Validation of the PRS in the Prospective Test Dataset
The final PRSs were evaluated using data from 11,428 invasive breast cancer-affected case subjects and 18,323 control subjects from ten prospective studies. The ORs for both the overall and subtype-specific PRSs were slightly lower in the prospective test set compared to the validation set (Table 2). The difference between validation and test set may reflect some overfitting due to choosing the optimum p value threshold and for the lasso, the optimum lambda, in the validation set, but could also be due to somewhat different characteristics of the prospective studies. The ORs for overall and ER-positive, but not ER-negative, breast cancer were slightly higher for the 3,820-SNP PRS (PRS3820) compared with PRS313.
The odds ratio (OR) for overall disease per 1 standard deviation (SD) of the PRS313 in the prospective studies was 1.61 (95%CI: 1.57–1.65) while for the 77-SNP PRS (PRS77) derived previously OR = 1.46 (95%CI: 1.42–1.49). For ER-negative disease the difference was OR = 1.45 (95%CI: 1.37–1.53) versus 1.35 (95%CI: 1.27–1.43) (Table 2).
The associations between the PRS and overall, ER-positive, and ER-negative breast cancer by percentiles of the PRS313 are shown in Figure 1 and Table S9. Compared with women in the middle quintile (40th to 60th percentile), those in the highest 1% of risk for the subtype-specific PRS313 had 4.37 (95%CI: 3.59–5.33)- and 2.78 (95%CI: 1.83–4.24)-fold risks, and those in the lowest 1% had 0.16 (95%CI: 0.09–0.30)- and 0.27 (95%CI: 0.09–0.86)-fold risks of developing ER-positive and ER-negative disease, respectively. The ORs by percentile of the PRS3820 were similar (Table S10).
Figure 1 Association between the 313 SNP Polygenic Risk Score and Breast Cancer Risk
Association between the 313 SNP polygenic risk score (PRS) and breast cancer risk in women of European origin for (A) overall breast cancers, (B) estrogen receptor (ER)-positive disease, and (C) ER-negative disease, in the validation (dashed line) and test (solid line) sets. Odds ratios are for different quantiles of the PRS relative to the mean PRS. Odds ratios and 95% confidence intervals are shown.