Clinical Utility of Genomic Sequencing for Hereditary Cancer Syndromes: An Observational Cohort Study

Genomic sequencing (GS) is increasingly used to improve diagnoses and inform targeted therapies. GS can also be used to identify the 10% of cancer patients with an underlying hereditary cancer syndrome (HCS), who can benefit from surveillance and preventive surgery that reduce morbidity/mortality. However, the evidence on clinical utility of GS for HCS is limited: we aimed to fill this gap by assessing yield of all cancer results and associated recommendations for patients undergoing GS for HCS.

An observational chart review and survey were conducted for cancer patients with previous uninformative cancer gene panel results, who received GS as part of the Incidental Genomics Trial (ClinicalTrials.gov identifier: NCT03597165). Descriptive statistics were used to describe demographics and clinical history. Proportions were calculated to compare frequencies of result types and recommendations made and followed.

A total of 276 patients were eligible and included. Participants were mostly female (n = 240), European (n = 158), and with breast cancer history (n = 168). Yield: 25 patients (9.1%) received ≥1 pathogenic/likely pathogenic variant, 246 (89%) received ≥1 variant of uncertain significance (VUS), and 27 (10%) were negative. Most pathogenic variants (20/26) were in low/moderate cancer risk genes. The mean number of VUS was 2.7/patient and higher in non-Europeans versus Europeans (3.5 v 2.5, P < .05). Recommendations: Pathogenic variants triggered 100 recommendations in 21/25 patients; most were for genetic counseling, communication to relatives, and cascade testing.

GS provided a modest increase in utility after first-tier cancer gene panels, at the cost of a high frequency of uncertain results. Furthermore, most positives were low/moderate cancer risk results that did not have corresponding evidence-based, management guidelines.