Research Article: Addition of a polygenic risk score, mammographic density, and endogenous hormones to existing breast cancer risk prediction models: A nested case–control study

Date Published: September 4, 2018

Publisher: Public Library of Science

Author(s): Xuehong Zhang, Megan Rice, Shelley S. Tworoger, Bernard A. Rosner, A. Heather Eliassen, Rulla M. Tamimi, Amit D. Joshi, Sara Lindstrom, Jing Qian, Graham A. Colditz, Walter C. Willett, Peter Kraft, Susan E. Hankinson, Wei Zheng

Abstract: BackgroundNo prior study to our knowledge has examined the joint contribution of a polygenic risk score (PRS), mammographic density (MD), and postmenopausal endogenous hormone levels—all well-confirmed risk factors for invasive breast cancer—to existing breast cancer risk prediction models.Methods and findingsWe conducted a nested case–control study within the prospective Nurses’ Health Study and Nurses’ Health Study II including 4,006 cases and 7,874 controls ages 34–70 years up to 1 June 2010. We added a breast cancer PRS using 67 single nucleotide polymorphisms, MD, and circulating testosterone, estrone sulfate, and prolactin levels to existing risk models. We calculated area under the curve (AUC), controlling for age and stratified by menopausal status, for the 5-year absolute risk of invasive breast cancer. We estimated the population distribution of 5-year predicted risks for models with and without biomarkers. For the Gail model, the AUC improved (p-values < 0.001) from 55.9 to 64.1 (8.2 units) in premenopausal women (Gail + PRS + MD), from 55.5 to 66.0 (10.5 units) in postmenopausal women not using hormone therapy (HT) (Gail + PRS + MD + all hormones), and from 58.0 to 64.9 (6.9 units) in postmenopausal women using HT (Gail + PRS + MD + prolactin). For the Rosner–Colditz model, the corresponding AUCs improved (p-values < 0.001) by 5.7, 6.2, and 6.5 units. For estrogen-receptor-positive tumors, among postmenopausal women not using HT, the AUCs improved (p-values < 0.001) by 14.3 units for the Gail model and 7.3 units for the Rosner–Colditz model. Additionally, the percentage of 50-year-old women predicted to be at more than twice 5-year average risk (≥2.27%) was 0.2% for the Gail model alone and 6.6% for the Gail + PRS + MD + all hormones model. Limitations of our study included the limited racial/ethnic diversity of our cohort, and that general population exposure distributions were unavailable for some risk factors.ConclusionsIn this study, the addition of PRS, MD, and endogenous hormones substantially improved existing breast cancer risk prediction models. Further studies will be needed to confirm these findings and to determine whether improved risk prediction models have practical value in identifying women at higher risk who would most benefit from chemoprevention, screening, and other risk-reducing strategies.

Partial Text: Breast cancer is the most commonly diagnosed cancer in women. Risk prediction models have been developed to estimate an individual woman’s breast cancer risk, and have been used to both set clinical trial entry criteria [1] and provide tailored recommendations for screening, chemoprevention, and other risk-reducing strategies. Among such models, the Gail and Rosner–Colditz models have been well validated and have been used to identify high-risk women [2–4]. The original Gail model includes 5 confirmed risk factors (e.g., family history of breast cancer and reproductive factors) [3]; the Rosner–Colditz model includes the same factors plus additional established breast cancer risk factors such as BMI, alcohol intake, and postmenopausal hormone therapy (HT) use [5]. Both models are well calibrated in white populations, although their discriminatory ability is relatively modest [6,7]. Neither model includes biological markers of risk.

Compared with controls, cases were more likely to have benign breast disease, have breast cancer family history, and consume alcohol. Also, the PRS, MD, and circulating hormone levels were higher among cases than controls (Tables 1 and S3 for individuals included in the Gail and Rosner–Colditz models, respectively).

To our knowledge, this is the first study to examine the added value of incorporating multiple biomarkers, including PRS, MD, and endogenous hormones, into the Gail and Rosner–Colditz models. Although these factors individually and together improved risk prediction for both invasive and ER+ breast cancer, the model improved the most among postmenopausal women not using HT, where each of the biomarkers significantly predicted risk.



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