Abstract B08: Predictors of delay to single-site confirmatory testing for familial BRCA1/2 mutations
Authors: Hall Michael J. , Rainey Kim , Davis Allison , Handorf Elizabeth , Kaldate Rajesh , Moyes Kelsey , Daly Mary B. 
Published: May 2019

Abstract
Background: Genetic testing for cancer predisposition genes like BRCA1/2 allows the quantification of future cancer risks and the adoption of preventive measures such as chemoprevention, screening, and prophylactic surgeries to mitigate risks. First-in-family mutations in BRCA1/2 are generally identified in a proband via full-sequence analysis. Once a familial mutation is identified, probands may share test information with family members to alert them of risks. Family members may then pursue single-site testing (SST) to determine if the familial mutation was inherited. Despite the high cancer risks associated with BRCA1/2 mutations, research suggests many family members remain untested or experience delays to confirmatory SST. Few studies have characterized the diverse factors influencing transmission of risk information and uptake of SST within families.
Methods: Probands undergoing full-sequence BRACAnalysis by Myriad Genetic Laboratories (MGL) who were found to have unique mutations in BRCA1/2 were randomly selected across 6 years (~50 per year, 2007-2012) from the MGL BRCA1/2 database. In the same time frame, putative “relatives” were identified by linking the proband unique mutation to all downstream requests for SST at the same site. Clinical characteristics for probands and putative relatives were extracted from the MGL Test Request Form (TRF). Pedigrees were independently constructed by two members of the research team for each family based on personal/family history data. Disputed family structures were resolved through group consensus after input from a third member of the research team.
Results: Linked data for 298 probands and 701 linked relatives undergoing SST were included in analyses. Overall ≥1 relative was tested in 265/298 (89%) families. Probands were primarily women (97%) of Western/Northern European ancestry (56%). Proband mean age of testing was 49.6 years [range 22-87], and over 90% had a personal history of cancer: [breast (73%) or ovarian (12%), multiple cancers (22%)]. A median 2 relatives were tested per proband [range 0-13]. Median number of days between proband and first relative tested was 75 (2.5 mos). Median time until first test decreased by an average of 11 days per year from 2007-2012 (p=0.01) and there was a trend toward increased SST testing in year one (39% families had ≥1 SST in the first year of follow-up in 2007 vs 78% in 2012, p=0.001). Siblings (n=275/701, 39%) were overall the most frequently tested relative followed by children (22%), parents (11%) and cousins (11%), while delay was shortest for parents (mean 136 days) and longest for cousins (mean 460 days). Univariate analyses found that relationship to proband (p&lt;0.0001), sex (p=0.05), and age (p=0.01) were associated with SST delay. A linear multivariable model found, compared to siblings, parents had significantly shorter times to testing (p&lt;0.001) and cousins (p=0.02) and nieces/nephews (p&lt;0.001) significantly longer. Male sex was associated with longer delay (p=0.03), and a personal history of ovarian cancer (compared to breast) with a shorter delay (p=0.005).
Conclusion: Uptake of SST in BRCA1/2 families peaks in year 1 but occurs over many years and primarily among first-degree relatives. Testing delays have decreased over time (2007-2012) and may indicate more frequent sharing of high risk information in families, greater access (e.g. insurance, geographic) to BRCA1/2 SST for relatives, and/or greater awareness of the options for risk reduction once BRCA1/2 status is determined. Over an observation period ≥1 and ≤5 years, a striking 11% of positive BRCA1/2 tests were not followed by a SST.
Citation Format: Michael J. Hall, Kim Rainey, Allison Davis, Elizabeth Handorf, Rajesh Kaldate, Kelsey Moyes, Mary B. Daly. Predictors of delay to single-site confirmatory testing for familial BRCA1/2 mutations. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B08.