Evaluating Breast Cancer Risk With Genome-Wide Association Studies: Is This Approach Patient Ready?
Authors: Jennifer K. Litton, Ana Maria Gonzalez-Angulo
Journal: Journal of Clinical Oncology (2012)

Testing for mutation in BRCA genes is widely used to identify women at high risk for a familial or inherited predisposition to breast cancer. The increased risk of developing breast cancer during a lifetime as a result of a mutation in a BRCA gene is estimated at 45% to 84% and also carries with it a high risk of a second primary breast cancer. Because of these considerably high risks, models such as BRCAPRO (http://bcb.dfci.harvard.edu/bayesmendel/brcapro.php) estimate the likelihood of a mutation, whereas expert panels have established guidelines to assist in identifying persons who should be tested for a BRCA mutation. Interventions such as enhanced breast screening with magnetic resonance imaging, tamoxifen, and prophylactic mastectomy have been evaluated as appropriate, efficacious, and in some cases cost-effective strategies to reduce risk and/or suffering. When a BRCA mutation has not been identified, other risk models have been effective in assessing this risk in women with strong family histories of breast cancer. In contrast to mutation analysis, Genome-Wide Association Studies (GWASs) involve the identification of single-nucleotide polymorphisms (SNPs) in large cohorts of patients, with the goal of discovering variants that may identify or contribute to risk of different traits or diseases. Through this approach, multiple SNPs have been identified with possible risk associations for breast cancer using advanced biostatistics and sound scientific methods. Through the use of GWASs, there is promise of further refining risk models to aid in counseling patients and making risk reduction interventions. However, GWASs of individual SNPs have not yet been able to propel this technology to a clinically meaningful use for patients, even in the setting of high-risk BRCA mutation carriers. Although risk has been identified, often only modest increases have been seen, and the level of increased risk has not yet reached a threshold to rule in or rule out preventative measures in high-risk persons. Therefore, given the polygenic nature of breast cancer, harnessing this technology to find a potential SNP panel that is clinically meaningful is ongoing and important. In the article that accompanies this editorial, Sawyer et al used the Victorian Familial Breast Cancer Cohort to identify persons found to have a high risk of familial breast cancer from 1997 to 2010. Study participants then answered questionnaires and underwent comprehensive BRCA testing. From this cohort, 1,143 women were identified with at least one diagnosis of breast cancer, 142 had a BRCA1 mutation, and 116 had a BRCA2 mutation. On the basis of published studies identifying candidate SNPs that potentially could contribute to risk, 22 SNPs were selected and a polygenic risk score (PRS) was constructed and fit to a normal distribution in appropriate control groups. Sawyer et al found that the PRS was elevated above that of the population control group in women without an identified BRCA mutation, whereas women with a known BRCA mutation had a low PRS compared with population controls. PRS alone was a poor predictor of a BRCA mutation, and although these trends were interesting, they should not replace pedigree analysis and current BRCA testing guidelines. For the group of women who did not have an identified mutation in the BRCA gene, those within the top PRS quartile had an odds ratio (OR) of developing breast cancer before the age of 35 of 1.88 (95% CI, 0.99 to 3.25; P .50), and an OR of developing breast cancer before the age of 30 of 3.37 (95% CI, 1.03 to 10.26; P .03). This increase also held true for a risk of second primary breast cancers (OR, 1.96; 95% CI, 1.09 to 3.52). From this study, several strengths and potential applications could be considered. The cohort that was analyzed was well defined and the statistical analysis was comprehensive. This study factored several important variables into the analysis such as prophylactic mastectomy and salpingo-oophorectomy. Interestingly, the PRS did not show any significance in women with a history of ovarian cancer as well, and an elevation in PRS was not identified as significant in families with a history of ovarian cancer. Likely this is a result of the higher rates of BRCA mutations found in this population. This may further provide evidence that routine oophorectomy in women from families without a detected BRCA mutation but with multiple cases of breast cancer is not indicated for ovarian cancer prevention. Additionally, other important factors should be considered when assessing the implications of this study. The study was conducted in a highly selective Australian population of women who were identified as having a high familial risk of breast cancer, and it is unclear if the SNPs that were identified and the proposed PRS would be translatable to other populations. Other inherited genetic mutations such as p53 may also be considered in those women affected with breast cancer before the age of 30, and this was the group in which the PRS demonstrated a greater than three-fold elevation in risk. Although an interesting association, this PRS was not constructed to replace testing recommendations for BRCA and other hereditary breast cancer syndromes. Sawyer et al have provided a convincing argument that multiple SNPs could be used to begin to better assess breast cancer risk by evaluating associations in this high-risk population. Their study is JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 35 DECEMBER 1