Investigation of Genetic Alterations Associated With Interval Breast Cancer

Area of Science:

• Oncology
• Genetics
• Radiology

Background:

• Interval cancers (ICs) are diagnosed between screenings and have poorer outcomes than screen-detected cancers (SDCs).
• The role of rare germline genetic variants in IC development and prognosis is not well understood.

Purpose of the Study:

• To investigate the association between rare germline deleterious protein-truncating variants (PTVs) and the occurrence of ICs versus SDCs.
• To assess the impact of these PTVs on breast cancer-specific survival.
• To explore the influence of mammographic density on these associations.

Main Methods:

• A population-based genetic association study in Sweden included women aged 40-76 undergoing mammographic screening.
• Germline PTVs in 34 breast cancer susceptibility genes were analyzed using targeted sequencing.
• Logistic and Cox regression models were used to compare ICs with SDCs and analyze survival, respectively.

Main Results:

• PTVs in ATM, BRCA1, BRCA2, CHEK2, and PALB2 were more frequent in ICs than SDCs (OR, 1.48).
• A family history of breast cancer combined with PTVs significantly increased the likelihood of an IC diagnosis (OR, 3.95).
• Carriers of PTVs in these five genes diagnosed with IC had significantly worse 10-year breast cancer-specific survival (HR, 2.04).
• Associations were more pronounced in patients with low mammographic density.

Conclusions:

• Rare germline PTVs in specific genes are associated with interval breast cancers and reduced survival.
• Family history and PTVs synergistically increase IC risk.
• Findings may inform breast cancer screening program optimization and clinical treatment strategies.