Personalizing Breast Cancer Screening Based on Polygenic Risk and Family History.
Ontology highlight
ABSTRACT: Background
We assessed the clinical utility of a first-degree breast cancer family history and polygenic risk score (PRS) to inform screening decisions among women aged 30-50 years.Methods
Two established breast cancer models evaluated digital mammography screening strategies in the 1985 US birth cohort by risk groups defined by family history and PRS based on 313 single nucleotide polymorphisms. Strategies varied in initiation age (30, 35, 40, 45, and 50 years) and interval (annual, hybrid, biennial, triennial). The benefits (breast cancer deaths averted, life-years gained) and harms (false-positive mammograms, overdiagnoses) were compared with those seen with 3 established screening guidelines.Results
Women with a breast cancer family history who initiated biennial screening at age 40 years (vs 50 years) had a 36% (model range = 29%-40%) increase in life-years gained and 20% (model range = 16%-24%) more breast cancer deaths averted, but 21% (model range = 17%-23%) more overdiagnoses and 63% (model range = 62%-64%) more false positives. Screening tailored to PRS vs biennial screening from 50 to 74 years had smaller positive effects on life-years gained (20%) and breast cancer deaths averted (11%) but also smaller increases in overdiagnoses (10%) and false positives (26%). Combined use of family history and PRS vs biennial screening from 50 to 74 years had the greatest increase in life-years gained (29%) and breast cancer deaths averted (18%).Conclusions
Our results suggest that breast cancer family history and PRS could guide screening decisions before age 50 years among women at increased risk for breast cancer but expected increases in overdiagnoses and false positives should be expected.
SUBMITTER: van den Broek JJ
PROVIDER: S-EPMC8599807 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundThere is growing evidence for personalizing colorectal cancer screening based on risk factors. We compared the cost-effectiveness of personalized colorectal cancer screening based on polygenic risk and family history to uniform screening.MethodsUsing the MISCAN-Colon model, we simulated a cohort of 100 million 40-year-olds, offering them uniform or personalized screening. Individuals were categorized based on polygenic risk and family history of colorectal cancer. We varied screening strategies by start age, interval and test and estimated costs, and quality-adjusted life years (QALY). In our analysis, we (i) assessed the cost-effectiveness of uniform screening; (ii) developed personalized screening scenarios based on optimal screening strategies by risk group; and (iii) compared the cost-effectiveness of both.ResultsAt a willingness-to-pay threshold of $50,000/QALY, the optimal uniform screening scenario was annual fecal immunochemical testing (FIT) from ages 50 to 74 years, whereas for personalized screening the optimal screening scenario consisted of annual and biennial FIT screening except for those at highest risk who were offered 5-yearly colonoscopy from age 50 years. Although these scenarios gained the same number of QALYs (17,887), personalized screening was not cost-effective, costing an additional $428,953 due to costs associated with determining risk (assumed to be $240 per person). Personalized screening was cost-effective when these costs were less than ?$48.ConclusionsUniform colorectal cancer screening currently appears more cost-effective than personalized screening based on polygenic risk and family history. However, cost-effectiveness is highly dependent on the cost of determining risk.ImpactPersonalized screening could become increasingly viable as costs for determining risk decrease.
| S-EPMC7159991 | biostudies-literature
Project description:PurposeWe compared a simple breast cancer risk prediction model, BRISK (which includes mammographic density, polygenic risk and clinical factors), against a similar model with more risk factors (simplified Rosner) and against two commonly used clinical models (Gail and IBIS).MethodsUsing nested case-control data from the Nurses' Health Study, we compared the models' association, discrimination and calibration. Classification performance was compared between Gail and BRISK for 5-year risks and between IBIS and BRISK for remaining lifetime risk.ResultsThe odds ratio per standard deviation was 1.43 (95% CI 1.32, 1.55) for BRISK 5-year risk, 1.07 (95% CI 0.99, 1.14) for Gail 5-year risk, 1.72 (95% CI 1.59, 1.87) for simplified Rosner 10-year risk, 1.51 (95% CI 1.41, 1.62) for BRISK remaining lifetime risk and 1.26 (95% CI 1.16, 1.36) for IBIS remaining lifetime risk. The area under the receiver operating characteristic curve (AUC) was improved for BRISK over Gail for 5-year risk (AUC = 0.636 versus 0.511, P < 0.0001) and for BRISK over IBIS for remaining lifetime risk (AUC = 0.647 versus 0.571, P < 0.0001). BRISK was well calibrated for the estimation of both 5-year risk (expected/observed [E/O] = 1.03; 95% CI 0.73, 1.46) and remaining lifetime risk (E/O = 1.01; 95% CI 0.86, 1.17). The Gail 5-year risk (E/O = 0.85; 95% CI 0.58, 1.24) and IBIS remaining lifetime risk (E/O = 0.73; 95% CI 0.60, 0.87) were not well calibrated, with both under-estimating risk. BRISK improves classification of risk compared to Gail 5-year risk (NRI = 0.31; standard error [SE] = 0.031) and IBIS remaining lifetime risk (NRI = 0.287; SE = 0.035).ConclusionBRISK performs better than two commonly used clinical risk models and no worse compared to a similar model with more risk factors.
| S-EPMC10020257 | biostudies-literature
Project description:Background & aimsColorectal cancer (CRC) screening decisions for elderly individuals are often made primarily on the basis of age, whereas other factors that influence the effectiveness and cost effectiveness of screening are often not considered. We investigated the relative importance of factors that could be used to identify elderly individuals most likely to benefit from CRC screening and determined the maximum ages at which screening remains cost effective based on these factors.MethodsWe used a microsimulation model (Microsimulation Screening Analysis-Colon) calibrated to the incidence of CRC in the United States and the prevalence of adenomas reported in autopsy studies to determine the appropriate age at which to stop colonoscopy screening in 19,200 cohorts (of 10 million individuals), defined by sex, race, screening history, background risk for CRC, and comorbidity status. We applied a willingness-to-pay threshold of $100,000 per quality-adjusted life-year (QALY) gained.ResultsLess intensive screening history, higher background risk for CRC, and fewer comorbidities were associated with cost-effective screening at older ages. Sex and race had only a small effect on the appropriate age to stop screening. For some individuals likely to be screened in current practice (for example, 74-year-old white women with moderate comorbidities, half the average background risk for CRC, and negative findings from a screening colonoscopy 10 years previously), screening resulted in a loss of QALYs, rather than a gain. For some individuals unlikely to be screened in current practice (for example, 81-year-old black men with no comorbidities, an average background risk for CRC, and no previous screening), screening was highly cost effective. Although screening some previously screened, low-risk individuals was not cost effective even when they were 66 years old, screening some healthy, high-risk individuals remained cost effective until they reached the age of 88 years old.ConclusionsThe current approach to CRC screening in elderly individuals, in which decisions are often based primarily on age, is inefficient, resulting in underuse of screening for some and overuse of screening for others. CRC screening could be more effective and cost effective if individual factors for each patient are considered.
| S-EPMC4631390 | biostudies-literature
Project description:Background: The utility of incorporating detailed family history into breast cancer risk prediction hinges on its independent contribution to breast cancer risk. We evaluated associations between detailed family history and breast cancer risk while accounting for breast density.Methods: We followed 222,019 participants ages 35 to 74 in the Breast Cancer Surveillance Consortium, of whom 2,456 developed invasive breast cancer. We calculated standardized breast cancer risks within joint strata of breast density and simple (1st-degree female relative) or detailed (first-degree, second-degree, or first- and second-degree female relative) breast cancer family history. We fit log-binomial models to estimate age-specific breast cancer associations for simple and detailed family history, accounting for breast density.Results: Simple first-degree family history was associated with increased breast cancer risk compared with no first-degree history [Risk ratio (RR), 1.5; 95% confidence interval (CI), 1.0-2.1 at age 40; RR, 1.5; 95% CI, 1.3-1.7 at age 50; RR, 1.4; 95% CI, 1.2-1.6 at age 60; RR, 1.3; 95% CI, 1.1-1.5 at age 70). Breast cancer associations with detailed family history were strongest for women with first- and second-degree family history compared with no history (RR, 1.9; 95% CI, 1.1-3.2 at age 40); this association weakened in higher age groups (RR, 1.2; 95% CI, 0.88-1.5 at age 70). Associations did not change substantially when adjusted for breast density.Conclusions: Even with adjustment for breast density, a history of breast cancer in both first- and second-degree relatives is more strongly associated with breast cancer than simple first-degree family history.Impact: Future efforts to improve breast cancer risk prediction models should evaluate detailed family history as a risk factor. Cancer Epidemiol Biomarkers Prev; 26(6); 938-44. ©2017 AACR.
| S-EPMC5457358 | biostudies-literature
Project description:BackgroundMammographic density has been shown to be a strong independent predictor of breast cancer and a causative factor in reducing the sensitivity of mammography. There remain questions as to the use of mammographic density information in the context of screening and risk management, and of the association with cancer in populations known to be at increased risk of breast cancer.AimTo assess the association of breast density with presence of cancer by measuring mammographic density visually as a percentage, and with two automated volumetric methods, Quantra™ and VolparaDensity™.MethodsThe TOMosynthesis with digital MammographY (TOMMY) study of digital breast tomosynthesis in the Breast Screening Programme of the National Health Service (NHS) of the United Kingdom (UK) included 6020 breast screening assessment cases (of whom 1158 had breast cancer) and 1040 screened women with a family history of breast cancer (of whom two had breast cancer). We assessed the association of each measure with breast cancer risk in these populations at enhanced risk, using logistic regression adjusted for age and total breast volume as a surrogate for body mass index (BMI).ResultsAll density measures showed a positive association with presence of cancer and all declined with age. The strongest effect was seen with Volpara absolute density, with a significant 3% (95% CI 1-5%) increase in risk per 10 cm3 of dense tissue. The effect of Volpara volumetric density on risk was stronger for large and grade 3 tumours.ConclusionsAutomated absolute breast density is a predictor of breast cancer risk in populations at enhanced risk due to either positive mammographic findings or family history. In the screening context, density could be a trigger for more intensive imaging.
| S-EPMC5768323 | biostudies-literature
Project description:BackgroundAs breast cancer represents a major morbidity and mortality burden in the U.S., with about one in eight women developing invasive breast cancer over her lifetime, accurate low-cost screening is an important public health issue. First-degree family history, often simplified as a dichotomous or three-level categorical variable (0/1/>1) based on number of affected relatives, is an important risk factor for many conditions. However, detailed family structure information such as the total number of first-degree relatives, and for each, their current or death age, and age at diagnosis are also important for risk prediction.MethodsWe develop a family history score under a Bayesian framework, based on first-degree family structure. We tested performance of the proposed score using data from a large prospective cohort study of women with a first-degree breast cancer family history. We used likelihood ratio tests to evaluate whether the proposed score added additional information to a Cox model with known breast cancer risk factors and the three-level family history variable. We also compared prediction performance through Receiver Operating Characteristic (ROC) curves and goodness-of-fit testing.ResultsOur proposed Bayesian family history score improved fit compared to the commonly used three-level family history score, both without and with adjustment for other risk factors (likelihood ratio tests p = 0.003 without adjustment for other risk factors, and p = 0.007 and 0.009 under adjustment with two candidate sets of risk factors). AUCs of ROC curves for the two models were similar, though in all cases were higher after addition of the BFHS.ConclusionsCapturing detailed family history data through the proposed family history score can improve risk assessment and prediction. Such approaches could enable better-targeted personalized screening schedules and prevention strategies.
| S-EPMC6917296 | biostudies-literature
Project description:BackgroundEarly identification of individuals at high risk for alcohol use disorder (AUD) coupled with prompt interventions could reduce the incidence of AUD. In this study, we investigated whether Polygenic Risk Scores (PRS) can be used to evaluate the risk for AUD and AUD severity (as measured by the number of DSM-5 AUD diagnostic criteria met) and compared their performance with a measure of family history of AUD.MethodsWe studied individuals of European ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA). DSM-5 diagnostic criteria were available for 7203 individuals, of whom 3451 met criteria for DSM-IV alcohol dependence or DSM-5 AUD and 1616 were alcohol-exposed controls aged ≥21 years with no history of AUD or drug dependence. Further, 4842 individuals had a positive first-degree family history of AUD (FH+), 2722 had an unknown family history (FH?), and 336 had a negative family history (FH-). PRS were derived from a meta-analysis of a genome-wide association study of AUD from the Million Veteran Program and scores from the problem subscale of the Alcohol Use Disorders Identification Test in the UK Biobank. We used mixed models to test the association between PRS and risk for AUD and AUD severity.ResultsAUD cases had higher PRS than controls with PRS increasing as the number of DSM-5 diagnostic criteria increased (p-values ≤ 1.85E-05 ) in the full COGA sample, the FH+ subsample, and the FH? subsample. Individuals in the top decile of PRS had odds ratios (OR) for developing AUD of 1.96 (95% CI: 1.54 to 2.51, p-value = 7.57E-08 ) and 1.86 (95% CI: 1.35 to 2.56, p-value = 1.32E-04 ) in the full sample and the FH+ subsample, respectively. These values are comparable to previously reported ORs for a first-degree family history (1.91 to 2.38) estimated from national surveys. PRS were also significantly associated with the DSM-5 AUD diagnostic criterion count in the full sample, the FH+ subsample, and the FH? subsample (p-values ≤6.7E-11 ). PRS remained significantly associated with AUD and AUD severity after accounting for a family history of AUD (p-values ≤6.8E-10 ).ConclusionsBoth PRS and family history were associated with AUD and AUD severity, indicating that these risk measures assess distinct aspects of liability to AUD traits.
| S-EPMC8928056 | biostudies-literature
Project description:Family history of complex traits may reflect transmitted rare pathogenic variants, intra-familial shared exposures to environmental and lifestyle factors, as well as a common genetic predisposition. We developed a latent factor model to quantify trait heritability in excess of that captured by a common variant-based polygenic risk score, but inferable from family history. For 941 children in the Avon Longitudinal Study of Parents and Children cohort, a joint predictor combining a polygenic risk score for height and mid-parental height was able to explain ~55% of the total variance in sex-adjusted adult height z-scores, close to the estimated heritability. Marginal yet consistent risk prediction improvements were also achieved among ~400,000 European ancestry participants for 11 complex diseases in the UK Biobank. Our work showcases a paradigm for risk calculation, and supports incorporation of family history into polygenic risk score-based genetic risk prediction models.
| S-EPMC9203758 | biostudies-literature
Project description:BACKGROUND: With 14.234 diagnoses and over 4047 deaths reported in 2007, colorectal cancer (CRC) is the second most common cancer and second most common cause of cancer-related mortality in Australia. The direct treatment cost has recently been estimated to be around AU$1.2 billion for the year 2011, which corresponds to a four-fold increase, compared the cost reported in 2001. Excluding CRCs due to known rare genetic disorders, 20% to 25% of all CRCs occur in a familial aggregation setting due to genetic variants or shared environmental risk factors that are yet to be characterised. A targeted screening strategy addressed to this segment of the population is a potentially valuable tool for reducing the overall burden of CRC. METHODS: We developed a Markov model to assess the cost-effectiveness of three screening strategies offered to people at increased risk due to a strong family history of CRC. The model simulated the evolution of a cohort of 10,000 individuals from age 50 to 90 years. We compared screening with biennial iFOBT, five-yearly colonoscopy and ten-yearly colonoscopy versus the current strategy of the Australian National Bowel Cancer Screening Programme (i.e. base case). RESULTS: Under the NBCSP scenario, 6,491 persons developed CRC with an average screening lifetime cost of AU$3,441 per person. In comparison, screening with biennial iFOBT, colonoscopy every ten years, and colonoscopy every five years reduced CRC incidence by 27%, 35% and 60%, and mortality by 15%, 26% and 46% respectively. All three screening strategies had a cost under AU$50,000 per life year gained, which is regarded as the upper limit of acceptable cost-effectiveness in the Australian health system. At AU$12,405 per life year gained and an average lifetime expectancy of 16.084 years, five-yearly colonoscopy screening was the most cost-effective strategy. CONCLUSION: The model demonstrates that intensive CRC screening strategies targeting people at increased risk would be cost-effective in the Australian context. Our findings provide evidence that substantial health benefits can be generated from risk-based CRC screening at a relatively modest incremental cost.
| S-EPMC4021190 | biostudies-other
Project description:Family history of cancer remains underused in general clinical practice. We assess age at diagnosis and the role of family history in risk of breast cancer. Prospective follow-up of nurses' health study participants from 1980 to 2006. Updated assessment of family history in mother and sister including age at diagnosis. We used youngest age at diagnosis for family member when classifying risk. We confirmed 4327 incident invasive breast cancers confirmed. Breast cancer incidence models fitted to women with and without family history to assess variation in the risk for established risk factors. Compared to women with no family history those whose mother was diagnosed before age 50 had an adjusted relative risk of 1.69 (95% CI 1.39-2.05) and those with mother diagnosed at 50 or older had a relative risk of 1.37 (1.22-1.53). Sister history was associated with increased relative risk; 1.66 (1.38-1.99) for those with sister history before age 50 and 1.52 (1.29-1.77) for those with sister diagnosed at age 50 or older. Women with either mother or sister diagnosed before age 50 had a relative risk of 1.70 (1.48-1.95) significantly higher than those with diagnosis at age 50 or older (RR = 1.30; (1.27-1.54), P = 0.016). The magnitude of risk associated with established reproductive and lifestyle risk factors did not differ significantly between women with and those without family history with the exception of risk after bilateral oophorectomy in which setting women with family history had greater reduction in risk of subsequent breast cancer. Women with a family member diagnosed with breast cancer before age 50 had increased risk of breast cancer compared to women with family members diagnosed at older ages. Consistent findings for risk factors regardless of family history adds to robust evidence for risk identification and risk stratification in clinical settings where prevention strategies will apply equally to women with and without family history.
| S-EPMC3387322 | biostudies-literature