Abstract
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-SNP 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 1,865 screen-detected and 782 interval cancers in the LIBRO-1 study (age-adjusted
ORperSD [95% confidence interval]=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 screendetected
and interval cancers. It is an affirmation that the two types of breast cancer may have
unique underlying biology.
