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Breast cancer risk models: a comprehensive overview of existing models, validation, and clinical applications

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Abstract

Numerous models have been developed to quantify the combined effect of various risk factors to predict either risk of developing breast cancer, risk of carrying a high-risk germline genetic mutation, specifically in the BRCA1 and BRCA2 genes, or the risk of both. These breast cancer risk models can be separated into those that utilize mainly hormonal and environmental factors and those that focus more on hereditary risk. Given the wide range of models from which to choose, understanding what each model predicts, the populations for which each is best suited to provide risk estimations, the current validation and comparative studies that have been performed for each model, and how to apply them practically is important for clinicians and researchers seeking to utilize risk models in their practice. This review provides a comprehensive guide for those seeking to understand and apply breast cancer risk models by summarizing the majority of existing breast cancer risk prediction models including the risk factors they incorporate, the basic methodology in their development, the information each provides, their strengths and limitations, relevant validation studies, and how to access each for clinical or investigative purposes.
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... Te identifed breast cancer risk prediction models were developed and validated for use in a clinical (genetic) setting and/or to identify specifc patient groups eligible for preventive intervention but not for population-based screening [47]. For example, the Gail/BRCAT model is considered suitable for identifying women who would beneft from chemoprevention [39,42]. ...
... [46]; SNPs enhanced: 0.60 [45]-0.69 [47] Model assessing the prognostic quality in ER-positive, HER2-negative, invasive, and noninvasive cancers without and with SNPs Moreover, risk-based breast cancer screening requires valid risk prediction instruments with good prognostic quality and risk-adjusted screening strategies. Solely conducting risk assessments is not enough. ...
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Purpose. Breast cancer is the most common cancer among women globally, with an incidence of approximately two million cases in 2018. Organised age-based breast cancer screening programs were established worldwide to detect breast cancer earlier and to reduce mortality. Currently, there is substantial anticipation regarding risk-adjusted screening programs, considering various risk factors in addition to age. The present study investigated the discriminatory accuracy of breast cancer risk prediction models and whether they suit risk-based screening programs. Methods. Following the PICO scheme, we conducted an overview of reviews and systematically searched four databases. All methodological steps, including the literature selection, data extraction and synthesis, and the quality appraisal were conducted following the 4-eyes principle. For the quality assessment, the AMSTAR 2 tool was used. Results. We included eight systematic reviews out of 833 hits based on the prespecified inclusion criteria. The eight systematic reviews comprised ninety-nine primary studies that were also considered for the data analysis. Three systematic reviews were assessed as having a high risk of bias, while the others were rated with a moderate or low risk of bias. Most identified breast cancer risk prediction models showed a low prognostic quality. Adding breast density and genetic information as risk factors only moderately improved the models’ discriminatory accuracy. Conclusion. All breast cancer risk prediction models published to date show a limited ability to predict the individual breast cancer risk in women. Hence, it is too early to implement them in national breast cancer screening programs. Relevant randomised controlled trials about the benefit-harm ratio of risk-adjusted breast cancer screening programs compared to conventional age-based programs need to be awaited.
... 15 For those that prefer a quantitative approach to identifying patients with germline PVs, there are also mathematical models that will estimate a patient's risk of having a PV, such as BRCAPRO, MYRIAD I/II, and Tyrer Cuzick. 16 ...
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As genetic testing becomes increasingly more accessible and more applicable with a broader range of clinical implications, it may also become more challenging for breast cancer providers to remain up‐to‐date. This review outlines some of the current clinical guidelines and recent literature surrounding germline genetic testing, as well as genomic testing, in the screening, prevention, diagnosis, and treatment of breast cancer, while identifying potential areas of further research.
... The prediction model or breast cancer risk assessment tool will not be accurate without the complete information on genetic component especially the mutation of the BRCA1 or BRCA2 gene. 5 The establishment of work exposure is needed to determine the diagnosis. Among the list of chemical agents that she had a contact with, the highly toxic inorganic form of Arsenic Trioxide falls under the Group 1 carcinogen which is a known carcinogen to human. ...
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A 28-year-old female laboratory technologist who was exposed to highly concentrated inorganic arsenic for 7 years, 25 hours a week, presented with left breast cancer. When most epidemiologic evidence reported by the IARC supported the relationship between arsenic exposure and cancers of lung, skin and bladder; literature had documented increased risk of breast cancer in specific populational subgroups due to the estrogen-like activity of arsenic. The causal assessment of occupational cancer is challenging due to the lack of relevant data on the worker’s biological monitoring and environmental exposure monitoring data, together with the insufficient genetic composition information like BRCA1 gene. Moreover, the poor work practice and hygiene had made the exposure through dermal contact and digestion possible. The interpretation of work causal relationship while distinct occupational cancer from those of non-occupational must consider individual susceptibility as low-level short-period exposure might increase the risk for certain worker. Therefore, a systematically collected medical surveillance data along with industry hygiene data is highly recommended in order to assist in the refinement of human dose-response relationship of specific work carcinogen
... The prediction model or breast cancer risk assessment tool will not be accurate without the complete information on genetic component especially the mutation of the BRCA1 or BRCA2 gene. 5 The establishment of work exposure is needed to determine the diagnosis. Among the list of chemical agents that she had a contact with, the highly toxic inorganic form of Arsenic Trioxide falls under the Group 1 carcinogen which is a known carcinogen to human. ...
Article
Full-text available
A 28-year-old female laboratory technologist who was exposed to highly concentrated inorganic arsenic for 7 years, 25 hours a week, presented with left breast cancer. When most epidemiologic evidence reported by the International Agency for Research on Cancer (IARC) supported the relationship between arsenic exposure and cancers of lung, skin and bladder; literature had documented increased risk of breast cancer in specific populational subgroups due to the estrogen-like activity of arsenic. The existing available control measures are restricted to the administrative control such as training and job rotation, hence making the causal assessment of occupational cancer is challenging due to the lack of relevant data on the worker's biological monitoring and environmental exposure monitoring data, together with the insufficient genetic composition information like Breast Cancer Genes1 (BRCA1). Moreover, the poor work practice and hygiene had made the exposure through dermal contact and digestion possible. The interpretation of work causal relationship while distinct occupational cancer from those of non-occupational must consider individual susceptibility as low-level short-period exposure might increase the risk for certain worker. Therefore, a systematically collected medical surveillance data along with industry hygiene data is highly recommended in order to assist in the refinement of human dose-response relationship of specific work carcinogen
Article
PURPOSE We extended the Breast Cancer Surveillance Consortium (BCSC) version 2 (v2) model of invasive breast cancer risk to include BMI, extended family history of breast cancer, and age at first live birth (version 3 [v3]) to better inform appropriate breast cancer prevention therapies and risk-based screening. METHODS We used Cox proportional hazards regression to estimate the age- and race- and ethnicity-specific relative hazards for family history of breast cancer, breast density, history of benign breast biopsy, BMI, and age at first live birth for invasive breast cancer in the BCSC cohort. We evaluated calibration using the ratio of expected-to-observed (E/O) invasive breast cancers in the cohort and discrimination using the area under the receiver operating characteristic curve (AUROC). RESULTS We analyzed data from 1,455,493 women age 35-79 years without a history of breast cancer. During a mean follow-up of 7.3 years, 30,266 women were diagnosed with invasive breast cancer. The BCSC v3 model had an E/O of 1.03 (95% CI, 1.01 to 1.04) and an AUROC of 0.646 for 5-year risk. Compared with the v2 model, discrimination of the v3 model improved most in Asian, White, and Black women. Among women with a BMI of 30.0-34.9 kg/m ² , the true-positive rate in women with an estimated 5-year risk of 3% or higher increased from 10.0% (v2) to 19.8% (v3) and the improvement was greater among women with a BMI of ≥35 kg/m ² (7.6%-19.8%). CONCLUSION The BCSC v3 model updates an already well-calibrated and validated breast cancer risk assessment tool to include additional important risk factors. The inclusion of BMI was associated with the largest improvement in estimated risk for individual women.
Article
Dense breast tissue at mammography is associated with higher breast cancer incidence and mortality rates, which have prompted new considerations for breast cancer screening in women with dense breasts. The authors review the definition and classification of breast density, density assessment methods, breast cancer risk, current legislation, and future efforts and summarize trials and key studies that have affected the existing guidelines for supplemental screening. Cases of breast cancer in dense breasts are presented, highlighting a variety of modalities and specific imaging findings that can aid in cancer detection and staging. Understanding the current state of breast cancer screening in patients with dense breasts and its challenges is important to shape future considerations for care. Shifting the paradigm of breast cancer detection toward early diagnosis for women with dense breasts may be the answer to reducing the number of deaths from this common disease. ©RSNA, 2023 Online supplemental material is available for this article. Quiz questions for this article are available through the Online Learning Center. See the invited commentary by Yeh in this issue.
Article
Background: To support mammography screening decision-making, we developed a competing-risk model to estimate 5-year breast cancer (BC) risk and 10-year non-BC death for women ≥55 using Nurses' Health Study (NHS) data and examined model performance in the Black Women's Health Study (BWHS). Here, we examine model performance in predicting 10-year outcomes in the BWHS, Women's Health Initiative-Extension Study (WHI-ES) and Multiethnic Cohort (MEC) and compare model performance to existing BC prediction models. Methods: We used competing-risk regression and Royston and Altman's methods for validating survival models to calculate our model's calibration and discrimination (c-index) in BWHS (n = 17,380), WHI-ES (n = 106,894) and MEC (n = 49,668). NHS development cohort (n = 48,102) regression coefficients were applied to the validation cohorts. We compared our model's performance to BCRAT "Gail" and IBIS models by computing BC risk estimates and c-statistics. Results: When predicting 10-year BC risk, our model's c-index was 0.569 in BWHS, 0.572 in WHI-ES, and 0.576 in MEC. BCRAT's c-statistic was 0.554 in BWHS, 0.564 in WHI-ES, and 0.551 in MEC; IBIS's c-statistic was 0.547 in BWHS, 0.552, in WHI-ES, and 0.562 in MEC. BCRAT underpredicted BC risk in WHI-ES; IBIS underpredicted BC risk in WHI-ES and in MEC but overpredicted BC risk in BWHS. Our model calibrated well. Our model's c-index for predicting 10-year non-BC death was 0.760 in WHI-ES and 0.763 in MEC. Conclusions: Our competing-risk model performs as well as existing BC prediction models in diverse cohorts and predicts non-BC death. We are developing a website to disseminate our model.
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Background: Risk prediction models are widely used in clinical genetic counselling. Despite their frequent use, the genetic risk models BOADICEA, BRCAPRO, IBIS and extended Claus model (eCLAUS), used to estimate BRCA1/2 mutation carrier probabilities, have never been comparatively evaluated in a large sample from central Europe. Additionally, a novel version of BOADICEA that incorporates tumour pathology information has not yet been validated. Patients and methods: Using data from 7352 German families we estimated BRCA1/2 carrier probabilities under each model and compared their discrimination and calibration. The incremental value of using pathology information in BOADICEA was assessed in a subsample of 4928 pedigrees with available data on breast tumour molecular markers oestrogen receptor, progesterone receptor and human epidermal growth factor 2. Results: BRCAPRO (area under receiver operating characteristic curve (AUC)=0.80 (95% CI 0.78 to 0.81)) and BOADICEA (AUC=0.79 (0.78-0.80)), had significantly higher diagnostic accuracy than IBIS and eCLAUS (p<0.001). The AUC increased when pathology information was used in BOADICEA: AUC=0.81 (95% CI 0.80 to 0.83, p<0.001). At carrier thresholds of 10% and 15%, the net reclassification index was +3.9% and +5.4%, respectively, when pathology was included in the model. Overall, calibration was best for BOADICEA and worst for eCLAUS. With eCLAUS, twice as many mutation carriers were predicted than observed. Conclusions: Our results support the use of BRCAPRO and BOADICEA for decision making regarding genetic testing for BRCA1/2 mutations. However, model calibration has to be improved for this population. eCLAUS should not be used for estimating mutation carrier probabilities in clinical settings. Whenever possible, breast tumour molecular marker information should be taken into account.
Article
PURPOSE: To assess the characteristics that correlate best with the presence of mutations in BRCA1 and BRCA2 in individuals tested in a clinical setting. PATIENTS AND METHODS: The results of 10,000 consecutive gene sequence analyses performed to identify mutations anywhere in the BRCA1 and BRCA2 genes (7,461 analyses) or for three specific Ashkenazi Jewish founder mutations (2,539 analyses) were correlated with personal and family history of cancer, ancestry, invasive versus noninvasive breast neoplasia, and sex. RESULTS: Mutations were identified in 1,720 (17.2%) of the 10,000 individuals tested, including 968 (20%) of 4,843 women with breast cancer and 281 (34%) of 824 with ovarian cancer, and the prevalence of mutations was correlated with specific features of the personal and family histories of the individuals tested. Mutations were as prevalent in high-risk women of African (25 [19%] of 133) and other non-Ashkenazi ancestries as those of European ancestry (712 [16%] of 4379) and were significantly less prevalent in women diagnosed before 50 years of age with ductal carcinoma in situ than with invasive breast cancer (13% v 24%, P = .0007). Of the 74 mutations identified in individuals of Ashkenazi ancestry through full sequence analysis of both BRCA1 and BRCA2, 16 (21.6%) were nonfounder mutations, including seven in BRCA1 and nine in BRCA2. Twenty-one (28%) of 76 men with breast cancer carried mutations, of which more than one third occurred in BRCA1. CONCLUSION: Specific features of personal and family history can be used to assess the likelihood of identifying a mutation in BRCA1 or BRCA2 in individuals tested in a clinical setting.
Article
Background There is no model to estimate absolute invasive breast cancer risk for Hispanic women. Methods The San Francisco Bay Area Breast Cancer Study (SFBCS) provided data on Hispanic breast cancer case patients (533 US-born, 553 foreign-born) and control participants (464 US-born, 947 foreign-born). These data yielded estimates of relative risk (RR) and attributable risk (AR) separately for US-born and foreign-born women. Nativity-specific absolute risks were estimated by combining RR and AR information with nativity-specific invasive breast cancer incidence and competing mortality rates from the California Cancer Registry and Surveillance, Epidemiology, and End Results program to develop the Hispanic risk model (HRM). In independent data, we assessed model calibration through observed/expected (O/E) ratios, and we estimated discriminatory accuracy with the area under the receiver operating characteristic curve (AUC) statistic. Results The US-born HRM included age at first full-term pregnancy, biopsy for benign breast disease, and family history of breast cancer; the foreign-born HRM also included age at menarche. The HRM estimated lower risks than the National Cancer Institute’s Breast Cancer Risk Assessment Tool (BCRAT) for US-born Hispanic women, but higher risks in foreign-born women. In independent data from the Women’s Health Initiative, the HRM was well calibrated for US-born women (observed/expected [O/E] ratio = 1.07, 95% confidence interval [CI] = 0.81 to 1.40), but seemed to overestimate risk in foreign-born women (O/E ratio = 0.66, 95% CI = 0.41 to 1.07). The AUC was 0.564 (95% CI = 0.485 to 0.644) for US-born and 0.625 (95% CI = 0.487 to 0.764) for foreign-born women. Conclusions The HRM is the first absolute risk model that is based entirely on data specific to Hispanic women by nativity. Further studies in Hispanic women are warranted to evaluate its validity.
Article
Purpose: The proliferation of gene panel testing precipitates the need for a breast cancer (BC) risk model that incorporates the effects of mutations in several genes and family history (FH). We extended the BOADICEA model to incorporate the effects of truncating variants in PALB2, CHEK2, and ATM. Methods: The BC incidence was modeled via the explicit effects of truncating variants in BRCA1/2, PALB2, CHEK2, and ATM and other unobserved genetic effects using segregation analysis methods. Results: The predicted average BC risk by age 80 for an ATM mutation carrier is 28%, 30% for CHEK2, 50% for PALB2, and 74% for BRCA1 and BRCA2. However, the BC risks are predicted to increase with FH burden. In families with mutations, predicted risks for mutation-negative members depend on both FH and the specific mutation. The reduction in BC risk after negative predictive testing is greatest when a BRCA1 mutation is identified in the family, but for women whose relatives carry a CHEK2 or ATM mutation, the risks decrease slightly. Conclusions: The model may be a valuable tool for counseling women who have undergone gene panel testing for providing consistent risks and harmonizing their clinical management. A Web application can be used to obtain BC risks in clinical practice (http://ccge. medschl.cam.ac.uk/boadicea/).
Article
This statement summarizes the U.S. Preventive Services Task Force (USPSTF) recommendations on genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility, along with the supporting scientific evidence. The complete information on which this statement is based, including evidence tables and references, is included in the evidence synthesis available through the USPSTF Web site (www.preventiveservices.ahrq.gov). The recommendation is also posted on the Web site of the National Guideline Clearinghouse (www.guideline.gov).
Article
Background. Improvements in screening techniques have made significant contributions to the early detection of breast cancer. Physicians thus face the task of providing appropriate screening schedules for their patients. One group for whom this is particularly important are those women with a family history of breast cancer. Methods. In this report, data from the Cancer and Steroid Hormone Study, a population-based, case-control study conducted by the Centers for Disease Control, are used to provide age-specific risk estimates of breast cancer for women with a family history of breast cancer