Investigation of Genetic Alterations Associated With Interval Breast Cancer

Abstract

ImportanceBreast cancers (BCs) diagnosed between 2 screening examinations are called interval cancers (ICs), and they have worse clinicopathological characteristics and poorer prognosis than screen-detected cancers (SDCs). However, the association of rare germline genetic variants with IC have not been studied.ObjectiveTo evaluate whether rare germline deleterious protein-truncating variants (PTVs) can be applied to discriminate between IC and SDC while considering mammographic density.Design, Setting, and ParticipantsThis population-based genetic association study was based on women aged 40 to 76 years who were attending mammographic screening in Sweden. All women with a diagnosis of BC between January 2001 and January 2016 were included, together with age-matched controls. Patients with BC were followed up for survival until 2021. Statistical analysis was performed from September 2021 to December 2022.ExposureGermline PTVs in 34 BC susceptibility genes as analyzed by targeted sequencing.Main Outcomes and MeasuresOdds ratios (ORs) were used to compare IC with SDC using logistic regression. Hazard ratios were used to investigate BC-specific survival using Cox regression.ResultsAll 4121 patients with BC (IC, n = 1229; SDC, n = 2892) were female, with a mean (SD) age of 55.5 (7.1) years. There were 5631 age-matched controls. The PTVs of the ATM, BRCA1, BRCA2, CHEK2, and PALB2 genes were more common in patients with IC compared with SDC (OR, 1.48; 95% CI, 1.06-2.05) and associated with BRCA1/2 and PALB2 variants. A family history of BC together with PTVs of any of these genes synergistically increased the probability of receiving a diagnosis of IC rather than SDC (OR, 3.95; 95% CI, 1.97-7.92). Furthermore, 10-year BC-specific survival revealed that if a patient received a diagnosis of an IC, carriers of PTVs in any of these 5 genes had significantly worse survival compared with patients not carrying any of them (hazard ratio, 2.04; 95% CI, 1.06-3.92). All of these associations were further pronounced in a subset of patients with IC who had a low mammographic density at prior screening examination.Conclusions and RelevanceThe results of this study may be helpful in future optimizations of screening programs that aim to lower mortality as well as the clinical treatment of patients with BC.