The Role of Genome Sequencing in Personalized Breast Cancer Prevention

+Author Affiliations

Stanford University School of Medicine, Department of Health Research and Policy, Stanford, California.

↵*Corresponding Author:
Alice S. Whittemore, Department of Health Research and Policy, Stanford University School of Medicine, Redwood Building, Room T204, Stanford, CA 94305-5405. Phone: 650-723-5460; Fax: 650-725-6951; E-mail: alicesw@stanford.edu

Abstract

Background: There is uncertainty about the benefits of using genome-wide sequencing to implement personalized preventive strategies at the population level, with some projections suggesting little benefit. We used data for all currently known breast cancer susceptibility variants to assess the benefits and harms of targeting preventive efforts to a population subgroup at highest genomic risk of breast cancer.

Methods: We used the allele frequencies and effect sizes of 86 known breast cancer variants to estimate the population distribution of breast cancer risks and evaluate the strategy of targeting preventive efforts to those at highest risk. We compared the efficacy of this strategy with that of a “best-case” strategy based on a risk distribution estimated from breast cancer concordance in monozygous twins, and with strategies based on previously estimated risk distributions.

Results: Targeting those in the top 25% of the risk distribution would include approximately half of all future breast cancer cases, compared with 70% captured by the best-case strategy and 35% based on previously known variants. In addition, current evidence suggests that reducing exposure to modifiable nongenetic risk factors will have greatest benefit for those at highest genetic risk.

Conclusions: These estimates suggest that personalized breast cancer preventive strategies based on genome sequencing will bring greater gains in disease prevention than previously projected. Moreover, these gains will increase with increased understanding of the genetic etiology of breast cancer.