Breast cancer genetic risk profile is differentially associated with interval and screen-detected breast cancers.

ABSTRACT This is a report looking into the genetic differences between screen-detected and interval cancers. It is an affirmation that screen-detected and interval cancers may have unique underlying biology. Genetic risk discrimination has potential relevance in clinical care where interval cancers, which are usually rapidly growing and aggressive, do not currently benefit from mammography screening. Background Polygenic risk profiles computed from multiple common susceptibility alleles for breast cancer have been shown to identify women at different levels of breast cancer risk. We evaluated whether this genetic risk stratification can also be applied to discriminate between screen-detected and interval cancers, which are usually associated with clinicopathological and survival differences. Patients and methods A 77 single-nucleotide polymorphism polygenic risk score (PRS) was constructed for breast cancer overall and by estrogen receptor (ER) status. PRS was inspected as a continuous (per standard deviation increment) variable in a case-only design. Modification of the PRS by mammographic density was evaluated by fitting an additional interaction term. Results PRS weighted by breast cancer overall estimates was found to be differentially associated with 1865 screen-detected and 782 interval cancers in the LIBRO-1 study {age-adjusted odds ratio (OR)perSD [95% confidence interval (CI)] 0.91 [0.83–0.99],P = 0.023}. The association was found to be more significant for PRS weighted by ER-positive breast cancer estimates [ORperSD = 0.90 (0.82–0.98),P = 0.011]. This result was corroborated by two independent studies [combined ORperSD = 0.87 (0.76–1.00),P = 0.058] with no evidence of heterogeneity. When enriched for ‘true’ interval cancers among nondense breasts, the difference in the association with PRS in screen-detected and interval cancers became more pronounced [ORperSD = 0.74 (0.62–0.89),P = 0.001], with a significant interaction effect between PRS and mammographic density (Pinteraction = 0.017). Conclusion To our knowledge, this is the first report looking into the genetic differences between screen-detected and interval cancers. It is an affirmation that the two types of breast cancer may have unique underlying biology.

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