Outcomes of retesting in patients with previously uninformative cancer genetics evaluations

Advances in cancer genetics have increased germline pathogenic/likely pathogenic variant (PV/LPV) detection rates. More data is needed to inform which patients with previously uninformative results could benefit most from retesting, especially beyond breast/ovarian cancer populations. Here, we describe retesting outcomes and predictors of PV/LPVs in a cohort of patients unselected by cancer diagnosis. Retrospective chart reviews were conducted for patients at a cancer genetics clinic between 1998 and 2019 who underwent genetic testing (GT) on ≥ 2 dates with ≥ 1 year between tests, with no PV/LPVs on first-line GT. Demographics, retesting indications, and GT details were reviewed to evaluate predictive factors of PV/LPV identification. 139 patients underwent retesting, of whom 24 (17.3%) had a PV/LPV, encompassing 15 genes. 14 PV/LPV carriers (58.3%) only returned for retesting after personal or familial history changes (typically new cancer diagnoses), while 10 (41.7%) retested due to updated GT availability. No specific GT method was most likely to identify PV/LPVs and no specific clinical factors were predictive of a PV/LPV. The identified PV/LPVs were consistent with patients' personal or family histories, but were discordant with the initial referral indication for GT. For 16 (66.7%) PV/LPV carriers, the genetic diagnosis changed clinical management. This study adds to the limited body of literature on retesting outcomes beyond first-line BRCA analysis alone and confirms the utility of multigene panel testing. Retesting certain affected individuals when updated GT is available could result in earlier PV/LPV identification, significantly impacting screening recommendations and potentially reducing cancer-related morbidity and mortality.