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Article

Genomic Risk Prediction for Breast Cancer in Older Women

1
Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia
2
Clinical and Translational Epidemiology Unit, MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02108, USA
3
Alvin J. Siteman Cancer Center, Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO 63110, USA
4
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, VIC 3168, Australia
5
Department of Clinical Pathology, University of Melbourne, Melbourne, VIC 3010, Australia
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Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC 3004, Australia
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Division of Cancer Prevention, National Cancer Institute, Rockville, MD 20892, USA
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Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
9
Personalised Oncology Division, Walter and Eliza Hall Institute Medical Research, Faculty of Medicine, University of Melbourne, Melbourne, VIC 3052, Australia
10
Department of Genomic Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Melbourne, VIC 3050, Australia
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Department of Anatomical Pathology, Alfred Hospital, Melbourne, VIC 3004, Australia
12
Berman Center for Outcomes and Clinical Research, Hennepin Healthcare Research Institute, Hennepin Healthcare, University of Minnesota, Minneapolis, MN 55404, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Antonio Russo
Cancers 2021, 13(14), 3533; https://doi.org/10.3390/cancers13143533
Received: 11 June 2021 / Revised: 8 July 2021 / Accepted: 12 July 2021 / Published: 14 July 2021
(This article belongs to the Special Issue Risk Assessment for Breast Cancer)
We designed a study specifically to assess the performance of genomic risk prediction for breast cancer (BC) in older women aged ≥70 years. We assessed the effects of a polygenic risk score (PRS) for BC and rare pathogenic variants (PVs) in BC susceptibility genes, on incident BC risk in a prospective cohort of 6339 older women (mean age 75 years). During a median follow-up time of 4.7 years, the PRS was an independent predictor of incident BC risk, with women in the top quintile of the PRS distribution having over two-fold higher incident BC risk than women in the lowest quintile. Among 41 carriers of PVs in BC susceptibility genes, we observed no incident BC diagnoses. Our study demonstrates that a PRS still predicts incident BC risk in women aged 70 years and older, suggesting the potential clinical utility of the PRS extends to this older age group.
Genomic risk prediction models for breast cancer (BC) have been predominantly developed with data from women aged 40–69 years. Prospective studies of older women aged ≥70 years have been limited. We assessed the effect of a 313-variant polygenic risk score (PRS) for BC in 6339 older women aged ≥70 years (mean age 75 years) enrolled into the ASPREE trial, a randomized double-blind placebo-controlled clinical trial investigating the effect of daily 100 mg aspirin on disability-free survival. We evaluated incident BC diagnoses over a median follow-up time of 4.7 years. A multivariable Cox regression model including conventional BC risk factors was applied to prospective data, and re-evaluated after adding the PRS. We also assessed the association of rare pathogenic variants (PVs) in BC susceptibility genes (BRCA1/BRCA2/PALB2/CHEK2/ATM). The PRS, as a continuous variable, was an independent predictor of incident BC (hazard ratio (HR) per standard deviation (SD) = 1.4, 95% confidence interval (CI) 1.3–1.6) and hormone receptor (ER/PR)-positive disease (HR = 1.5 (CI 1.2–1.9)). Women in the top quintile of the PRS distribution had over two-fold higher risk of BC than women in the lowest quintile (HR = 2.2 (CI 1.2–3.9)). The concordance index of the model without the PRS was 0.62 (95% CI 0.56–0.68), which improved after addition of the PRS to 0.65 (95% CI 0.59–0.71). Among 41 (0.6%) carriers of PVs in BC susceptibility genes, we observed no incident BC diagnoses. Our study demonstrates that a PRS predicts incident BC risk in women aged 70 years and older, suggesting potential clinical utility extends to this older age group. View Full-Text
Keywords: genomics; breast cancer; risk prediction; polygenic risk score; germline genomics; breast cancer; risk prediction; polygenic risk score; germline
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Figure 1

MDPI and ACS Style

Lacaze, P.; Bakshi, A.; Riaz, M.; Orchard, S.G.; Tiller, J.; Neumann, J.T.; Carr, P.R.; Joshi, A.D.; Cao, Y.; Warner, E.T.; Manning, A.; Nguyen-Dumont, T.; Southey, M.C.; Milne, R.L.; Ford, L.; Sebra, R.; Schadt, E.; Gately, L.; Gibbs, P.; Thompson, B.A.; Macrae, F.A.; James, P.; Winship, I.; McLean, C.; Zalcberg, J.R.; Woods, R.L.; Chan, A.T.; Murray, A.M.; McNeil, J.J. Genomic Risk Prediction for Breast Cancer in Older Women. Cancers 2021, 13, 3533. https://doi.org/10.3390/cancers13143533

AMA Style

Lacaze P, Bakshi A, Riaz M, Orchard SG, Tiller J, Neumann JT, Carr PR, Joshi AD, Cao Y, Warner ET, Manning A, Nguyen-Dumont T, Southey MC, Milne RL, Ford L, Sebra R, Schadt E, Gately L, Gibbs P, Thompson BA, Macrae FA, James P, Winship I, McLean C, Zalcberg JR, Woods RL, Chan AT, Murray AM, McNeil JJ. Genomic Risk Prediction for Breast Cancer in Older Women. Cancers. 2021; 13(14):3533. https://doi.org/10.3390/cancers13143533

Chicago/Turabian Style

Lacaze, Paul, Andrew Bakshi, Moeen Riaz, Suzanne G. Orchard, Jane Tiller, Johannes T. Neumann, Prudence R. Carr, Amit D. Joshi, Yin Cao, Erica T. Warner, Alisa Manning, Tú Nguyen-Dumont, Melissa C. Southey, Roger L. Milne, Leslie Ford, Robert Sebra, Eric Schadt, Lucy Gately, Peter Gibbs, Bryony A. Thompson, Finlay A. Macrae, Paul James, Ingrid Winship, Catriona McLean, John R. Zalcberg, Robyn L. Woods, Andrew T. Chan, Anne M. Murray, and John J. McNeil 2021. "Genomic Risk Prediction for Breast Cancer in Older Women" Cancers 13, no. 14: 3533. https://doi.org/10.3390/cancers13143533

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