International Breast Cancer Intervention Study Research Articles

Validating a model for predicting breast cancer and nonbreast cancer death in women aged 55 years and older.

To support mammography screening decision making, we developed a competing-risk model to estimate 5-year breast cancer risk and 10-year nonbreast cancer death for women aged 55 years and older using Nurses' Health Study 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 breast cancer prediction models. We used competing-risk regression and Royston and Altman 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). The Nurses' Health Study development cohort (n = 48 102) regression coefficients were applied to the validation cohorts. We compared our model's performance with breast cancer risk assessment tool (Gail) and International Breast Cancer Intervention Study (IBIS) models by computing breast cancer risk estimates and C statistics. When predicting 10-year breast cancer risk, our model's C index was 0.569 in BWHS, 0.572 in WHI-ES, and 0.576 in MEC. The Gail model'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. The Gail model underpredicted breast cancer risk in WHI-ES; IBIS underpredicted breast cancer risk in WHI-ES and in MEC but overpredicted breast cancer risk in BWHS. Our model calibrated well. Our model's C index for predicting 10-year nonbreast cancer death was 0.760 in WHI-ES and 0.763 in MEC. Our competing-risk model performs as well as existing breast cancer prediction models in diverse cohorts and predicts nonbreast cancer death. We are developing a website to disseminate our model.

Validation of the International Breast Cancer Intervention Study (IBIS) model in the High Risk Ontario Breast Screening Program: A retrospective cohort study

PurposeWomen with a remaining lifetime risk of breast cancer of ≥25%, estimated using the International Breast Cancer Intervention Study (IBIS) model, were eligible for the High Risk Ontario Breast Screening Program. This study examined the performance of IBIS 10-year risk estimates in the program. MethodsThis retrospective study included 7487 women aged 30 to 69 years referred to the High Risk Ontario Breast Screening Program between July 1, 2011, and December 31, 2016, with follow-up until December 31, 2018. Model calibration and discrimination were assessed. Analyses were conducted overall and stratified by age (< or ≥50 years). Different 10-year risk thresholds were compared with the current eligibility criteria. ResultsOverall, IBIS overestimated the risk of breast cancer with an expected vs observed case ratio of 1.17 (95% CI = 1.04-1.35). Overestimation was highest in women aged 50 to 69 years (expected vs observed case ratio = 1.29, 95% CI = 1.03-1.69) and for those in the top quartile of risk. Overall discrimination was fair with a concordance statistic of 0.66 (95% CI = 0.63-0.70). Furthermore, when using different 10-year risk eligibility thresholds, most cases would have been missed in the 30 to 49 age group using the 8% 10-year risk threshold, whereas relatively few women aged 50 to 69 would have been ineligible at any of the thresholds examined. ConclusionWe found that IBIS overestimated the risk of breast cancer in this screening cohort but had adequate discrimination. Age-specific risk thresholds should be considered to optimize the program eligibility criteria.

Abstract P3-03-07: The Breast Cancer Prevention Clinic: A Single Institution’s Experience

Abstract The Breast Cancer Prevention Clinic: A Single Institution’s Experience Authors: Joe J. Stephenson MD1, LeAnn Perkins, FNP-BC, DipACLM1, Erinn Crowe, RN, BSN, OCN1, Regina Franco, MSN, NP-C, DipACLM1, Pamela Cloys, MSN, ANP-C1, Carmen Hancock, MSN, APRN, FNP-C, AOCNP1, Marie Smith, MS1 1Prisma Health Cancer Institute, Center for Integrative Oncology &amp; Survivorship Background: Roughly 1 in 8 women will be diagnosed with invasive breast cancer in their lifetime1. Some women have higher risk for developing breast cancer due to numerous factors such as elevated risk modeling scores, a history of chest radiation therapy, a history of atypical cells on a breast biopsy or a pathogenic genetic mutation. Enhanced surveillance to detect cancers early and addressing modifiable lifestyle risks are helpful to mitigate risks. Methods: The Prisma Health’s Breast Cancer Prevention Clinic (BCPC) approaches prevention by monitoring non-modifiable risks with regular surveillance and education on optimizing lifestyle habits to decrease modifiable risks. Established in 2017, the BCPC team now includes multiple medical oncologists and nurse practitioners, allowing the clinic to be offered any day of the week. During the visit, patients receive a personal risk assessment. Recommendations are given for surveillance imaging, risk-reducing endocrine therapy, and risk-reducing lifestyle modifications such as diet, alcohol consumption, and exercise routines. Family history is also reviewed to recommend Genetic Counseling if appropriate. In March 2022, a statement was added to patient mammograms, generating referrals for those with calculated elevated risk (a calculated lifetime risk &amp;gt;20% using the Tyrer-Cuzick or International Breast Cancer Intervention Study model and/or a 5-year risk &amp;gt;1.7% using the National Cancer Institute Breast Cancer Risk Assessment Tool or Gail model). Results: In a 12-month period from June 1, 2021 through May 31, 2022, 56.2% of patients were referred based on family history, 26.9% for higher-risk breast pathology, 8.1% for calculated elevated risk, 4.4 % for a pathogenic genetic variant that increases breast cancer risk and 4.1% for mammographic identification risk modeling. Following the BCPC visit, referrals for patients may include imaging such as mammograms, MRIs, genetic counseling or testing, or surgical evaluations. Referrals for lifestyle modifications may include nutrition, exercise navigation, mindfulness classes, or Sexual Health Evaluations. From June 2021 through May 2022, 41.4% of patients were referred for a breast MRI, 26.6% were referred to genetic counselors for genetic testing recommendations, 11.1% were referred to nutrition or exercise services, 8.42% were referred for a Bone Density Scan (DXA), 4% were referred to a Breast Surgeon and 3.7% were referred to the Genetic Management Clinic. Additionally, 79.5% of patients were referred to the High-Risk Breast Lifetime Clinic for continued monitoring and surveillance for early detection of breast cancer, continued reinforcement of lifestyle modifications, and management of risk-reduction endocrine therapy. Conclusion: The unique structure of this model allows for enhanced surveillance through greater use of evidence-based cancer prevention, early detection methods, and increased education for lifestyle medicine practices with the overall goals of reducing breast cancer risk, earlier breast cancer detection, and increasing quality of life. Reference List 1. DeSantis C, Ma J, Gaudet, M, et al. Breast cancer statistics, 2019. CA: A Cancer Journal for Clinicians. 2019;69(6), 438-451. https://doi.org/10.3322/caac.21583. Citation Format: Joe Stephenson, LeAnn Perkins, Erinn Crowe, Regina Franco, Carmen Hancock, Pamela Cloys, Marie Smith. The Breast Cancer Prevention Clinic: A Single Institution’s Experience [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-03-07.

Performance of risk prediction models in breast cancer screening among women in Cyprus.

Tools that can predict breast cancer risk in women will have a significant impact on women and healthcare systems in low- and middle-income countries. We compared the performances of the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model, the International Breast Cancer Intervention Study (IBIS) model, and the Gail model in predicting breast cancer risk among women in Cyprus. We recruited 655 women from Dr Burhan Nalbantoglu Devlet Hastanesi Hospital in Lefkosa: 318 had breast cancer and 337 did not have breast cancer (hospital-based controls). We collected retrospective data from the hospital's medical records and interviews with the women after informed consent. Data collected included: age, age at diagnosis, age at menarche, menopausal status, presence of benign breast disease, breast cancer in relatives, BRCA-1 and BRCA-2 mutations, history of hormone replacement therapy, and breast density. We calculated the 5-year risk of breast cancer and the risk values were used to plot receiver operating curves. For the area under the curve (95% confidence interval, CI), sensitivity and specificity for the models were: BOADICEA 0.81 (95% CI: 0.77-0.84), 26.4% and 98.8%; IBIS 0.80 (95% CI: 0.77-0.84), 19.4% and 97.3%; and Gail 0.76 (95% CI: 0.73-0.80), 17.3% and 98.5%. The breast cancer risk prediction models performed similarly although on closer appraisal, the BOADICEA and IBIS models performed slightly better. These models are simple, appropriate, cost-effective, and non-invasive tools for identifying high-risk women in low- and middle-income countries who could benefit from mammography screening.

Prospective Evaluation of the Addition of Polygenic Risk Scores to Breast Cancer Risk Models.

BackgroundThe Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm and the International Breast Cancer Intervention Study breast cancer risk models are used to provide advice on screening intervals and chemoprevention. We evaluated the performance of these models, which now incorporate polygenic risk scores (PRSs), using a prospective cohort study.MethodsWe used a case-cohort design, involving women in the Melbourne Collaborative Cohort Study aged 50-75 years when surveyed in 2003-2007, of whom 408 had a first primary breast cancer diagnosed within 10 years (cases), and 2783 were from the subcohort. Ten-year risks were calculated based on lifestyle factors, family history data, and a 313-variant PRS. Discrimination was assessed using a C-statistic compared with 0.50 and calibration using the ratio of expected to observed number of cases (E/O).ResultsWhen the PRS was added to models with lifestyle factors and family history, the C-statistic (95% confidence interval [CI]) increased from 0.57 (0.54 to 0.60) to 0.62 (0.60 to 0.65) using IBIS and from 0.56 (0.53 to 0.59) to 0.62 (0.59 to 0.64) using BOADICEA. IBIS underpredicted risk (E/O = 0.62, 95% CI = 0.48 to 0.80) for women in the lowest risk category (<1.7%) and overpredicted risk (E/O = 1.40, 95% CI = 1.18 to 1.67) in the highest risk category (≥5%), using the Hosmer-Lemeshow test for calibration in quantiles of risk and a 2-sided P value less than .001. BOADICEA underpredicted risk (E/O = 0.82, 95% CI = 0.67 to 0.99) in the second highest risk category (3.4%-5%); the Hosmer-Lemeshow test and a 2-sided P value was equal to .02.ConclusionsAlthough the inclusion of a 313 genetic variant PRS doubles discriminatory accuracy (relative to reference 0.50), models with and without this PRS have relatively modest discrimination and might require recalibration before their clinical and wider use are promoted.

Abnormal screens among nonmutation carriers in the High Risk Ontario Breast Screening Program.

The Ontario Breast Screening Program was expanded in 2011 to offer annual MRI and mammography to women with high-risk genetic mutations (e.g., BRCA1/2) and women with strong family histories and ≥25% estimated lifetime risk of breast cancer. Data to support high-risk screening is less clear in the nonmutation carrier group, as MRI has lower specificity among this population. The potential unintended consequences may be considerable and need to be explored. We aimed to describe the frequency of abnormal screens and biopsies. Demographic surveys and chart review consent were sent to a sample of 441 individuals enrolled in a high-risk screening program at two tertiary care hospitals in Toronto, Ontario. Retrospective cross-sectional chart review was undertaken for clinicopathologic data. The frequencies of abnormal screens and biopsies were calculated. One hundred sixty-nine nonmutation carriers were included. The majority were white, employed, and highly educated. The median International Breast Cancer Intervention Study lifetime risk of breast cancer was 28.0% (range 24.5%-89.0%). 108 individuals (64%) experienced at least 1 abnormal screen and 13 (8%) had 3 or more over a median 3years of screening (range 1-6years). Of 55 biopsies, 3 (5.5%) were malignant. The cancer detection rate was 8.4/1000 screens (95% CI 3.2-22.4). An MRI-based screening program for nonmutation carriers was effective at diagnosing breast cancer. However, this population experienced a high rate of abnormal screens and intervention. Further research is needed to improve the performance of MRI-based screening in these women.

Impact of Personalized Genetic Breast Cancer Risk Estimation With Polygenic Risk Scores on Preventive Endocrine Therapy Intention and Uptake.

Endocrine therapy is underutilized to reduce breast cancer incidence among women at increased risk. Polygenic risk scores (PRSs) assessing 77 breast cancer genetic susceptibility loci personalizes risk estimates. We examined effect of personalized PRS breast cancer risk prediction on intention to take and endocrine therapy uptake among women at increased risk. Eligible participants had a 10-year breast cancer risk ≥5% by Tyrer-Cuzick model [International Breast Cancer Intervention Study (IBIS)] or ≥3.0 % 5-year Gail Model risk with no breast cancer history or hereditary breast cancer syndrome. Breast cancer risk was estimated, endocrine therapy options were discussed, and endocrine therapy intent was assessed at baseline. After genotyping, PRS-updated breast cancer risk estimates, endocrine therapy options, and intent to take endocrine therapy were reassessed; endocrine therapy uptake was assessed during follow-up. From March 2016 to October 2017, 151 patients were enrolled [median (range) age, 56.1 (36.0-76.4 years)]. Median 10-year and lifetime IBIS risks were 7.9% and 25.3%. Inclusion of PRS increased lifetime IBIS breast cancer risk estimates for 81 patients (53.6%) and reduced risk for 70 (46.4%). Of participants with increased breast cancer risk by PRS, 39 (41.9%) had greater intent to take endocrine therapy; of those with decreased breast cancer risk by PRS, 28 (46.7%) had less intent to take endocrine therapy (P < 0.001). On multivariable regression, increased breast cancer risk by PRS was associated with greater intent to take endocrine therapy (P < 0.001). Endocrine therapy uptake was greater among participants with increased breast cancer risk by PRS (53.4%) than with decreased risk (20.9%; P < 0.001). PRS testing influenced intent to take and endocrine therapy uptake. Assessing PRS effect on endocrine therapy adherence is needed.Prevention Relevance: Counseling women at increased breast cancer risk using polygenic risk score (PRS) risk estimates can significantly impact preventive endocrine therapy uptake. Further development of PRS testing to personalize breast cancer risk assessments and endocrine therapy counselling may serve to potentially reduce the incidence of breast cancer in the future.

Comparing 5-Year and Lifetime Risks of Breast Cancerusing the Prospective Family Study Cohort.

Clinical guidelines often use predicted lifetime risk from birth to define criteria for making decisions regarding breast cancer screening rather than thresholds based on absolute 5-year risk from current age. We used the Prospective Family Cohort Study of 14657 women without breast cancer at baseline in which, during a median follow-up of 10 years, 482 women were diagnosed with invasive breast cancer. We examined the performances of the International Breast Cancer Intervention Study (IBIS) and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk models when using the alternative thresholds by comparing predictions based on 5-year risk with those based on lifetime risk from birth and remaining lifetime risk. All statistical tests were 2-sided. Using IBIS, the areas under the receiver-operating characteristic curves were 0.66 (95% confidence interval = 0.63 to 0.68) and 0.56 (95% confidence interval = 0.54 to 0.59) for 5-year and lifetime risks, respectively (Pdiff < .001). For equivalent sensitivities, the 5-year incidence almost always had higher specificities than lifetime risk from birth. For women aged 20-39 years, 5-year risk performed better than lifetime risk from birth. For women aged 40 years or older, receiver-operating characteristic curves were similar for 5-year and lifetime IBIS risk from birth. Classifications based on remaining lifetime risk were inferior to 5-year risk estimates. Results were similar using BOADICEA. Our analysis shows that risk stratification using clinical models will likely be more accurate when based on predicted 5-year risk compared with risks based on predicted lifetime and remaining lifetime, particularly for women aged 20-39 years.

Screening Strategy Modification Based on Personalized Breast Cancer Risk Stratification and its Implementation in the National Guidelines - Pilot Study.

BackgroundOne of the most consistent models for estimating personalized breast cancer (BC) risk is the Tyrer-Cuzick algorithm that is incorporated into the International Breast Cancer Intervention Study (IBIS) software. Our main objective was to provide criteria for the classification of the Slovenian population, which has BC incidence below the European average, into risk groups, and to evaluate the integration of the criteria in Slovenian guidelines. Our main focus was on women age <50 with higher BC risk, since no organized BC screening is available for these women.MethodsSlovenian age-specific BC risks were incorporated into IBIS software and threshold values of risk categories were determined. Risk categories were assigned according to the individual’s ten-year risk for women aged 40 and older, and lifetime risk for women between 20 and 39. To test the software, we compared screening strategies with the use vs. no use of IBIS.ResultsOf the 197 women included in the study IBIS assigned 75.1% to the BC risk group, and the rest to the moderately increased risk. Without IBIS 80 women were offered mammographic and 33 ultrasound screening. In contrast, 28 instead of 80 would have been offered mammographic screening and there would have been no referrals for ultrasound if IBIS had been used.ConclusionsThe Slovenian IBIS has been developed, tested and suggested for personalized breast cancer risk assessment. The implementation of the software with the consideration of Slovenian risk thresholds enables a more accurate and nationally unified assessment.

Screening women at high risk for breast cancer: one program fits all? : Subgroup analysis of a large population high risk breast screening program.

The Ontario High Risk Breast Screening program follows women aged 30-69 at an increased risk of breast cancer, using a yearly mammography and breast MRI. The aim of this study is to determine the clinical outcomes for the enrolled women. Observational cohort study following 2081 participants in the high-risk screening program 2011-2017. The participants were divided into three subgroup according to their risk criteria: (a) known carriers of pathogenic variants (PV) in hereditary breast cancer genes. (b) Previous chest radiotherapy. (c) Estimated life time risk (ELR) ≥ 25%, calculated using the International Breast Cancer Intervention Study (IBIS) tool, with no known mutation or previous radiation. All Breast Cancer (BC) diagnosed during the follow-up time were recorded. 673 women carried PVs in hereditary breast cancer genes, 159 had a history of chest radiotherapy, and 1249 had an ELR ≥ 25%. The total cohort of screening years was 8126. Median age at BC diagnosis was 41 for the first group, 47 for the second group and 51 for the third. BC incidence rate was 18.2 for PV mutation carriers, 17.9 for the chest radiotherapy group and 6.2 for ELR ≥ 25%. Hazard ratio was similar for the first two groups, but significantly lower for the ELR ≥ 25% group. When stratifying by age, the incidence rate in the ELR ≥ 25% increased over time, until it became similar to that of the other subgroups after age 50. Our findings question the need to screen women with an elevated lifetime risk using the same screening practices used for women who are PV mutation carriers, or with a history of chest radiation, prior to the age of 50.

Abstract GS4-04: Ten year results of the international breast cancer intervention study II

Abstract Background: Two large clinical trials have shown the benefit of aromatase inhibitors in healthy women to reduce the risk of developing breast cancer (MAP.3 and IBIS-II). Here, we report blinded 10-year median follow-up efficacy data for the IBIS-II trial, which compared anastrozole to placebo in women at increased risk of developing breast cancer. Material and Methods: 3864 postmenopausal women at increased risk of developing breast cancer were recruited into a double-blind trial of anastrozole (N=1920) versus matching placebo (N=1944) for 5 years. The primary objective of this study was to determine the efficacy of anastrozole in preventing breast cancer (both invasive and ductal carcinoma in situ (DCIS)), overall and particularly for the post 5-year time period. Secondary endpoints included prevention of oestrogen receptor positive breast cancer, breast cancer mortality, non-breast cancer deaths, other cancers, cardiovascular disease, fractures, and musculoskeletal events. Results: After a median follow-up of 10.9 years (IQR 8.8-13.0), a total of 241 breast cancers have been reported (HR=0.50 (0.38-0.65), P&amp;lt;0.0001) (Table). The reduction was larger in the first 5 years (HR=0.39 (0.27-0.58), P&amp;lt;0.0001), but still significant after 5 years (117 (49%) new cases; HR=0.63 (0.43-0.91), P=0.015) (Table). The effects in the two time periods were not significantly different (P=0.11). Invasive oestrogen receptor (ER) positive breast cancer was reduced by 54% with anastrozole (HR=0.46 (0.33-0.65), P&amp;lt;0.0001), with a continued significant effect observed in the post treatment follow-up period (Table). A non-significant effect was observed in invasive ER-negative breast cancer (HR=0.76 (0.39-1.45), P=0.4). A reduction in DCIS overall was observed (Table), with a very large reduction in those known to be ER-positive (HR=0.23 (0.08-0.69), P&amp;lt;0.0001). A total of 129 deaths have been reported, with no significant difference in all-cause mortality between the two treatment arms (63 vs. 66; HR=0.93 (0.66-1.32), P=0.7). Only 5 deaths from breast cancer (2 vs. 3) were reported, but number of events are very small and longer follow-up is needed. 321 cancers other than breast were reported, with a significant decrease observed with anastrozole (129 vs. 192, OR=0.66 (0.52-0.83), P=0.0004). Specifically, fewer endometrial cancers (4 vs. 8), ovarian cancers (5 vs. 9), lung cancers (5 vs. 12), and melanomas (9 vs. 18) were observed with anastrozole. A comprehensive adverse event profile will be reported. Conclusion: This updated analysis of the IBIS-II trial confirms the significant reduction in breast cancer occurrence with anastrozole in the post-treatment follow-up period. These results indicate a long-term preventive benefit with anastrozole for ER-positive breast cancer in postmenopausal women. Table: Number of events and Hazard Ratios (95% CI) according to follow-up period.Number of eventsHR (95% CI)P-valueOverall241 (81 vs. 160)0.50 (0.38-0.65)&amp;lt;0.00010-5 years124 (35 vs. 89)0.39 (0.27-0.58)&amp;lt;0.00015+ years117 (46 vs. 71)0.63 (0.43-0.91)0.015Invasive ER-positive151 (48 vs. 103)0.46 (0.33-0.65)&amp;lt;0.00010-5 years72 (20 vs. 52)0.38 (0.23-0.64)&amp;lt;0.00015+ years79 (28 vs. 51)0.53 (0.34-0.84)0.007All DCIS42 (13 vs. 29)0.44 (0.23-0.85)0.0150-5 years22 (5 vs. 17)0.29 (0.11-0.80)0.0115+ years20 (8 vs. 12)0.65 (0.26-1.59)0.34 Citation Format: Jack Cuzick, Ivana Sestak, John Forbes, Mitchell Dowsett, Simon Cawthorn, Robert Mansell, Sibylle Loibl, Bernardo Bonanni, Anthony Howell, IBIS-II investigators. Ten year results of the international breast cancer intervention study II [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS4-04.

Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial

SummaryBackgroundTwo large clinical trials have shown a reduced rate of breast cancer development in high-risk women in the initial 5 years of follow-up after use of aromatase inhibitors (MAP.3 and International Breast Cancer Intervention Study II [IBIS-II]). Here, we report blinded long-term follow-up results for the IBIS-II trial, which compared anastrozole with placebo, with the objective of determining the efficacy of anastrozole for preventing breast cancer (both invasive and ductal carcinoma in situ) in the post-treatment period.MethodsIBIS-II is an international, randomised, double-blind, placebo-controlled trial. Postmenopausal women at increased risk of developing breast cancer were recruited and were randomly assigned (1:1) to either anastrozole (1 mg per day, oral) or matching placebo daily for 5 years. After treatment completion, women were followed on a yearly basis to collect data on breast cancer incidence, death, other cancers, and major adverse events (cardiovascular events and fractures). The primary outcome was all breast cancer.Findings3864 women were recruited between Feb 2, 2003, and Jan 31, 2012. 1920 women were randomly assigned to 5 years anastrozole and 1944 to placebo. After a median follow-up of 131 months (IQR 105–156), a 49% reduction in breast cancer was observed for anastrozole (85 vs 165 cases, hazard ratio [HR] 0·51, 95% CI 0·39–0·66, p<0·0001). The reduction was larger in the first 5 years (35 vs 89, 0·39, 0·27–0·58, p<0·0001), but still significant after 5 years (50 vs 76 new cases, 0·64, 0·45–0·91, p=0·014), and not significantly different from the first 5 years (p=0·087). Invasive oestrogen receptor-positive breast cancer was reduced by 54% (HR 0·46, 95% CI 0·33–0·65, p<0·0001), with a continued significant effect in the period after treatment. A 59% reduction in ductal carcinoma in situ was observed (0·41, 0·22–0·79, p=0·0081), especially in participants known to be oestrogen receptor-positive (0·22, 0·78–0·65, p<0·0001). No significant difference in deaths was observed overall (69 vs 70, HR 0·96, 95% CI 0·69–1·34, p=0·82) or for breast cancer (two anastrozole vs three placebo). A significant decrease in non-breast cancers was observed for anastrozole (147 vs 200, odds ratio 0·72, 95% CI 0·57–0·91, p=0·0042), owing primarily to non-melanoma skin cancer. No excess of fractures or cardiovascular disease was observed.InterpretationThis analysis has identified a significant continuing reduction in breast cancer with anastrozole in the post-treatment follow-up period, with no evidence of new late side-effects. Further follow-up is needed to assess the effect on breast cancer mortality.FundingCancer Research UK, the National Health and Medical Research Council Australia, Breast Cancer Research Foundation, Sanofi Aventis, and AstraZeneca.

Considerations When Using Breast Cancer Risk Models for Women with Negative BRCA1/BRCA2 Mutation Results.

The performance of breast cancer risk models for women with a family history but negative BRCA1 and/or BRCA2 mutation test results is uncertain. We calculated the cumulative 10-year invasive breast cancer risk at cohort entry for 14 657 unaffected women (96.1% had an affected relative) not known to carry BRCA1 or BRCA2 mutations at baseline using three pedigree-based models (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, BRCAPRO, and International Breast Cancer Intervention Study). During follow-up, 482 women were diagnosed with invasive breast cancer. Mutation testing was conducted independent of incident cancers. All models underpredicted risk by 26.3%-56.7% for women who tested negative but whose relatives had not been tested (n = 1363; 63 breast cancers). Although replication studies with larger sample sizes are needed, until these models are recalibrated for women who test negative and have no relatives tested, caution should be used when considering changing the breast cancer risk management intensity of such women based on risk estimates from these models.

Accuracy of Risk Estimates from the iPrevent Breast Cancer Risk Assessment and Management Tool.

BackgroundiPrevent is an online breast cancer (BC) risk management decision support tool. It uses an internal switching algorithm, based on a woman’s risk factor data, to estimate her absolute BC risk using either the International Breast Cancer Intervention Study (IBIS) version 7.02, or Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm version 3 models, and then provides tailored risk management information. This study assessed the accuracy of the 10-year risk estimates using prospective data.MethodsiPrevent-assigned 10-year invasive BC risk was calculated for 15 732 women aged 20–70 years and without BC at recruitment to the Prospective Family Study Cohort. Calibration, the ratio of the expected (E) number of BCs to the observed (O) number and discriminatory accuracy were assessed.ResultsDuring the 10 years of follow-up, 619 women (3.9%) developed BC compared with 702 expected (E/O = 1.13; 95% confidence interval [CI] =1.05 to 1.23). For women younger than 50 years, 50 years and older, and BRCA1/2-mutation carriers and noncarriers, E/O was 1.04 (95% CI = 0.93 to 1.16), 1.24 (95% CI = 1.11 to 1.39), 1.13 (95% CI = 0.96 to 1.34), and 1.13 (95% CI = 1.04 to 1.24), respectively. The C-statistic was 0.70 (95% CI = 0.68 to 0.73) overall and 0.74 (95% CI = 0.71 to 0.77), 0.63 (95% CI = 0.59 to 0.66), 0.59 (95% CI = 0.53 to 0.64), and 0.65 (95% CI = 0.63 to 0.68), respectively, for the subgroups above. Applying the newer IBIS version 8.0b in the iPrevent switching algorithm improved calibration overall (E/O = 1.06, 95% CI = 0.98 to 1.15) and in all subgroups, without changing discriminatory accuracy.ConclusionsFor 10-year BC risk, iPrevent had good discriminatory accuracy overall and was well calibrated for women aged younger than 50 years. Calibration may be improved in the future by incorporating IBIS version 8.0b.

Comparative Validation of Breast Cancer Risk Prediction Models and Projections for Future Risk Stratification.

External validation of risk models is critical for risk-stratified breast cancer prevention. We used the Individualized Coherent Absolute Risk Estimation (iCARE) as a flexible tool for risk model development and comparative model validation and to make projections for population risk stratification. Performance of two recently developed models, one based on the Breast and Prostate Cancer Cohort Consortium analysis (iCARE-BPC3) and another based on a literature review (iCARE-Lit), were compared with two established models (Breast Cancer Risk Assessment Tool and International Breast Cancer Intervention Study Model) based on classical risk factors in a UK-based cohort of 64 874 white non-Hispanic women (863 patients) age 35-74 years. Risk projections in a target population of US white non-Hispanic women age 50-70 years assessed potential improvements in risk stratification by adding mammographic breast density (MD) and polygenic risk score (PRS). The best calibrated models were iCARE-Lit (expected to observed number of cases [E/O] = 0.98, 95% confidence interval [CI] = 0.87 to 1.11) for women younger than 50 years, and iCARE-BPC3 (E/O = 1.00, 95% CI = 0.93 to 1.09) for women 50 years or older. Risk projections using iCARE-BPC3 indicated classical risk factors can identify approximately 500000 women at moderate to high risk (>3% 5-year risk) in the target population. Addition of MD and a 313-variant PRS is expected to increase this number to approximately 3.5 million women, and among them, approximately 153 000 are expected to develop invasive breast cancer within 5 years. iCARE models based on classical risk factors perform similarly to or better than BCRAT or IBIS in white non-Hispanic women. Addition of MD and PRS can lead to substantial improvements in risk stratification. However, these integrated models require independent prospective validation before broad clinical applications.

A systematic review and quality assessment of individualised breast cancer risk prediction models

BackgroundIndividualised breast cancer risk prediction models may be key for planning risk-based screening approaches. Our aim was to conduct a systematic review and quality assessment of these models addressed to women in the general population.MethodsWe followed the Cochrane Collaboration methods searching in Medline, EMBASE and The Cochrane Library databases up to February 2018. We included studies reporting a model to estimate the individualised risk of breast cancer in women in the general population. Study quality was assessed by two independent reviewers. Results are narratively summarised.ResultsWe included 24 studies out of the 2976 citations initially retrieved. Twenty studies were based on four models, the Breast Cancer Risk Assessment Tool (BCRAT), the Breast Cancer Surveillance Consortium (BCSC), the Rosner & Colditz model, and the International Breast Cancer Intervention Study (IBIS), whereas four studies addressed other original models. Four of the studies included genetic information. The quality of the studies was moderate with some limitations in the discriminative power and data inputs. A maximum AUROC value of 0.71 was reported in the study conducted in a screening context.ConclusionIndividualised risk prediction models are promising tools for implementing risk-based screening policies. However, it is a challenge to recommend any of them since they need further improvement in their quality and discriminatory capacity.

AB156. 129. Surveillance strategies for patients at a family history risk assessment clinic

Background: Women with a family history of breast cancer are assessed in University Hospital Limerick (UHL) using the Family History Risk Assessment Software (FaHRAS, Nottingham, UK) tool, which allows risk stratification of women using the International Breast Cancer Intervention Study (IBIS) risk model. Follow up surveillance of these women is then arranged according to the National Institute for Clinical Excellence (NICE) guidelines on Familial Breast Cancer. The aim was to assess the compliance of follow-up of patients attending the Family History Breast Clinic at UHL with the corresponding NICE guidelines. To establish the outcomes of patients who were assessed with the FaHRAS risk assessment software.

Value of Mammography for Women 30-39 Years Old Presenting With Breast Symptoms.

The purpose of this study was to determine the performance and added value of bilateral mammography in identifying cancers distant from sites of presenting breast symptoms in women 30-39 years old. A search identified consecutively registered women 30-39 years old who underwent mammography and ultrasound to evaluate focal breast symptoms between June 2006 and August 2016. Outcomes were determined by imaging and pathologic analysis through linkage with a tumor registry. Medical records were reviewed to determine the presence of breast cancer risk factors. Lifetime breast cancer risk was calculated with the International Breast Cancer Intervention Study model. The study included 4426 diagnostic examinations of 3997 women 30-39 years old. Sixty-eight breast cancers were diagnosed (cancer detection rate, 15.4 per 1000 examinations). Sixty examinations led to biopsy of a finding distant from the presenting symptom site, yielding nine incidental malignancies (positive predictive value, 15.0%; incidental cancer detection rate, 2.0 per 1000 examinations [9/4426]). Among the other 59 cancers diagnosed in the symptomatic area, bilateral mammography depicted multicentric or contra-lateral disease in seven (11.9%). Average lifetime risk of breast cancer among the 68 women with cancer was significantly higher than that among age-matched control subjects (22.8% vs 13.1%, p < 0.001); 45 of these 68 women (66.2%) had identifiable risk factors. Lifetime risk among the nine women with incidental cancers was higher than that of age-matched control subjects, although without statistical significance (24.9% vs 13.2%, p = 0.07). Bilateral mammographic evaluation of women 30-39 years old presenting with breast symptoms yielded an additional 2.0 incidental cancers per 1000 examinations. The low added cancer yield may support the judicious rather than routine use of mammography in this patient cohort.

Validation of the IBIS breast cancer risk evaluator for women with lobular carcinoma in-situ

BackgroundManagement advice for women with lobular carcinoma in situ (LCIS) is hampered by the lack of accurate personalised risk estimates for subsequent invasive breast cancer (BC). Prospective validation of the only tool that estimates individual BC risk for a woman with LCIS, the International Breast Cancer Intervention Study Risk Evaluation Tool (IBIS-RET), is lacking.MethodsUsing population-based cancer registry data for 732 women with LCIS, the calibration and discrimination accuracy of IBIS-RET Version 7.2 were assessed.ResultsThe mean observed 10-year risk of invasive BC was 14.1% (95% CI:11.3%-17.5%). IBIS-RET overestimated invasive BC risk (p = 0.0003) and demonstrated poor discriminatory accuracy (AUC 0.54, 95% CI: 0.48 – 0.62).ConclusionsClinicians should understand that IBIS-RET Version 7.2 may overestimate 10-year invasive BC risk for Australian women with LCIS. The newer IBIS-RET Version 8.0, released September 2017, includes mammographic density and may perform better, but validation is needed.

Early participant-reported symptoms as predictors of adherence to anastrozole in the International Breast Cancer Intervention Studies II

BackgroundAnastrozole reduces breast cancer risk in women at high risk, but implementing preventive therapy in clinical practice is difficult. Here, we evaluate adherence to anastrozole in the International Breast Cancer Intervention Study (IBIS)-II prevention and ductal carcinoma in situ (DCIS) trials, and its association with early symptoms.Patients and methodsIn the prevention trial, 3864 postmenopausal women were randomized to placebo versus anastrozole. A total of 2980 postmenopausal women with DCIS were randomized to tamoxifen versus anastrozole. Adherence to trial medication was calculated using the Kaplan–Meier method and all P-values were two-sided.ResultsIn the prevention trial, adherence was 65.8% [anastrozole (65.7%) versus placebo (65.9%); HR = 0.97 (0.87–1.09), P = 0.6]. Adherence was lower for those reporting arthralgia in the placebo group (P = 0.02) or gynecological symptoms in the anastrozole group (P = 0.003), compared with those not reporting these symptoms at 6 months. In the DCIS study, adherence was 66.7% [anastrozole (67.5%) versus tamoxifen (65.8%); HR = 1.06 (0.94–1.20), P = 0.4]. Hot flashes were associated with greater adherence in the anastrozole arm (P = 0.02). In both studies, symptoms were mostly mild or moderately severe, and adherence decreased with increasing severity for most symptoms. Drop-outs were highest in the first 1.5 years of therapy in both trials.ConclusionsIn the IBIS-II prevention and DCIS trials, over two-thirds of women were adherent to therapy, with no differences by treatment groups. Participants who reported specific symptoms in the IBIS-II prevention trial had a small but significant effect on adherence, which strengthened as severity increased. Strategies to promote adherence should target the first year of preventive therapy.