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.
View/ Open
Date
2017-03-01ICR Author
Author
Cuzick, J
Brentnall, AR
Segal, C
Byers, H
Reuter, C
Detre, S
Lopez-Knowles, E
Sestak, I
Howell, A
Powles, TJ
Newman, WG
Dowsett, M
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Humans
Breast Neoplasms
Genetic Predisposition to Disease
Tamoxifen
Estrogen Antagonists
Receptors, Estrogen
Anticarcinogenic Agents
Case-Control Studies
Polymorphism, Single Nucleotide
Middle Aged
Female
Research team
Endocrinology
Language
eng
Date accepted
2016-11-23
License start date
2017-03
Citation
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2017, 35 (7), pp. 743 - 750
Publisher
LIPPINCOTT WILLIAMS & WILKINS