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1.  Potential Usefulness of Single Nucleotide Polymorphisms to Identify Persons at High Cancer Risk: An Evaluation of Seven Common Cancers 
Journal of Clinical Oncology  2012;30(17):2157-2162.
Purpose
To estimate the likely number and predictive strength of cancer-associated single nucleotide polymorphisms (SNPs) that are yet to be discovered for seven common cancers.
Methods
From the statistical power of published genome-wide association studies, we estimated the number of undetected susceptibility loci and the distribution of effect sizes for all cancers. Assuming a log-normal model for risks and multiplicative relative risks for SNPs, family history (FH), and known risk factors, we estimated the area under the receiver operating characteristic curve (AUC) and the proportion of patients with risks above risk thresholds for screening. From additional prevalence data, we estimated the positive predictive value and the ratio of non–patient cases to patient cases (false-positive ratio) for various risk thresholds.
Results
Age-specific discriminatory accuracy (AUC) for models including FH and foreseeable SNPs ranged from 0.575 for ovarian cancer to 0.694 for prostate cancer. The proportions of patients in the highest decile of population risk ranged from 16.2% for ovarian cancer to 29.4% for prostate cancer. The corresponding false-positive ratios were 241 for colorectal cancer, 610 for ovarian cancer, and 138 or 280 for breast cancer in women age 50 to 54 or 40 to 44 years, respectively.
Conclusion
Foreseeable common SNP discoveries may not permit identification of small subsets of patients that contain most cancers. Usefulness of screening could be diminished by many false positives. Additional strong risk factors are needed to improve risk discrimination.
doi:10.1200/JCO.2011.40.1943
PMCID: PMC3397697  PMID: 22585702
2.  Discriminatory Accuracy from Single-Nucleotide Polymorphisms in Models to Predict Breast Cancer Risk 
One purpose for seeking common alleles that are associated with disease is to use them to improve models for projecting individualized disease risk. Two genome-wide association studies and a study of candidate genes recently identified seven common single-nucleotide polymorphisms (SNPs) that were associated with breast cancer risk in independent samples. These seven SNPs were located in FGFR2, TNRC9, MAP3K1, LSP1, CASP8, chromosomal region 8q, and chromosomal region 2q35. I used estimates of relative risks and allele frequencies from these studies to estimate how much these SNPs could improve discriminatory accuracy measured as the area under the receiver operating characteristic curve (AUC). A model with these seven SNPs (AUC = 0.574) and a hypothetical model with 14 such SNPs (AUC = 0.604) have less discriminatory accuracy than a model, the National Cancer Institute's Breast Cancer Risk Assessment Tool (BCRAT), which is based on ages at menarche and at first live birth, family history of breast cancer, and history of breast biopsy examinations (AUC = 0.607). Adding the seven SNPs to BCRAT improved discriminatory accuracy to an AUC of 0.632, which was, however, less than the improvement from adding mammographic density. Thus, these seven common alleles provide less discriminatory accuracy than BCRAT but have the potential to improve the discriminatory accuracy of BCRAT modestly. Experience to date and quantitative arguments indicate that a huge increase in the numbers of case patients with breast cancer and control subjects would be required in genome-wide association studies to find enough SNPs to achieve high discriminatory accuracy.
doi:10.1093/jnci/djn180
PMCID: PMC2528005  PMID: 18612136
3.  Discriminatory Accuracy From Single-Nucleotide Polymorphisms in Models to Predict Breast Cancer Risk 
One purpose for seeking common alleles that are associated with disease is to use them to improve models for projecting individualized disease risk. Two genome-wide association studies and a study of candidate genes recently identified seven common single-nucleotide polymorphisms (SNPs) that were associated with breast cancer risk in independent samples. These seven SNPs were located in FGFR2, TNRC9 (now known as TOX3), MAP3K1, LSP1, CASP8, chromosomal region 8q, and chromosomal region 2q35. I used estimates of relative risks and allele frequencies from these studies to estimate how much these SNPs could improve discriminatory accuracy measured as the area under the receiver operating characteristic curve (AUC). A model with these seven SNPs (AUC = 0.574) and a hypothetical model with 14 such SNPs (AUC = 0.604) have less discriminatory accuracy than a model, the National Cancer Institute’s Breast Cancer Risk Assessment Tool (BCRAT), that is based on ages at menarche and at first live birth, family history of breast cancer, and history of breast biopsy examinations (AUC = 0.607). Adding the seven SNPs to BCRAT improved discriminatory accuracy to an AUC of 0.632, which was, however, less than the improvement from adding mammographic density. Thus, these seven common alleles provide less discriminatory accuracy than BCRAT but have the potential to improve the discriminatory accuracy of BCRAT modestly. Experience to date and quantitative arguments indicate that a huge increase in the numbers of case patients with breast cancer and control subjects would be required in genome-wide association studies to find enough SNPs to achieve high discriminatory accuracy.
doi:10.1093/jnci/djn180
PMCID: PMC2528005  PMID: 18612136
4.  Discriminatory accuracy and potential clinical utility of genomic profiling for breast cancer risk in BRCA-negative women 
Several single nucleotide polymorphisms (SNPs) are associated with an increased risk of breast cancer. The clinical utility of genotyping individuals at these loci is not known. Subjects were 519 unaffected women without BRCA mutations. Gail, Claus, and IBIS models were used to estimate absolute breast cancer risks. Subjects were then genotyped at 15 independent risk loci. Published per-allele and genotype-specific odds ratios were used to calculate the composite cumulative genomic risk (CGR) for each subject. Affected age- and ethnicity-matched BRCA mutation-negative women were also genotyped as a comparison group for the calculation of discriminatory accuracy. The CGR was used to adjust absolute breast cancer risks calculated by Gail, Claus and IBIS models to determine the proportion of subjects whose recommendations for chemoprevention or MRI screening might be altered (reclassified) by such adjustment. Mean lifetime breast cancer risks calculated using the Gail, Claus, and IBIS models were 19.4, 13.0, and 17.7%, respectively. CGR did not correlate with breast cancer risk as calculated using any model. CGR was significantly higher in affected women (mean 3.35 vs. 3.12, P = 0.009). The discriminatory accuracy of the CGR alone was 0.55 (SE 0.019; P = 0.006). CGR adjustment of model-derived absolute risk estimates would have altered clinical recommendations for chemoprevention in 11–19% of subjects and for MRI screening in 8–32%. CGR has limited discriminatory accuracy. However, the use of a genomic risk term to adjust model-derived estimates has the potential to alter individual recommendations. These observations warrant investigation to evaluate the calibration of adjusted risk estimates.
doi:10.1007/s10549-010-1215-2
PMCID: PMC3310430  PMID: 20957429
Breast cancer risk; Single nucleotide polymorphism; Risk prediction model
5.  Evaluation of breast cancer risk assessment packages in the family history evaluation and screening programme 
Journal of Medical Genetics  2003;40(11):807-814.
Introduction: Accurate individualised breast cancer risk assessment is essential to provide risk–benefit analysis prior to initiating interventions designed to lower breast cancer risk. Several mathematical models for the estimation of individual breast cancer risk have been proposed. However, no single model integrates family history, hormonal factors, and benign breast disease in a comprehensive fashion. A new model by Tyrer and Cuzick has addressed these deficiencies. Therefore, this study has assessed the goodness of fit and discriminatory value of the Tyrer–Cuzick model against established models namely Gail, Claus, and Ford.
Methods: The goodness of fit and discriminatory accuracy of the models was assessed using data from 1933 women attending the Family History Evaluation and Screening Programme, of whom 52 developed cancer. All models were applied to these women over a mean follow up of 5.27 years to estimate risk of breast cancer.
Results: The ratios (95% confidence intervals) of expected to observed numbers of breast cancers were 0.48 (0.37 to 0.64) for Gail, 0.56 (0.43 to 0.75) for Claus, 0.49 (0.37 to 0.65) for Ford, and 0.81 (0.62 to 1.08) for Tyrer–Cuzick. The accuracy of the models for individual cases was evaluated using ROC curves. These showed that the area under the curve was 0.735 for Gail, 0.716 for Claus, 0.737 for Ford, and 0.762 for Tyrer–Cuzick.
Conclusion: The Tyrer–Cuzick model is the most consistently accurate model for prediction of breast cancer. The Gail, Claus, and Ford models all significantly underestimate risk, although the accuracy of the Claus model may be improved by adjustments for other risk factors.
doi:10.1136/jmg.40.11.807
PMCID: PMC1735317  PMID: 14627668
6.  Mammographic density, breast cancer risk and risk prediction 
In this review, we examine the evidence for mammographic density as an independent risk factor for breast cancer, describe the risk prediction models that have incorporated density, and discuss the current and future implications of using mammographic density in clinical practice. Mammographic density is a consistent and strong risk factor for breast cancer in several populations and across age at mammogram. Recently, this risk factor has been added to existing breast cancer risk prediction models, increasing the discriminatory accuracy with its inclusion, albeit slightly. With validation, these models may replace the existing Gail model for clinical risk assessment. However, absolute risk estimates resulting from these improved models are still limited in their ability to characterize an individual's probability of developing cancer. Promising new measures of mammographic density, including volumetric density, which can be standardized using full-field digital mammography, will likely result in a stronger risk factor and improve accuracy of risk prediction models.
doi:10.1186/bcr1829
PMCID: PMC2246184  PMID: 18190724
7.  Prevention of Breast Cancer in Postmenopausal Women: Approaches to Estimating and Reducing Risk 
Background
It is uncertain whether evidence supports routinely estimating a postmenopausal woman's risk of breast cancer and intervening to reduce risk.
Methods
We systematically reviewed prospective studies about models and sex hormone levels to assess breast cancer risk and used meta-analysis with random effects models to summarize the predictive accuracy of breast density. We also reviewed prospective studies of the effects of exercise, weight management, healthy diet, moderate alcohol consumption, and fruit and vegetable intake on breast cancer risk, and used random effects models for a meta-analyses of tamoxifen and raloxifene for primary prevention of breast cancer. All studies reviewed were published before June 2008, and all statistical tests were two-sided.
Results
Risk models that are based on demographic characteristics and medical history had modest discriminatory accuracy for estimating breast cancer risk (c-statistics range = 0.58–0.63). Breast density was strongly associated with breast cancer (relative risk [RR] = 4.03, 95% confidence interval [CI] = 3.10 to 5.26, for Breast Imaging Reporting and Data System category IV vs category I; RR = 4.20, 95% CI = 3.61 to 4.89, for >75% vs <5% of dense area), and adding breast density to models improved discriminatory accuracy (c-statistics range = 0.63–0.66). Estradiol was also associated with breast cancer (RR range = 2.0–2.9, comparing the highest vs lowest quintile of estradiol, P < .01). Most studies found that exercise, weight reduction, low-fat diet, and reduced alcohol intake were associated with a decreased risk of breast cancer. Tamoxifen and raloxifene reduced the risk of estrogen receptor–positive invasive breast cancer and invasive breast cancer overall.
Conclusions
Evidence from this study supports screening for breast cancer risk in all postmenopausal women by use of risk factors and breast density and considering chemoprevention for those found to be at high risk. Several lifestyle changes with the potential to prevent breast cancer should be recommended regardless of risk.
doi:10.1093/jnci/djp018
PMCID: PMC2720698  PMID: 19276457
8.  Prediction of breast cancer risk by genetic risk factors, overall and by hormone receptor status 
Journal of medical genetics  2012;49(9):601-608.
Objective
There is increasing interest in adding common genetic variants identified through genome wide association studies (GWAS) to breast cancer risk prediction models. First results from such models showed modest benefits in terms of risk discrimination. Heterogeneity of breast cancer as defined by hormone-receptor status has not been considered in this context. In this study we investigated the predictive capacity of 32 GWAS-detected common variants for breast cancer risk, alone and in combination with classical risk factors, and for tumors with different hormone receptor status.
Material and Methods
Within the Breast and Prostate Cancer Cohort Consortium (BPC3), we analyzed 6009 invasive breast cancer cases and 7827 matched controls of European ancestry, with data on classical breast cancer risk factors and 32 common gene variants identified through GWAS. Discriminatory ability with respect to breast cancer of specific hormone receptor-status was assessed with the age- and cohort-adjusted concordance statistic (AUROCa). Absolute risk scores were calculated with external reference data. Integrated discrimination improvement (IDI) was used to measure improvements in risk prediction.
Results
We found a small but steady increase in discriminatory ability with increasing numbers of genetic variants included in the model (difference in AUROCa going from 2.7 to 4%). Discriminatory ability for all models varied strongly by hormone receptor status
Discussion and Conclusion
Adding information on common polymorphisms provides small but statistically significant improvements in the quality of breast cancer risk prediction models. We consistently observed better performance for receptor positive cases, but the gain in discriminatory quality is not sufficient for clinical application.
doi:10.1136/jmedgenet-2011-100716
PMCID: PMC3793888  PMID: 22972951
breast cancer; risk prediction; genetic factors; hormone receptor status
9.  Evaluation of a breast cancer risk prediction model expanded to include category of prior benign breast disease lesion 
Cancer  2010;116(21):4944-4953.
Background
Benign breast diseases (BBD) encompass a number of histologic subtypes, with varying risks of subsequent breast cancer. Information on previous benign breast disease biopsies has been incorporated into breast cancer risk prediction models; however, the type of histologic lesion has not been taken into account. Given the substantial heterogeneity in breast cancer risk dependent on type of benign lesion, we evaluated whether incorporating this level of detail improves the discriminatory power of risk classification models.
Methods
Using data from the Nurses’ Health Study breast cancer nested case-control study (240 cases; 1036 controls), we determined predictors of categories of BBD lesions and developed imputation models. The type of BBD, imputed for each cohort member reporting a diagnosis, was added to a modified version of the Rosner-Colditz breast cancer risk prediction model.
Results
Compared to the model with only previous BBD (yes/no), the model with categories of benign breast disease was significantly improved (p<0.0001). Overall, including type of BBD increased the concordance statistic from 0.628 to 0.635. Using risk reclassification, inclusion of the type of BBD resulted in a 17% increase in incidence per increase of 1 risk decile, holding the model without BBD type risk decile constant.
Conclusions
Although these data suggest that inclusion of category of BBD may improve breast cancer risk classification, the clinical utility of such a model will depend on the consistency of histologic classification of benign breast disease lesions.
doi:10.1002/cncr.25386
PMCID: PMC2962878  PMID: 20645399
benign breast disease; breast cancer; risk prediction; Rosner-Colditz
10.  Genetic Variants of Diabetes Risk and Incident Cardiovascular Events in Chronic Coronary Artery Disease 
PLoS ONE  2011;6(1):e16341.
Objective
To determine whether information from genetic risk variants for diabetes is associated with cardiovascular events incidence.
Methods
From the about 30 known genes associated with diabetes, we genotyped single-nucleotide polymorphisms at the 10 loci most associated with type-2 diabetes in 425 subjects from the MASS-II Study, a randomized study in patients with multi-vessel coronary artery disease. The combined genetic information was evaluated by number of risk alleles for diabetes. Performance of genetic models relative to major cardiovascular events incidence was analyzed through Kaplan-Meier curve comparison and Cox Hazard Models and the discriminatory ability of models was assessed for cardiovascular events by calculating the area under the ROC curve.
Results
Genetic information was able to predict 5-year incidence of major cardiovascular events and overall-mortality in non-diabetic individuals, even after adjustment for potential confounders including fasting glycemia. Non-diabetic individuals with high genetic risk had a similar incidence of events then diabetic individuals (cumulative hazard of 33.0 versus 35.1% of diabetic subjects). The addition of combined genetic information to clinical predictors significantly improved the AUC for cardiovascular events incidence (AUC = 0.641 versus 0.610).
Conclusions
Combined information of genetic variants for diabetes risk is associated to major cardiovascular events incidence, including overall mortality, in non-diabetic individuals with coronary artery disease.
Clinical Trial Registration Information
Medicine, Angioplasty, or Surgery Study (MASS II). Unique identifier: ISRCTN66068876 URL.
doi:10.1371/journal.pone.0016341
PMCID: PMC3024434  PMID: 21283728
11.  Genetic and Clinical Predictors for Breast Cancer Risk Assessment and Stratification Among Chinese Women 
Background
Most of the genetic variants identified from genome-wide association studies of breast cancer have not been validated in Asian women. No risk assessment model that incorporates both genetic and clinical predictors is currently available to predict breast cancer risk in this population.
Methods
We analyzed 12 single-nucleotide polymorphisms (SNPs) identified in recent genome-wide association studies mostly of women of European ancestry as being associated with the risk of breast cancer in 3039 case patients and 3082 control subjects who participated in the Shanghai Breast Cancer Study. All participants were interviewed in person to obtain information regarding known and suspected risk factors for breast cancer. The c statistic, a measure of discrimination ability with a value ranging from 0.5 (random classification) to 1.0 (perfect classification), was estimated to evaluate the contribution of genetic and established clinical predictors of breast cancer to a newly established risk assessment model for Chinese women. Clinical predictors included in the model were age at menarche, age at first live birth, waist-to-hip ratio, family history of breast cancer, and a previous diagnosis of benign breast disease. The utility of the models in risk stratification was evaluated by estimating the proportion of breast cancer patients in the general population that could be accounted for above a given risk threshold as predicted by the models. All statistical tests were two-sided.
Results
Eight SNPs (rs2046210, rs1219648, rs3817198, rs8051542, rs3803662, rs889312, rs10941679, and rs13281615), each of which reflected a genetically independent locus, were found to be associated with the risk of breast cancer. A dose–response association was observed between the risk of breast cancer and the genetic risk score, which is an aggregate measure of the effect of these eight SNPs (odds ratio for women in the highest quintile of genetic risk score vs those in the lowest = 1.85, 95% confidence interval = 1.58 to 2.18, Ptrend = 2.5 × 10−15). The genetic risk score, the waist-to-hip ratio, and a previous diagnosis of benign breast disease were the top three predictors of the risk of breast cancer, each contributing statistically significantly (P < .001) to the full risk assessment model. The model, with a c statistic of 0.6295 after adjustment for overfitting, showed promise for stratifying women into different risk groups; women in the top 30% risk group accounted for nearly 50% of the breast cancers diagnosed in the general population.
Conclusion
A risk assessment model that includes both genetic markers and clinical predictors may be useful to classify Asian women into relevant risk groups for cost-efficient screening and other prevention programs.
doi:10.1093/jnci/djq170
PMCID: PMC2897876  PMID: 20484103
12.  Comparison of discriminatory power and accuracy of three lung cancer risk models 
British Journal of Cancer  2010;103(3):423-429.
Background:
Three lung cancer (LC) models have recently been constructed to predict an individual's absolute risk of LC within a defined period. Given their potential application in prevention strategies, a comparison of their accuracy in an independent population is important.
Methods:
We used data for 3197 patients with LC and 1703 cancer-free controls recruited to an ongoing case–control study at the Harvard School of Public Health and Massachusetts General Hospital. We estimated the 5-year LC risk for each risk model and compared the discriminatory power, accuracy, and clinical utility of these models.
Results:
Overall, the Liverpool Lung Project (LLP) and Spitz models had comparable discriminatory power (0.69), whereas the Bach model had significantly lower power (0.66; P=0.02). Positive predictive values were highest with the Spitz models, whereas negative predictive values were highest with the LLP model. The Spitz and Bach models had lower sensitivity but better specificity than did the LLP model.
Conclusion:
We observed modest differences in discriminatory power among the three LC risk models, but discriminatory powers were moderate at best, highlighting the difficulty in developing effective risk models.
doi:10.1038/sj.bjc.6605759
PMCID: PMC2920015  PMID: 20588271
lung cancer; risk model; 5-year lung cancer risk; relative risks; discriminatory power
13.  Breast Cancer Risk Prediction and Mammography Biopsy Decisions 
Background
Controversy continues about screening mammography, in part because of the risk of false-negative and false-positive mammograms. Pre-test breast cancer risk factors may improve the positive and negative predictive value of screening.
Purpose
To create a model that estimates the potential impact of pre-test risk prediction using clinical and genomic information on the reclassification of women with abnormal mammograms (BI-RADS3 and BI-RADS4 [Breast Imaging-Reporting and Data System]) above and below the threshold for breast biopsy.
Methods
The current study modeled 1-year breast cancer risk in women with abnormal screening mammograms using existing data on breast cancer risk factors, 12 validated breast cancer single nucleotide polymorphisms (SNPs), and probability of cancer given the BI-RADS category. Examination was made of reclassification of women above and below biopsy thresholds of 1%, 2%, and 3% risk. The Breast Cancer Surveillance Consortium data were collected from 1996 to 2002. Data analysis was conducted in 2010 and 2011.
Results
Using a biopsy risk threshold of 2% and the standard risk factor model, 5% of women with a BI-RADS3 mammogram had a risk above the threshold, and 3% of women with BIRADS4A mammograms had a risk below the threshold. The addition of 12 SNPs in the model resulted in 8% of women with a BI-RADS3 mammogram above the threshold for biopsy and 7% of women with BI-RADS4A mammograms below the threshold.
Conclusions
The incorporation of pre-test breast cancer risk factors could change biopsy decisions for a small proportion of women with abnormal mammograms. The greatest impact comes from standard breast cancer risk factors.
doi:10.1016/j.amepre.2012.10.002
PMCID: PMC3527848  PMID: 23253645
14.  Breast cancer risk prediction and individualised screening based on common genetic variation and breast density measurement 
Introduction
Over the last decade several breast cancer risk alleles have been identified which has led to an increased interest in individualised risk prediction for clinical purposes.
Methods
We investigate the performance of an up-to-date 18 breast cancer risk single-nucleotide polymorphisms (SNPs), together with mammographic percentage density (PD), body mass index (BMI) and clinical risk factors in predicting absolute risk of breast cancer, empirically, in a well characterised Swedish case-control study of postmenopausal women. We examined the efficiency of various prediction models at a population level for individualised screening by extending a recently proposed analytical approach for estimating number of cases captured.
Results
The performance of a risk prediction model based on an initial set of seven breast cancer risk SNPs is improved by additionally including eleven more recently established breast cancer risk SNPs (P = 4.69 × 10-4). Adding mammographic PD, BMI and all 18 SNPs to a Swedish Gail model improved the discriminatory accuracy (the AUC statistic) from 55% to 62%. The net reclassification improvement was used to assess improvement in classification of women into low, intermediate, and high categories of 5-year risk (P = 8.93 × 10-9). For scenarios we considered, we estimated that an individualised screening strategy based on risk models incorporating clinical risk factors, mammographic density and SNPs, captures 10% more cases than a screening strategy using the same resources, based on age alone. Estimates of numbers of cases captured by screening stratified by age provide insight into how individualised screening programs might appear in practice.
Conclusions
Taken together, genetic risk factors and mammographic density offer moderate improvements to clinical risk factor models for predicting breast cancer.
doi:10.1186/bcr3110
PMCID: PMC3496143  PMID: 22314178
15.  Heminested inverse PCR for IS6110 fingerprinting of Mycobacterium tuberculosis strains. 
Journal of Clinical Microbiology  1996;34(7):1686-1690.
A heminested inverse PCR (HIP) for the amplification of sequences flanking the Mycobacterium tuberculosis insertion sequence IS6110 has been developed. The method depends upon primers that anneal to IS6110 at sites between its 5' end and the closest BsrFI site. The accuracy of HIP was demonstrated by the amplification of sequences within plasmid constructs carrying one or two copies of the insertion sequence IS986 in different orientations. The identities of the amplicons produced from strains carrying a single copy of IS6110 were verified by nucleotide sequencing. Analyses of 204 M. tuberculosis strains including those involved in outbreaks showed that IS6110 HIP is highly discriminatory and reproducible. HIP fingerprinting of these 204 strains generated 136 distinct types, and its discriminatory power was equivalent to that of standard restriction fragment length polymorphism analysis. The method is therefore of value for the rapid fingerprinting of M. tuberculosis strains for epidemiological purposes.
PMCID: PMC229095  PMID: 8784570
16.  Predicting Survival of De Novo Metastatic Breast Cancer in Asian Women: Systematic Review and Validation Study 
PLoS ONE  2014;9(4):e93755.
Background
In Asia, up to 25% of breast cancer patients present with distant metastases at diagnosis. Given the heterogeneous survival probabilities of de novo metastatic breast cancer, individual outcome prediction is challenging. The aim of the study is to identify existing prognostic models for patients with de novo metastatic breast cancer and validate them in Asia.
Materials and Methods
We performed a systematic review to identify prediction models for metastatic breast cancer. Models were validated in 642 women with de novo metastatic breast cancer registered between 2000 and 2010 in the Singapore Malaysia Hospital Based Breast Cancer Registry. Survival curves for low, intermediate and high-risk groups according to each prognostic score were compared by log-rank test and discrimination of the models was assessed by concordance statistic (C-statistic).
Results
We identified 16 prediction models, seven of which were for patients with brain metastases only. Performance status, estrogen receptor status, metastatic site(s) and disease-free interval were the most common predictors. We were able to validate nine prediction models. The capacity of the models to discriminate between poor and good survivors varied from poor to fair with C-statistics ranging from 0.50 (95% CI, 0.48–0.53) to 0.63 (95% CI, 0.60–0.66).
Conclusion
The discriminatory performance of existing prediction models for de novo metastatic breast cancer in Asia is modest. Development of an Asian-specific prediction model is needed to improve prognostication and guide decision making.
doi:10.1371/journal.pone.0093755
PMCID: PMC3973579  PMID: 24695692
17.  Bilateral Mammographic Density Asymmetry and Breast Cancer Risk: A Preliminary Assessment 
European journal of radiology  2012;81(11):3222-3228.
To improve efficacy of breast cancer screening and prevention programs, it requires a risk assessment model with high discriminatory power. This study aimed to assess classification performance of using computed bilateral mammographic density asymmetry to predict risk of individual women developing breast cancer in near-term. The database includes 451 cases with multiple screening mammography examinations. The first (baseline) examinations of all case were interpreted negative. In the next sequential examinations, 187 cases developed cancer or surgically excised high-risk lesions, 155 remained negative (not-recalled), and 109 were recalled benign cases. From each of two bilateral cranio-caudal view images acquired from the baseline examination, we computed two features of average pixel value and local pixel value fluctuation. We then computed mean and difference of each feature computed from two images. When applying the computed features and other two risk factors (woman’s age and subjectively rated mammographic density) to predict risk of cancer development, areas under receiver operating characteristic curves (AUC) were computed to evaluate the discriminatory/classification performance. The AUCs are 0.633±0.030, 0.535±0.036, 0.567±0.031, and 0.719±0.027 when using woman’s age, subjectively rated, computed mean and asymmetry of mammographic density, to classify between two groups of cancer-verified and negative cases, respectively. When using an equal-weighted fusion method to combine woman’s age and computed density asymmetry, AUC increased to 0.761±0.025 (p<0.05). The study demonstrated that bilateral mammographic density asymmetry could be a significantly stronger risk factor associated to the risk of women developing breast cancer in near-term than woman’s age and assessed mean mammographic density.
doi:10.1016/j.ejrad.2012.04.018
PMCID: PMC3430819  PMID: 22579527
Breast cancer risk assessment; Full-field digital mammography; Mammographic density; Risk model
18.  Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers 
Human Molecular Genetics  2010;19(14):2886-2897.
Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 × 10−3) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (Ptrend < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR = 0.78, 95% CI: 0.69–0.90, Ptrend = 3.6 × 10−4 and HR = 1.25, 95% CI: 1.10–1.41, Ptrend = 4.2 × 10−4), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR = 1.55, 95% CI: 1.25–1.92, Ptrend = 6 × 10−5 and HR = 1.37, 95% CI: 1.16–1.62, Ptrend = 1.7 × 10−4). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.
doi:10.1093/hmg/ddq174
PMCID: PMC2893806  PMID: 20418484
19.  Breast cancer susceptibility associated with rs1219648 (FGFR2) and postmenopausal hormone therapy use in a population-based U.S. study 
Menopause (New York, N.Y.)  2013;20(3):354-358.
Objective
Genome-wide association studies have consistently found variants in FGFR2 to be associated with breast cancer. Recent reports suggest that postmenopausal hormone therapy use may modify the association between single nucleotide polymorphisms in FGFR2 and breast cancer risk. We assessed the hypothesis that the association between rs1219648 (FGFR2) single nucleotide polymorphism and breast cancer risk is modified by postmenopausal hormone therapy use in a population-based case-control study.
Methods
We evaluated rs1219648 single nucleotide polymorphism for an association with breast cancer risk using data obtained from 869 postmenopausal breast cancer cases diagnosed between the years of 1995-2000 and 808 postmenopausal community controls who participated in a study conducted in three U.S. states. Detailed postmenopausal hormone therapy information was collected through a structured telephone interview and DNA samples were collected through the mail using an established mouthwash protocol. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression models adjusted for age and state of residence.
Results
We observed a significant association with the rs1219648 and breast cancer risk (per-allele OR=1.22, 95%CI: 1.06-1.41; p-value=0.007), which did not vary significantly by ever use of estrogen plus progestogen therapy (interaction p-value=0.48). There was stronger evidence of an interaction between ever use of estrogen-only hormone therapy and increasing number of rs1219648 risk alleles to increase breast cancer risk (interaction p-value=0.08).
Conclusions
Our results are consistent with a risk association for FGFR2 but provide limited support for interaction with hormone therapy use. The study raises the possibility that the FGFR2 rs1219648 variant is more strongly associated with risk in estrogen-only hormone users, though this observation needs to be examined in larger studies.
doi:10.1097/GME.0b013e318268ca46
PMCID: PMC3549049  PMID: 23435034
breast cancer; genetics; hormone therapy; gene-environment interaction; epidemiology
20.  Comprehensive analysis of common genetic variation in 61 genes related to steroid hormone and insulin-like growth factor-I metabolism and breast cancer risk in the NCI breast and prostate cancer cohort consortium† 
Human Molecular Genetics  2010;19(19):3873-3884.
There is extensive evidence that increases in blood and tissue concentrations of steroid hormones and of insulin-like growth factor I (IGF-I) are associated with breast cancer risk. However, studies of common variation in genes involved in steroid hormone and IGF-I metabolism have yet to provide convincing evidence that such variants predict breast cancer risk. The Breast and Prostate Cancer Cohort Consortium (BPC3) is a collaboration of large US and European cohorts. We genotyped 1416 tagging single nucleotide polymorphisms (SNPs) in 37 steroid hormone metabolism genes and 24 IGF-I pathway genes in 6292 cases of breast cancer and 8135 controls, mostly Caucasian, postmenopausal women from the BPC3. We also imputed 3921 additional SNPs in the regions of interest. None of the SNPs tested was significantly associated with breast cancer risk, after correction for multiple comparisons. The results remained null when cases and controls were stratified by age at diagnosis/recruitment, advanced or nonadvanced disease, body mass index, with or without in situ cases; or restricted to Caucasians. Among 770 estrogen receptor-negative cases, an SNP located 3′ of growth hormone receptor (GHR) was marginally associated with increased risk after correction for multiple testing (Ptrend = 1.5 × 10−4). We found no significant overall associations between breast cancer and common germline variation in 61 genes involved in steroid hormone and IGF-I metabolism in this large, comprehensive study. Although previous studies have shown that variations in these genes can influence endogenous hormone levels, the magnitude of the effect of single SNPs does not appear to be sufficient to alter breast cancer risk.
doi:10.1093/hmg/ddq291
PMCID: PMC2935856  PMID: 20634197
21.  Distinct inherited metastasis susceptibility exists for different breast cancer subtypes: a prognosis study 
Introduction
Previous studies in mouse models and pilot epidemiology studies have demonstrated that inherited polymorphisms are associated with inherited risk of tumor progression and poor outcome in human breast cancer. To extend these studies and gain better understanding of the function of inherited polymorphism in breast cancer progression, a validation prognosis study was performed in a large independent breast cancer patient population.
Methods
The study population consisted of 1863 Dutch patients with operable primary breast cancer from Rotterdam, The Netherlands. Genomic DNA was genotyped for the missense Pro436Leu RRP1B single nucleotide polymorphism (SNP) rs9306160 and the intronic SIPA1 SNP rs2448490 by SNP-specific PCR.
Results
A significant association of variants in RRP1B with metastasis-free survival was observed (P = 0.012), validating the role of RRP1B with inherited metastatic susceptibility. Stratification of patients revealed that association with patients' survival was found to be specifically restricted to estrogen receptor positive, lymph node-negative (ER+/LN-) patients (P = 0.011). The specific association with metastasis-free survival only in ER+/LN- patients was replicated for SIPA1, a second metastasis susceptibility gene known to physically interact with RRP1B (P = 0.006). Combining the genotypes of these two genes resulted in the significant ability to discriminate patients with poor metastasis-free survival (HR: 0.40, 95% CI: 0.24 to 0.68, P = 0.001).
Conclusions
These results validate SIPA1 and RRP1B as metastasis susceptibility genes and suggest that genotyping assays may be a useful supplement to other clinical and molecular indicators of prognosis. The results also suggest that lymphatic and hematogeneous metastases are genetically distinct that may involve different mechanisms. If true, these results suggest that metastatic disease, like primary breast cancer, may be multiple diseases and that stratification of late stage patients may therefore be required to fully understand breast cancer progression and metastasis.
doi:10.1186/bcr2412
PMCID: PMC2790856  PMID: 19825179
22.  Evidence of Gene–Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors 
Nickels, Stefan | Truong, Thérèse | Hein, Rebecca | Stevens, Kristen | Buck, Katharina | Behrens, Sabine | Eilber, Ursula | Schmidt, Martina | Häberle, Lothar | Vrieling, Alina | Gaudet, Mia | Figueroa, Jonine | Schoof, Nils | Spurdle, Amanda B. | Rudolph, Anja | Fasching, Peter A. | Hopper, John L. | Makalic, Enes | Schmidt, Daniel F. | Southey, Melissa C. | Beckmann, Matthias W. | Ekici, Arif B. | Fletcher, Olivia | Gibson, Lorna | dos Santos Silva, Isabel | Peto, Julian | Humphreys, Manjeet K. | Wang, Jean | Cordina-Duverger, Emilie | Menegaux, Florence | Nordestgaard, Børge G. | Bojesen, Stig E. | Lanng, Charlotte | Anton-Culver, Hoda | Ziogas, Argyrios | Bernstein, Leslie | Clarke, Christina A. | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Brauch, Hiltrud | Brüning, Thomas | Harth, Volker | The GENICA Network,  | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | kConFab,  | Group, AOCS Management | Lambrechts, Diether | Smeets, Dominiek | Neven, Patrick | Paridaens, Robert | Flesch-Janys, Dieter | Obi, Nadia | Wang-Gohrke, Shan | Couch, Fergus J. | Olson, Janet E. | Vachon, Celine M. | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Offit, Kenneth | John, Esther M. | Miron, Alexander | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Chanock, Stephen J. | Lissowska, Jolanta | Liu, Jianjun | Cox, Angela | Cramp, Helen | Connley, Dan | Balasubramanian, Sabapathy | Dunning, Alison M. | Shah, Mitul | Trentham-Dietz, Amy | Newcomb, Polly | Titus, Linda | Egan, Kathleen | Cahoon, Elizabeth K. | Rajaraman, Preetha | Sigurdson, Alice J. | Doody, Michele M. | Guénel, Pascal | Pharoah, Paul D. P. | Schmidt, Marjanka K. | Hall, Per | Easton, Doug F. | Garcia-Closas, Montserrat | Milne, Roger L. | Chang-Claude, Jenny | Horwitz, Marshall S.
PLoS Genetics  2013;9(3):e1003284.
Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene–environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4×10−6) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1×10−4). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01–1.16) in nulliparous women and ranged from 1.03 (0.96–1.10) in parous women with one birth to 1.26 (1.16–1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85–0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14–1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3×10−5), with a per-allele OR of 1.14 (1.11–1.17) in parous women and 0.98 (0.92–1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.
Author Summary
Breast cancer involves combined effects of numerous genetic, environmental, and behavioral risk factors that are unique to each individual. High risk genes, such as BRCA1 and BRCA2, account for only a small proportion of disease occurrence. Recent genome-wide research has identified more than 20 common genetic variants, which individually alter breast cancer risk very moderately. We undertook an international collaborative study to determine whether the effect of these genetic variants vary with environmental factors, such as parity, body mass index (BMI), height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, and physical activity, which are known to affect risk of developing breast cancer. Using pooled data from 24 studies of the Breast Cancer Association Consortium (BCAC), we provide first convincing evidence that the breast cancer risk associated with a genetic variant in LSP1 differs with the number of births and that the risk associated with a CASP8 variant is altered by high alcohol consumption. The effect of an additional genetic variant might also be modified by reproductive factors. This knowledge will stimulate new research towards a better understanding of breast cancer development.
doi:10.1371/journal.pgen.1003284
PMCID: PMC3609648  PMID: 23544014
23.  Support Vector Machine Classifier for Estrogen Receptor Positive and Negative Early-Onset Breast Cancer 
PLoS ONE  2013;8(7):e68606.
Two major breast cancer sub-types are defined by the expression of estrogen receptors on tumour cells. Cancers with large numbers of receptors are termed estrogen receptor positive and those with few are estrogen receptor negative. Using genome-wide single nucleotide polymorphism genotype data for a sample of early-onset breast cancer patients we developed a Support Vector Machine (SVM) classifier from 200 germline variants associated with estrogen receptor status (p<0.0005). Using a linear kernel Support Vector Machine, we achieved classification accuracy exceeding 93%. The model indicates that polygenic variation in more than 100 genes is likely to underlie the estrogen receptor phenotype in early-onset breast cancer. Functional classification of the genes involved identifies enrichment of functions linked to the immune system, which is consistent with the current understanding of the biological role of estrogen receptors in breast cancer.
doi:10.1371/journal.pone.0068606
PMCID: PMC3716652  PMID: 23894323
24.  Assessment of Clinical Validity of a Breast Cancer Risk Model Combining Genetic and Clinical Information 
Background
The Gail model is widely used for the assessment of risk of invasive breast cancer based on recognized clinical risk factors. In recent years, a substantial number of single-nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified. However, it remains unclear how to effectively integrate clinical and genetic risk factors for risk assessment.
Methods
Seven SNPs associated with breast cancer risk were selected from the literature and genotyped in white non-Hispanic women in a nested case–control cohort of 1664 case patients and 1636 control subjects within the Women’s Health Initiative Clinical Trial. SNP risk scores were computed based on previously published odds ratios assuming a multiplicative model. Combined risk scores were calculated by multiplying Gail risk estimates by the SNP risk scores. The independence of Gail risk and SNP risk was evaluated by logistic regression. Calibration of relative risks was evaluated using the Hosmer–Lemeshow test. The performance of the combined risk scores was evaluated using receiver operating characteristic curves. The net reclassification improvement (NRI) was used to assess improvement in classification of women into low (<1.5%), intermediate (1.5%–2%), and high (>2%) categories of 5-year risk. All tests of statistical significance were two-sided.
Results
The SNP risk score was nearly independent of Gail risk. There was good agreement between predicted and observed SNP relative risks. In the analysis for receiver operating characteristic curves, the combined risk score was more discriminating, with area under the curve of 0.594 compared with area under the curve of 0.557 for Gail risk alone (P < .001). Classification also improved for 5.6% of case patients and 2.9% of control subjects, showing an NRI value of 0.085 (P = 1.0 × 10−5). Focusing on women with intermediate Gail risk resulted in an improved NRI of 0.195 (P = 8.6 × 10−5).
Conclusions
Combining validated common genetic risk factors with clinical risk factors resulted in modest improvement in classification of breast cancer risks in white non-Hispanic postmenopausal women. Classification performance was further improved by focusing on women at intermediate risk.
doi:10.1093/jnci/djq388
PMCID: PMC2970578  PMID: 20956782
25.  Relation of FGFR2 Genetic Polymorphisms to the Association Between Oral Contraceptive Use and the Risk of Breast Cancer in Chinese Women 
American Journal of Epidemiology  2011;173(8):923-931.
The fibroblast growth factor receptor 2 gene (FGFR2) has been associated with the risk of breast cancer in multiple ethnic populations, and its effect has been suggested to be hormone-dependent. A large, 2-stage, population-based case-control study was conducted in urban Shanghai, China, during the periods of 1996–1998 and 2002–2005. Exposure and genotyping information from 2,073 patients with breast cancer and 2,084 age-matched population controls was available for evaluation of the interactions between FGFR2 polymorphisms and exogenous estrogen exposure in the development of breast cancer. A logistic regression model was used to compute adjusted odds ratios and 95% confidence intervals. Of 20 genotyped and 25 imputed single nucleotide polymorphisms (SNPs), 22 were significantly associated with breast cancer. Three genotyped SNPs in close linkage disequilibrium, rs2303568, rs3135730, and rs1078806, and an imputed SNP of rs755793 in complete linkage disequilibrium with other 8 SNPs were observed to interact significantly with oral contraceptive (OC) use. The SNP-cancer association was evident only among OC users, and the OC use was only associated with the risk of breast cancer among carriers of these minor alleles at these loci. These findings suggest that genetic variants in FGFR2 may modify the role of OC use in causing breast cancer in Chinese women.
doi:10.1093/aje/kwq460
PMCID: PMC3071853  PMID: 21382839
breast neoplasms; contraceptives, oral; hormone replacement therapy; polymorphism, single nucleotide; receptor, fibroblast growth factor, type 2

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