norwegian families with known mutations can easily be tested specifically for that mutation. There are still limited data on the appropriate medical management for BRCA mutation carriers, and more studies are needed to resolve this.