title: Impact of a Panel of 88 Single Nucleotide Polymorphisms on the Risk of Breast Cancer in High-Risk Women: Results From Two Randomized Tamoxifen Prevention Trials.
abstract: Purpose At least 94 common single nucleotide polymorphisms (SNPs) are associated with breast cancer. The extent to which an SNP panel can refine risk in women who receive preventive therapy has not been directly assessed previously. Materials and Methods A risk score on the basis of 88 SNPs (SNP88) was investigated in a nested case-control study of women enrolled in the International Breast Intervention Study (IBIS-I) or the Royal Marsden study. A total of 359 women who developed cancer were matched to 636 controls by age, trial, follow-up time, and treatment arm. Genotyping was done using the OncoArray. Conditional logistic regression and matched concordance indices (mC) were used to measure the performance of SNP88 alone and with other breast cancer risk factors assessed using the Tyrer-Cuzick (TC) model. Results SNP88 was predictive of breast cancer risk overall (interquartile range odds ratio [IQ-OR], 1.37; 95% CI, 1.14 to 1.66; mC, 0.55), but mainly for estrogen receptor-positive disease (IQ-OR, 1.44; 95% CI, 1.16 to 1.79; P for heterogeneity = .10) versus estrogen receptor-negative disease. However, the observed risk of SNP88 was only 46% (95% CI, 19% to 74%) of expected. No significant interaction was observed with treatment arm (placebo IQ-OR, 1.46; 95% CI, 1.13 to 1.87; tamoxifen IQ-OR, 1.25; 95% CI, 0.96 to 1.64; P for heterogeneity = .5). The predictive power was similar to the TC model (IQ-OR, 1.45; 95% CI, 1.21 to 1.73; mC, 0.55), but SNP88 was independent of TC (Spearman rank-order correlation, 0.012; P = .7), and when combined multiplicatively, a substantial improvement was seen (IQ-OR, 1.64; 95% CI, 1.36 to 1.97; mC, 0.60). Conclusion A polygenic risk score may be used to refine risk from the TC or similar models in women who are at an elevated risk of breast cancer and considering preventive therapy. Recalibration may be necessary for accurate risk assessment.
authors.affiliation: Jack Cuzick, Adam R. Brentnall, Caroline Reuter, and Ivana Sestak, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London; Corrinne Segal, The Institute of Cancer Research; Corrinne Segal, Simone Detre, Elena Lopez-Knowles, and Mitchell Dowsett, Royal Marsden Hospital; Trevor J. Powles, Cancer Centre London, London; Helen Byers and William G. Newman, University of Manchester and Central Manchester Foundation Trust; and Anthony Howell, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Jack
authors.initials: J
authors.lastname: Cuzick
authors.affiliation: Jack Cuzick, Adam R. Brentnall, Caroline Reuter, and Ivana Sestak, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London; Corrinne Segal, The Institute of Cancer Research; Corrinne Segal, Simone Detre, Elena Lopez-Knowles, and Mitchell Dowsett, Royal Marsden Hospital; Trevor J. Powles, Cancer Centre London, London; Helen Byers and William G. Newman, University of Manchester and Central Manchester Foundation Trust; and Anthony Howell, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Brentnall
authors.affiliation: Jack Cuzick, Adam R. Brentnall, Caroline Reuter, and Ivana Sestak, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London; Corrinne Segal, The Institute of Cancer Research; Corrinne Segal, Simone Detre, Elena Lopez-Knowles, and Mitchell Dowsett, Royal Marsden Hospital; Trevor J. Powles, Cancer Centre London, London; Helen Byers and William G. Newman, University of Manchester and Central Manchester Foundation Trust; and Anthony Howell, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Corrinne
authors.initials: C
authors.lastname: Segal
authors.affiliation: Jack Cuzick, Adam R. Brentnall, Caroline Reuter, and Ivana Sestak, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London; Corrinne Segal, The Institute of Cancer Research; Corrinne Segal, Simone Detre, Elena Lopez-Knowles, and Mitchell Dowsett, Royal Marsden Hospital; Trevor J. Powles, Cancer Centre London, London; Helen Byers and William G. Newman, University of Manchester and Central Manchester Foundation Trust; and Anthony Howell, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Byers
authors.affiliation: Jack Cuzick, Adam R. Brentnall, Caroline Reuter, and Ivana Sestak, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London; Corrinne Segal, The Institute of Cancer Research; Corrinne Segal, Simone Detre, Elena Lopez-Knowles, and Mitchell Dowsett, Royal Marsden Hospital; Trevor J. Powles, Cancer Centre London, London; Helen Byers and William G. Newman, University of Manchester and Central Manchester Foundation Trust; and Anthony Howell, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Reuter
authors.affiliation: Jack Cuzick, Adam R. Brentnall, Caroline Reuter, and Ivana Sestak, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London; Corrinne Segal, The Institute of Cancer Research; Corrinne Segal, Simone Detre, Elena Lopez-Knowles, and Mitchell Dowsett, Royal Marsden Hospital; Trevor J. Powles, Cancer Centre London, London; Helen Byers and William G. Newman, University of Manchester and Central Manchester Foundation Trust; and Anthony Howell, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Simone
authors.initials: S
authors.lastname: Detre
authors.affiliation: Jack Cuzick, Adam R. Brentnall, Caroline Reuter, and Ivana Sestak, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London; Corrinne Segal, The Institute of Cancer Research; Corrinne Segal, Simone Detre, Elena Lopez-Knowles, and Mitchell Dowsett, Royal Marsden Hospital; Trevor J. Powles, Cancer Centre London, London; Helen Byers and William G. Newman, University of Manchester and Central Manchester Foundation Trust; and Anthony Howell, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Elena
authors.initials: E
authors.lastname: Lopez-Knowles
authors.affiliation: Jack Cuzick, Adam R. Brentnall, Caroline Reuter, and Ivana Sestak, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London; Corrinne Segal, The Institute of Cancer Research; Corrinne Segal, Simone Detre, Elena Lopez-Knowles, and Mitchell Dowsett, Royal Marsden Hospital; Trevor J. Powles, Cancer Centre London, London; Helen Byers and William G. Newman, University of Manchester and Central Manchester Foundation Trust; and Anthony Howell, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Ivana
authors.initials: I
authors.lastname: Sestak
authors.affiliation: Jack Cuzick, Adam R. Brentnall, Caroline Reuter, and Ivana Sestak, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London; Corrinne Segal, The Institute of Cancer Research; Corrinne Segal, Simone Detre, Elena Lopez-Knowles, and Mitchell Dowsett, Royal Marsden Hospital; Trevor J. Powles, Cancer Centre London, London; Helen Byers and William G. Newman, University of Manchester and Central Manchester Foundation Trust; and Anthony Howell, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.affiliation: Jack Cuzick, Adam R. Brentnall, Caroline Reuter, and Ivana Sestak, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London; Corrinne Segal, The Institute of Cancer Research; Corrinne Segal, Simone Detre, Elena Lopez-Knowles, and Mitchell Dowsett, Royal Marsden Hospital; Trevor J. Powles, Cancer Centre London, London; Helen Byers and William G. Newman, University of Manchester and Central Manchester Foundation Trust; and Anthony Howell, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Powles
authors.affiliation: Jack Cuzick, Adam R. Brentnall, Caroline Reuter, and Ivana Sestak, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London; Corrinne Segal, The Institute of Cancer Research; Corrinne Segal, Simone Detre, Elena Lopez-Knowles, and Mitchell Dowsett, Royal Marsden Hospital; Trevor J. Powles, Cancer Centre London, London; Helen Byers and William G. Newman, University of Manchester and Central Manchester Foundation Trust; and Anthony Howell, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Jack Cuzick, Adam R. Brentnall, Caroline Reuter, and Ivana Sestak, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London; Corrinne Segal, The Institute of Cancer Research; Corrinne Segal, Simone Detre, Elena Lopez-Knowles, and Mitchell Dowsett, Royal Marsden Hospital; Trevor J. Powles, Cancer Centre London, London; Helen Byers and William G. Newman, University of Manchester and Central Manchester Foundation Trust; and Anthony Howell, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Dowsett
mesh_terms: D016588:Anticarcinogenic Agents / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D016022:Case-Control Studies; D004965:Estrogen Antagonists / Q000008:administration & dosage; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000008:administration & dosage*
chemical_list: D016588:Anticarcinogenic Agents; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D013629:Tamoxifen