Contribution of BRCA1/2 mutation testing to risk assessment for susceptibility to breast and ovarian cancer: summary report

Año de publicación: 2006


For both breast and ovarian cancer the strongest known risk factor, after adjusting for age, is family history. The figure most often cited is that approximately 1/3 of breast cancer is familial, where family history is defined by the presence of at least two cases of breast cancer, at any age, in fi rst- or second-degree relatives. Approximately 5% of all breast cancer cases are currently thought to be hereditary, that is, related to the transmission of mutations in a single gene. Clustering of cancer cases in families does not imply that genetic susceptibility is always present, since environmental factors and chance can also play a role. Conversely, the presence of a genetic susceptibility will not always translate into the occurrence of multiple cancer cases within one family. However, persons considered to be at highest risk of carrying a mutation in a breast or ovarian cancer susceptibility gene are those displaying the characteristics of a hereditary breast and ovarian cancer syndrome, HBOC. The HBOC syndrome is characterized by a pattern of occurrence of cancers in a family, involving multiple relatives affected by breast and/or ovarian cancer, and by early age at diagnosis. Currently, there is no consensus as to the minimal set of criteria defining an HBOC family.


A comprehensive search strategy using key words was designed in order to identify published, ‘grey’, and unpublished literature for each topic. The search was limited to human studies, and there were no language restrictions. A draft set of key words was tested for its precision before finalization. Databases of published literature were searched through December 2004. The reference lists of primary research studies, review articles, and reports were searched to identify other relevant articles. The detailed literature search strategies and study selection criteria used for the assessment are presented in Appendix A. Two reviewers independently made the final selection of studies to be included in the review based on the selection criteria. Study selection forms were developed and pilot tested for this purpose. The decision to order an article was based on the title and abstract, where available. In cases where these offered insufficient information, the article was ordered for further information. The degree of agreement between reviewers was noted, and any persisting differences were resolved by consensus. For articles containing quantitative data, forms that were specifically developed and pilot tested for this project were used to extract data. Various procedures were put in place to ensure quality control, including checking of extracted data by a second reviewer, discussion of all particularly complex articles by several reviewers, and reading of text and tables by a scientific reviewer not directly involved in data extraction.


In the process of reviewing the literature for this report, important limitations in the evidence have been found. Major problems are the lack of a consensual definition of HBOC and the quality of the study designs and reporting of data, which are not up to epidemiological standards for molecular test evaluation studies. The variability in the study population selection criteria and in the testing protocols for molecular testing complicates the synthesis of the evidence. This variability is particularly striking in the literature on prevalence, penetrance and clinical validity. Current knowledge in areas such as the distribution of BRCA1/2 mutations is dependent on the evolution of molecular techniques and testing criteria. Both prevalence and penetrance have been studied more thoroughly in high-risk families and in some founder populations than in families at moderate or low risk. Residual uncertainties and gaps in current knowledge have implications regarding decision making for individuals and families, for health-care providers and for policy makers. Among the conditions put forward by the American Society of Clinical Oncology for molecular testing in cancer genetics in general, the evidence was reviewed with respect to the assessment of prior (pre-test) risk based on family history and on the informativeness of test results for the post-test updating of the risk assessment. As far as current practices are concerned, the majority of families considered eligible for testing in cancer genetics clinics (typically families with two or three affected individuals) are not found to carry a BRCA1/2 mutation. Such a result is considered inconclusive and the residual risk of cancer remains higher than that of the general population. Providing precise post-test probabilities to these families is, however, difficult because good data on clinical negative predictive value are lacking. Another inconclusive test result which represents a challenging task for geneticists and genetic counsellors and does not substantially alleviate a family’s anxiety, is the discovery of a variant of unknown clinical significance. This situation is relatively frequent, possibly almost as frequent as a positive test finding, but may be resolved over time as new knowledge about these variants accrues. In practice, for the very high risk families, the pre-test (prior) risk will not be substantially modified by an inconclusive test result. Testing primarily benefits families in which a BRCA1/2 mutation has been discovered. For unaffected relatives who undergo testing and are found not to carry the mutation present in the family, breast cancer risk drops from a high prior probability to a post-test risk comparable to that in the general population. Unaffected relatives in whom a mutation is identified, on the other hand, have a substantially higher cancer risk than that of the general population. In addition, individuals with breast or ovarian cancer in whom a BRCA1/2 mutation is identified are at increased risk of developing a second cancer. For families in which a BRCA1/2 mutation is identified, both positive and negative test results have implications for clinical management, either in the sense of a ‘demedicalization’ or of increased requirements for surveillance, prevention or prophylactic measures. A review of the effectiveness of these interventions did not fall within the purview of this report. Consequently, a balanced view of benefits and risks, and formal recommendations with respect to the use of BRCA1/2 mutation testing, cannot be presented at this time. It is, however, already apparent that the balance of benefits and risks will be heavily dependent on the prior risk assessment and that the knowledge base to derive decisions is stronger for high-risk families than for populations at lower risk. In the subsequent AETMIS report, the forthcoming evidence from other systematic reviews on issues such as the analytical validity of molecular tests, the psychosocial consequences of testing, and the effectiveness of available interventions will be integrated with our further analysis of the economic and organizational issues surrounding cancer genetic services.

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