The Role of Genome Sequencing in Personalized Breast Cancer Prevention

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 to that of a “best-case” strategy based on a risk distribution estimated from breast cancer concordance in monozygous twins, and to 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 to 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. Impact These results support the feasibility of using genome-wide sequencing to target the women who would benefit from mammography screening.

Primary care providers’ cancer genetic testing-related knowledge, attitudes, and communication behaviors: A systematic review and research agenda

“…[13][14][15][16] For example, estimating an individual's cancer risk based on genetic markers and traditional risk factors may lead to a more refined use of currently recommended screening tests (e.g., mammography). 17,18 Information derived from genetic testing could also shift the balance of harms and benefits for some individuals such that screening tests like the PSA test, which is not recommended for the general population, may have utility in those with greatest genetic risk for prostate cancer. [19][20][21] Those at higher genetic risk may also be candidates for more sensitive screening approaches (e.g., breast MRI).…”

Information Topics of Greatest Interest for Return of Genome Sequencing Results among Women Diagnosed with Breast Cancer at a Young Age

“…Breast cancer patients who carry inherited germline mutations contributing to breast cancer risk, such as BRCA1 or BRCA2 , are at increased risk for a second primary breast cancer and other cancers (Mavaddat et al 2013); patients who are diagnosed at age 40 or younger are more likely to carry such gene mutations (Anders et al 2008; Bonadona et al 2005; Golshan et al 2006). For carriers of BRCA1 or BRCA2 , genome sequencing can be beneficial for surveillance and surgical decisions (Heemskerk-Gerritsen et al 2015; Ingham et al 2013; Riedl et al 2014; Sieh et al 2014; Trujillano et al 2015). Moreover, even for BRCA1 or BRCA2 -negative patients, genome sequencing may be beneficial in identifying other genes, such as PALB2 , CHEK2 , and ATM , that may confer an increased risk of familial breast cancer (Cybulski et al 2011; Desmond et al 2015; Janatova et al 2013; Renwick et al 2006).…”

How, who, and when: preferences for delivery of genome sequencing results among women diagnosed with breast cancer at a young age

“…Among younger women, breast cancer tends to present at a later stage, be more aggressive, and have a poorer prognosis (Anders et al 2008;Assi et al 2013). For carriers of known deleterious mutations in cancer susceptibility genes (e.g., BRCA1/2), genome sequencing can be beneficial to surveillance and surgical decisions (Ingham et al 2013;Riedl et al 2014;Sieh et al 2014;Heemskerk-Gerritsen et al 2015;Trujillano et al 2015). Sequencing might also be used to identify and choose targeted therapeutic agents for some cancer patients (Ellis et al 2012;Meiser et al 2012;Yauch and Settleman 2012;Zardavas et al 2013).…”