Authors' objectives:

This report aims to review the contribution of BRCA1/2 mutation testing to risk assessment for susceptibility to breast and ovarian cancer

Authors' recommendations: 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 healthcare 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.

Authors' methods: Review

Project Status: Completed

URL for project: http://www.aetmis.gouv.qc.ca/

Year Published: 2006

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: Canada

Organisation Name: Agence d'évaluation des technologies et des modes d'intervention en santé

Contact Address: 2021, avenue Union, Bureau 10.083,Montreal, Quebec H3A S29, Canada.Tel: +1 514 873 2563; Fax: +1 514 873 1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: Agence d'Evaluation des Technologies et des Modes d'Intervention en Sante (AETMIS)