Adjusting the estimated proportion of breast cancer cases associated with BRCA1 and BRCA2 mutations: Public health implications

Abstract

Purpose: Mutations in BRCA1 or BRCA2 genes increase breast cancer risk. Assuring reliability of information about these mutations is increasingly important to the health care community; mutation testing is becoming more widespread. We describe a methodology for assessing such information. Methods: Our approach integrates four interdependent epidemiologic parameters: (1) the probability of developing breast cancer, (2) the proportion of breast cancer cases with a BRCA1 or BRCA2 mutation, (3) the proportion of women that carries a mutation, and (4) the proportion of women with a mutation that develops cancer. We assess the plausibility of estimates of these parameters from published reports and commonly accessed information sources. Results: Assuming a fixed probability of developing breast cancer, the following estimates for the other three epidemiologic parameters are derived for women by age 70: 1% to 2% of all breast cancer cases are associated with a BRCA1 or BRCA2 mutation; 1 in 300 to 1 in 465 women carry a mutation; and 35 to 65% of mutation carriers develop breast cancer. Within these ranges, however, only selected combinations are plausible. The proportion of mutation-related breast cancer is lower than listed in some common information sources (1 to 2% vs 6%). Also, penetrance is somewhat lower and the carrier rate somewhat higher. Conclusions: The four epidemiologic parameters can be integrated to test their plausibility. BRCA1 and BRCA2 mutations are associated with only one-third as many breast cancer cases in the Guidelines have been developed to aid clinicians in deciding when to offer BRCA1 and BRCA2 mutation testing. 1-6 These guidelines recommend testing in specific circumstances, such as in women whose family history indicates an inherited predisposition to breast cancer. When a mutation is identified in an index case, cascade testing can be offered to other family members, thereby allowing primary prevention options to be considered. Implementation of BRCA1 and BRCA2 mutation testing by primary care providers has been sporadic and driven, in part, by direct-to-consumer advertising. [7][8][9][10][11] At least two information sources about BRCA1 and BRCA2 mutation testing have been developed for use by primary care providers in the United States. 12,13 In addition, two comprehensive reviews on BRCA1 and BRCA2 and hereditary breast cancer are available via internet access to health care providers, as well as the general public. 14,15 The data summarized by these sources are not always complete and/or consistent, either internally or with each other. These data are composed of three epidemiologic parameters: (1) the penetrance of BRCA1 and BRCA2 mutations, (2) the mutation carrier rate in the general population, and (3) the proportion of all breast cancer cases that is associated with a mutation. Almost all estimates quoted for each of these epidemiologic parameters are indirectly derived in the original studies. For example, there have been no published studies where a large population-based samp...

Is it time for BRCA1/2 mutation screening in the general adult population?: impact of population characteristics

“…These four factors are interrelated; knowing three will allow the fourth to be computed. 10 As an example, three founder mutations account for the majority of deleterious BRCA1/2 mutations in the Ashkenazi Jewish population, allowing an inexpensive molecular test to be used. A reasonably confident estimate of the carrier rate in this population is about 1 in 40 (2.5%; range, 1 in 33 to 1 in 56).…”

Methionine-Dependence Phenotype in the de novo Pathway in BRCA1 and BRCA2 Mutation Carriers with and without Breast Cancer

“…BRCA1 (13) and BRCA2 (14) germline mutations are linked to 5% to 10% of all breast cancer cases diagnosed. BRCA1 and BRCA2 code for proteins of importance to genome stability as both have been shown to be involved in several cellular mechanisms such as homologous recombinational repair of DNA strand breaks, transcriptional regulation, cell cycle control, and/or mitotic spindle formation (15,16); however, not all BRCA1 and BRCA2 mutation carriers develop breast cancer (f85% of women carrying a BRCA1 or BRCA2 mutation will develop breast cancer by age 70 years) and other inherited traits may modify their cancer risk (17). Therefore, the primary aim of this study was to test the hypothesis that MDP in peripheral blood lymphocytes may be an inherited or acquired trait associated with an increased risk for developing breast cancer in BRCA1 and BRCA2 germline mutation carriers.…”

Family history of breast cancer and young age at diagnosis of breast cancer increase risk of second primary malignancies in women: a population-based cohort study

“…Up to 7% of breast cancer cases are estimated to be due to breast cancer susceptibility genes (e.g. BRCA1, BRCA2, p53, and PTEN) (Edlich et al, 2005), adding to the risk of other cancers (Edlich et al, 2005;McClain et al, 2005).…”