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Breast cancer polygenic risk scores are associated with short-term risk of poor prognosis breast cancer

  • Epidemiology
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Polygenic risk scores (PRS) for breast cancer may help guide screening decisions. However, few studies have examined whether PRS are associated with risk of short-term or poor prognosis breast cancers. The study purpose was to evaluate the association of the 313 SNP breast cancer PRS with 2-year risk of poor prognosis breast cancer.


We evaluated the association of breast cancer PRS with breast cancer overall, ER + and ER- breast cancer, and poor prognosis breast cancer diagnosed within 2 years of a negative mammogram among a cohort of 3657 women using logistic regression adjusted for age, breast density, race/ethnicity, year of screening, and genetic ancestry principal components. Breast cancers were considered poor prognosis if they were metastatic, positive lymph nodes, ER/PR + HER2− and > 2 cm, ER/PR/HER2−, or HER2 + and > 1 cm.


Of the 308 breast cancers, 137 (44%) were poor prognosis. The overall breast cancer PRS was significantly associated with breast cancer diagnosis within 2 years (OR 1.39, 95% CI 1.23–1.57, p < 0.001). The breast cancer PRS was also associated specifically with diagnosis of poor prognosis disease (OR 1.24, 95% CI 1.03–1.49, p = 0.018), but was more strongly associated with good prognosis cancer (OR 1.52 95% CI 1.29–1.80 p = 3.60 × 10–7) The ER + PRS was significantly associated with ER/PR + breast cancer (OR 1.41, 95% CI 1.24–1.61, p < 0.001) and the ER− PRS was significantly associated with ER− breast cancer (OR 1.48, 95% CI 1.08–2.02, p = 0.015).


Breast cancer PRS was independently and significantly associated with diagnosis of both breast cancer overall and poor prognosis breast cancer within 2 years of a negative mammogram, suggesting PRS may help guide decisions about screening intervals and supplemental screening.

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Data availability

The datasets generated during and/or analyzed during the current study are not publicly available due to patient privacy protections, but de-identified data are available from the corresponding author on reasonable request and with institutional approval.


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This work was supported by the Susan G. Komen Foundation (PI McCarthy CCR17480662).

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Correspondence to Anne Marie McCarthy.

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Dr. Lehman reports that her institution, Massachusetts General Hospital, receives research support from GE Healthcare and Hologic, Inc. and that she is a co-founder and serves as a consultant to Clairity, Inc. The other authors report no conflicts of interest.

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See Tables 5, 6, 7, 8, and 9.

Table 5 Recruitment of breast cancer cases for DNA analysis
Table 6 Comparison of full cohort and analytic sample by case status
Table 7 Sensitivity analyses: logistic regression of PRS and cancer diagnosis within 2 years of a negative mammogram, overall, by prognosis, and by ER status among women aged 40–74
Table 8 Comparison of models additionally adjusted for body mass index (BMI) as a continuous or categorical variable
Table 9 Comparison of models adjusting for race/ethnicity and PCs

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McCarthy, A.M., Manning, A.K., Hsu, S. et al. Breast cancer polygenic risk scores are associated with short-term risk of poor prognosis breast cancer. Breast Cancer Res Treat 196, 389–398 (2022).

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