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Assessment of clinical validity of a breast cancer risk model combining genetic and clinical information.

ABSTRACT: 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.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.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??). Focusing on women with intermediate Gail risk resulted in an improved NRI of 0.195 (P = 8.6 × 10??).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.

SUBMITTER: Mealiffe ME

PROVIDER: S-EPMC2970578 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Assessment of clinical validity of a breast cancer risk model combining genetic and clinical information.

Mealiffe Matthew E ME Stokowski Renee P RP Rhees Brian K BK Prentice Ross L RL Pettinger Mary M Hinds David A DA

Journal of the National Cancer Institute 20101018 21

<h4>Background</h4>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.<h4>Methods</h4>Seven SNPs associated with breast cancer risk were selected from the literature and genotyp ...[more]

PMID: 20956782

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Project description:ImportanceAccurate long-term breast cancer risk assessment for women attending routine screening could help reduce the disease burden and intervention-associated harms by personalizing screening recommendations and preventive interventions.ObjectiveTo report the accuracy of risk assessment for breast cancer during a period of 19 years.Design, setting, and participantsThis cohort study of the Kaiser Permanente Washington breast imaging registry included women without previous breast cancer, aged 40 to 73 years, who attended screening from January 1, 1996, through December 31, 2013. Follow-up was completed on December 31, 2014, and data were analyzed from March 2, 2016, through November 13, 2017.ExposuresRisk factors from a questionnaire and breast density from the Breast Imaging and Reporting Data System at entry; primary risk was assessed using the Tyrer-Cuzick model.Main outcomes and measuresIncidence of invasive breast cancer was estimated with and without breast density. Follow-up began 6 months after the entry mammogram and extended to the earliest diagnosis of invasive breast cancer, censoring at 75 years of age, 2014, diagnosis of ductal carcinoma in situ, death, or health plan disenrollment. Observed divided by expected (O/E) numbers of cancer cases were compared using exact Poisson 95% CIs. Hazard ratios for the top decile of 10-year risk relative to the middle 80% of the study population were estimated. Constancy of relative risk calibration during follow-up was tested using a time-dependent proportional hazards effect.ResultsIn this cohort study of 132 139 women (median age at entry, 50 years; interquartile range, 44-58 years), 2699 invasive breast cancers were subsequently diagnosed after a median 5.2 years of follow-up (interquartile range, 2.4-11.1 years; maximum follow-up, 19 years; annual incidence rate [IR] per 1000 women, 2.9). Observed number of cancer diagnoses was close to the expected number (O/E for the Tyrer-Cuzick model, 1.02 [95% CI, 0.98-1.06]; O/E for the Tyrer-Cuzick model with density, 0.98 [95% CI, 0.94-1.02]). The Tyrer-Cuzick model estimated 2554 women (1.9%) to be at high risk (10-year risk of ?8%), of whom 147 subsequently developed invasive breast cancer (O/E, 0.79; 95% CI, 0.67-0.93; IR per 1000 women, 8.7). The Tyrer-Cuzick model with density estimated more women to be at high risk (4645 [3.5%]; 273 cancers [10.1%]; O/E, 0.78; 95% CI, 0.69-0.88; IR per 1000 women, 9.2). The hazard ratio for the highest risk decile compared with the middle 80% was 2.22 (95% CI, 2.02-2.45) for the Tyrer-Cuzick model and 2.55 (95% CI, 2.33-2.80) for the Tyrer-Cuzick model with density. Little evidence was found for a decrease in relative risk calibration throughout follow-up for the Tyrer-Cuzick model (age-adjusted slope, -0.003; 95% CI, -0.018 to 0.012) or the Tyrer-Cuzick model with density (age-adjusted slope, -0.008; 95% CI, -0.020 to 0.004).Conclusions and relevanceBreast cancer risk assessment combining classic risk factors with mammographic density may provide useful data for 10 years or more and could be used to guide long-term, systematic, risk-adapted screening and prevention strategies.

Project description:BackgroundMost 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.MethodsWe 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.ResultsEight 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, P(trend) = 2.5 x 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.ConclusionA 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.

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Assessment of clinical validity of a breast cancer risk model combining genetic and clinical information.

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Assessment of clinical validity of a breast cancer risk model combining genetic and clinical information.

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