Building the What Comes Next Cohort for and testing: a descriptive analysis.

Background: Our understanding of how testing for and mutations of the and genes affect cancer risk and the use of risk-reduction strategies comes largely from studies of women recruited from specialized genetics clinics. Our aim was to assemble a generalizable cohort of women who underwent testing (the What Comes Next Cohort), irrespective of test result, to enable study of health care utilization and outcomes after testing.

Methods: This descriptive study included adult women (≥ 18 yr) who met at least 1 of 13 provincial criteria for / testing and who underwent genetic testing at sites in Ontario, Canada, from 2007 to 2016. Most of the women were tested at 1 of 2 main sites, which together capture about 70% of all testing in the province. We collected detailed demographic, genetic testing and family history data through chart review for linkage with data from administrative health databases providing information on cancer history before and after testing. We followed all women to September 2019, evaluating the demographic characteristics of the cohort, indications for testing and test results.

Results: We identified 15 986 women (mean age 52.5 [standard deviation 13.9] yr) who underwent / testing. Of these, 2033 women had positive results, 1175 women had variants of uncertain significance, and 12 778 women had negative results. Positive yields were 41.0% (955/2329) for predictive testing (for familial variants), 10.4% (216/2072) for Ashkenazi Jewish founder testing and 7.4% (862/11 585) for complete gene analysis. Six of the 13 provincial testing criteria had less than 10% positive yield. Among 403 women who tested negative for Ashkenazi Jewish founder mutations and subsequently underwent complete gene analysis, 12 (3.0%) tested positive for alternate pathogenic or likely pathogenic variants in the or gene.

Interpretation: Several provincial eligibility criteria for testing led to positive results in less than 10% of cases. How testing influences women's health care behaviours, particularly those with negative results and those found to carry variants of uncertain significance, is unknown; the What Comes Next Cohort will be instrumental in the study of long-term implications of testing.