Assessment of clinical validity of a breast cancer risk model combining genetic and clinical information

Abstract

Background: The Gail model is widely used for the assessment of risk of invasive breast cancer based on recognized clinical risk factors. In recent years, a substantial number of single-nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified. However, it remains unclear how to effectively integrate clinical and genetic risk factors for risk assessment.

Methods: Seven SNPs associated with breast cancer risk were selected from the literature and genotyped in white non-Hispanic women in a nested case-control cohort of 1664 case patients and 1636 control subjects within the Women's Health Initiative Clinical Trial. SNP risk scores were computed based on previously published odds ratios assuming a multiplicative model. Combined risk scores were calculated by multiplying Gail risk estimates by the SNP risk scores. The independence of Gail risk and SNP risk was evaluated by logistic regression. Calibration of relative risks was evaluated using the Hosmer-Lemeshow test. The performance of the combined risk scores was evaluated using receiver operating characteristic curves. The net reclassification improvement (NRI) was used to assess improvement in classification of women into low (<1.5%), intermediate (1.5%-2%), and high (>2%) categories of 5-year risk. All tests of statistical significance were two-sided.

Results: The SNP risk score was nearly independent of Gail risk. There was good agreement between predicted and observed SNP relative risks. In the analysis for receiver operating characteristic curves, the combined risk score was more discriminating, with area under the curve of 0.594 compared with area under the curve of 0.557 for Gail risk alone (P < .001). Classification also improved for 5.6% of case patients and 2.9% of control subjects, showing an NRI value of 0.085 (P = 1.0 × 10⁻⁵). Focusing on women with intermediate Gail risk resulted in an improved NRI of 0.195 (P = 8.6 × 10⁻⁵).

Conclusions: Combining validated common genetic risk factors with clinical risk factors resulted in modest improvement in classification of breast cancer risks in white non-Hispanic postmenopausal women. Classification performance was further improved by focusing on women at intermediate risk.

Figure 1

Observed odds of breast cancer for quintiles of single-nucleotide polymorphism (SNP) risk, stratified by Gail risk quintile (open circles). The overall odds of breast cancer in our study for case patients and control subjects were 1:1 because equal numbers of case patients and control subjects were selected. Quintiles of Gail and SNP risk are labeled 1–5 from lowest to highest risk. The straight lines represent linear least squares fits to the data within each Gail risk stratum. SNP risk was consistently associated with breast cancer odds within the Gail risk strata.

Figure 2

Observed vs expected proportions of case patients, for deciles of risk scores. A) Gail risk. B) The single-nucleotide polymorphism (SNP) risk score. C) The combined Gail × SNP risk score (risk score = open circles). If the risk scores are calibrated, the open circles should fall along the dashed line with a slope of 1.

Figure 3

Receiver operating characteristic curves and area under the curve (AUC) for Gail risk, single-nucleotide polymorphism (SNP) risk, and combined Gail × SNP risk.