International Breast Cancer Intervention Study Research Articles

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.

Participant-Reported Symptoms and Their Effect on Long-Term Adherence in the International Breast Cancer Intervention Study I (IBIS I).

PurposeTo assess the role of participant-reported symptoms on long-term adherence to preventive therapy in the United Kingdom sample of the International Breast Cancer Intervention Study (IBIS-I). IBIS-I was a randomized controlled trial that investigated the effectiveness of tamoxifen in reducing the risk of breast cancer among women at increased risk of the disease.Participants and MethodsWomen were randomly assigned to tamoxifen versus placebo (20 mg/day; n = 4,279). After 456 exclusions, 3,823 women were included in this analysis. Adherence (< 4.5 years or ≥ 4.5 years) was calculated using data from six monthly clinical visits. Analyses were adjusted for age, Tyrer-Cuzick risk, smoking, use of hormone replacement therapy, menopausal status, baseline menopausal symptoms, and treatment.ResultsOverall, 69.7% of women were adherent for at least 4.5 years (tamoxifen: 65.2% v placebo: 74.0%; P < .001). Differences in adherence between treatment arms were observed from 12 months onward (all P < .01) and were largest at 54 months. Dropout rates were highest in the first 12 to 18 months and decreased thereafter. Women reporting nausea/vomiting were less likely to be adherent in both the tamoxifen (odds ratio [OR], 0.57; 95% CI, 0.37 to 0.86; P = .007) and placebo (OR, 0.58; 95% CI, 0.37 to 0.93; P = .023) arms. Headaches were associated with adherence only in the placebo arm (OR, 0.62; 95% CI, 0.42 to 0.91; P = .016), whereas gynecologic symptoms were significant only in the tamoxifen arm (OR, 0.77; 95% CI, 0.62 to 0.97; P = .024). Effect sizes for each symptom on adherence were not significantly different between the treatment groups (P > .05). In both treatment arms, we observed significant trends for lower adherence with increasing severity for all symptoms (P < .01) except headaches (P = .054).ConclusionIn the IBIS-I trial, experiencing predefined symptoms in the first 6 months reduced long-term adherence. Effects were similar between treatment arms, suggesting that women were attributing age-related symptoms to preventive therapy. Interventions were required to support symptom management.

Breast cancer awareness among Indonesian women at moderate-to-high risk.

In this descriptive cross-sectional study, we examined awareness of breast cancer among Indonesian women at moderate-to high-risk of developing breast cancer. Data were obtained from 87 eligible participants using the Modified Breast Cancer Awareness Measure. The International Breast Cancer Intervention Study model was used to identify women at moderate-to-high risk of developing breast cancer. The data were analyzed using descriptive statistics. The results showed that none of the participants had knowledge of age-related risk (0%). Other domains that indicated low awareness were knowledge of lifetime risk (31%), followed by knowledge of risk factors, in particular the item regarding menstruation at an early age (12.6%). These results indicated that increasing awareness of breast cancer risks is highly needed, in particular among women at moderate-to-high risk of developing breast cancer in Indonesia.

Abstract PR07: Comparison of risk model recommendations for women at high-risk of breast cancer based on clinical thresholds using the Prospective Family Study Cohort (ProF-SC)

Abstract Background: Clinical guidelines for classifying women as high-risk for breast cancer when considering chemoprevention and/or MRI screening options include thresholds of remaining lifetime risk (RLR) of 20% or more and/or a fixed time interval (e.g., 5-year risk of 1.67 or higher, 10-year risk of 3.34 or higher). Although clinicians have noted differences in risk estimates from the existing risk models, there have been few prospective validations using large cohorts to describe the magnitude of the discordancies between these models. Methods: We prospectively followed 16,285 women without breast cancer at baseline for an average of 10.2 years to compare the RLR and 10-year risk assigned by two commonly used risk estimation models for high risk women: 1) The International Breast Cancer Intervention Study tool (IBIS); and 2) the Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA). We compared the model-assigned 10-year risks with subsequent incidence of breast cancer in the cohort. We used chi-square statistics to assess calibration and the area under the receiver operating characteristic curve (AUC) to assess discrimination. Results: We observed differences between risk models in terms of the proportion of women classified as high-risk based on 20% or more RLR (IBIS=56% vs BOADICEA=23%). Only 21% of women were classified as high risk by both models, 35% of women were classified as high risk by IBIS only and 2% of women were classified as high risk by BOADICEA only. The difference was not evident (IBIS=52% vs BOADICEA=51%) when using a 10-year risk threshold of 3.34%. Using this 10-year threshold, 43% of women were classified as high risk by both models, 9% of women were classified as high risk by IBIS only and 8% of women were classified as high risk by BOADICEA only. IBIS risk predictions (mean=4.9%) were better calibrated to observed breast cancer incidence (5.8%, 95% confidence interval (CI)=5.4% to 6.2%) than were those based on BOADICEA (mean=4.2%). When we compared the magnitude of the discordancy between IBIS and BOADICEA by age, race/ethnicity, and number of relatives affected, we observed the extent of discordancy (e.g. one model resulted in a woman being above the clinical threshold when the other did not) depended on age. Specifically, for women under the age of 40 years, only 3.1% of women were high risk with IBIS but not BOADICEA compared with 7.5% classified as high risk by BOADICEA but not IBIS. Both models gave similar predictions of high risk with same proportion discordant for women over 50, and the same proportion discordant by race/ethnicity. When we compared the discordancy by those unaffected and affected with breast cancer after ten years of follow-up, 51% of unaffected women were high risk by IBIS using the 10-year threshold and 50% by BOADICEA with only 8% discordant (high risk on only one model). For women who were diagnosed with breast cancer prospectively after baseline, 75% were classified as high risk at baseline by IBIS and 72% were classified by BOADICEA with 8% high risk by IBIS only and 5% high risk by BOADICEA only. Conclusion: These results suggest that there is a considerable discordancy between two commonly used risk models to determine high risk classification for MRI and chemoprevention. There is a greater concordancy between the two models when using a shorter time-horizon, especially for women over the age of 50 years. However, as MRI and chemoprevention for high-risk women often needs to start before the age of 50 years, there is a great need to enhance risk assessment for these younger high risk women. Citation Format: Mary Beth Terry, Kelly-Anne Phillips, Yuyan Liao, Robert J. MacInnis, Gillian S. Dite, Mary B. Daly, Esther M. John, Irene L. Andrulis, Saundra S. Buys, Richard Buchsbaum, John L. Hopper. Comparison of risk model recommendations for women at high-risk of breast cancer based on clinical thresholds using the Prospective Family Study Cohort (ProF-SC). [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr PR07.

Abstract S5-03: Menopausal symptoms as predictors of long-term adherence in the International breast cancer intervention study (IBIS-1)

Abstract Tamoxifen reduces the risk of breast cancer among women at increased risk of the disease. The effectiveness of the drug is dependent on its appropriate use for the duration of therapy. Adherence for the full course of preventive therapy ranges from 60-80%. Early discontinuation is largely attributed to side-effects, but no studies have validated this using 5-year follow-up data. We assessed the role of menopausal side-effects on long-term adherence in the UK arm of the International Breast Cancer Intervention Study (IBIS-1). In the IBIS-1 trial, 4279 women in the UK were randomised to placebo vs. tamoxifen (20mg/day). A total of 292 were excluded (breast cancer, death, or other cancer), leaving 3987 to be included in the analysis (2000 placebo arm, 1987 tamoxifen arm). Adherence was calculated using data from six monthly clinical visits during the trial. Adherence (&amp;lt;4.5 years, ≥4.5 years) was calculated using the Kaplan-Meier estimator. Our main objective was to investigate the effect of menopausal side effects experienced during the first six months on adherence overall and by treatment arm. All analyses were adjusted for age, Tyrer-Cuzick risk, smoking, hormone replacement therapy use, menopausal status, baseline symptoms, and treatment. Overall, 66.8% of women were adherent for at least 4.5 years (placebo: 71.5% vs. tamoxifen: 62.1%, p&amp;lt;0.001). Highest drop-out rates were found within the first 12 months of follow-up, and a significant difference in adherence between treatment arms was observed thereafter (p&amp;lt;0.05). A low number of women experienced nausea/vomiting (5.0%) and headaches (7.0%), while higher proportions reported gynaecological symptoms (irregular bleeding/vaginal dryness/vaginal discharge, 13.8%) and hot flushes (31.5%). Women reporting nausea/vomiting (OR=1.82 [95% CI, 1.35-2.47], p&amp;lt;0.001) and headaches (OR=1.41 [1.08-1.84], p=0.01) were significantly more likely to be non-adherent at 4.5 years. Long-term adherence was not significantly affected for those who reported hot flushes (OR=1.10 [0.94-1.30], p=0.2) or gynaecological symptoms (OR=1.18 [0.99-1.41], p=0.07) compared with their counterparts. Nausea/vomiting was significantly associated with non-adherence in both the placebo (OR=1.82 [1.16-2.87], p=0.009) and tamoxifen (OR=1.84 [1.22-2.76], p=0.004) arms. Headaches were associated with non-adherence in the placebo arm (OR=1.70 [1.16-2.50], p=0.006), while gynaecological symptoms were only significant in the tamoxifen arm (OR=1.30 [1.05-1.63], p=0.02). The majority of side effects were of mild or moderate severity and we observed significant trends for lower adherence with increasing severity for all symptoms (p&amp;lt;0.05 to &amp;lt;0.001). In the IBIS-I trial, we observed a significant effect of common menopausal symptoms on long-term adherence. These effects were largely similar between tamoxifen and placebo arms, suggesting women are attributing age-related menopausal symptoms to preventive therapy. To ensure women experience the full benefit of preventive therapy, interventions are required to support the management of menopausal symptoms and to promote adherence. The higher rate of drop-out in the early months of the trial suggests early intervention may be an effective way to promote long-term adherence. Citation Format: Smith SG, Sestak I, Forbes J, Howell A, Cuzick JJ. Menopausal symptoms as predictors of long-term adherence in the International breast cancer intervention study (IBIS-1) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S5-03.

Validating the IBIS and BOADICEA Models for Predicting Breast Cancer Risk in the Iranian Population

BackgroundSeveral approaches have been suggested for incorporating risk factors to predict the future risk of breast cancer. The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) and International Breast Cancer Intervention Study (IBIS) are among these approaches. We compared the performance of these models in discriminating between cases and noncases in the Iranian population. Patients and MethodsWe performed a case-control study in Tehran, from November 2015 to April 2016, and enrolled 1633 women aged 24 to 75 years, including 506 cases of breast cancer, 916 population-based controls, and 211 clinic-based controls. We calculated and compared the risk of breast cancer predicted by the IBIS and BOADICEA models and the logistic regression model. For model discrimination, we computed the area under the receiver operating characteristic (ROC) curve. ResultsThe risk of breast cancer predicted by the IBIS model was higher than the BOADICEA model, but lower than the logistic model. The area under the ROC plots indicated that the logistic regression model showed better discrimination between cases and noncases (71.53%) compared with the IBIS model (49.36%) and BOADICEA model (35.84%). Based on the Pierson correlation coefficient, the correlation between IBIS and BOADICEA models was much stronger than the correlation between IBIS and logistic models (0.3884 and 0.1639, respectively). ConclusionThe IBIS model discriminated cases and noncases better than the BOADICEA model in the Iranian population. However, the discrimination of the logistic regression model, which included a larger array of familial, genetic, and personal risk factors, was better than the 2 models.

Relationship of ZNF423 and CTSO with breast cancer risk in two randomised tamoxifen prevention trials.

A case-control study from two randomised breast cancer prevention trials of tamoxifen and raloxifene (P-1 and P-2) identified single-nucleotide polymorphisms (SNPs) in or near genes ZNF423 and CTSO as factors which predict which women will derive most anti-cancer benefit from selective oestrogen receptor modulator (SERM) therapy. In this article, we further examine this question using blood samples from two randomised tamoxifen prevention trials: the International Breast Cancer Intervention Study I (IBIS-I) and the Royal Marsden trial (Marsden). A nested case-control study was designed with 2:1 matching in IBIS-I and 1:1 matching in Marsden. The OncoArray was used for genotyping and included two SNPs previously identified (rs8060157 in ZNF423 and rs10030044 near CTSO), and 102 further SNPs within the same regions. Overall, there were 369 cases and 662 controls, with 148 cases and 268 controls from the tamoxifen arms. Odds ratios were estimated by conditional logistic regression, with Wald 95% confidence intervals. In the tamoxifen arms, the per-allele odds ratio for rs8060157 was 0.99 (95%CI 0.73-1.34) and 1.00 (95%CI 0.76-1.33) for rs10030044. In the placebo arm, the odds ratio was 1.10 (95%CI 0.87-1.40) for rs8060157 and 1.01 (95%CI 0.79-1.29) for rs10030044. There was no evidence to suggest that other SNPs in the surrounding regions of these SNPs might predict response to tamoxifen. Results from these two prevention trials do not support the earlier findings. rs8060157 in ZNF423 and rs10030044 near CTSO do not appear to predict response to tamoxifen.

Aromatase inhibitors for prevention of breast cancer in postmenopausal women: a narrative review.

The increasing incidence of breast cancer (BC) worldwide has resulted in widespread interest in primary prevention therapies. A number of large randomized trials have shown that selective estrogen receptor modulators can reduce the relative risk for BC by 30% to 40% in high-risk women. In early-stage BC, aromatase inhibitors (AIs) showed a 35% relative reduction in the risk of contralateral BCs compared with tamoxifen. In this narrative review, we discuss the role of AIs in the primary prevention of BC and novel research on combination hormone therapy-medical therapy for the primary prevention of BC. Using PubMed/Medline, we comprehensively searched for studies of BC primary prevention using AIs, including studies of novel methods of prevention using combination hormone therapy-BC prevention. Two large multicenter, prospective, randomized, placebo-controlled trials have evaluated AIs--anastrozole (International Breast Cancer Intervention Study II) and exemestane (Mammary Prevention 3)--for BC risk reduction in women at increased risk for BC, which we summarize. We identified five studies (three completed and two ongoing) of combination AI-hormone therapy that are undergoing investigation for BC risk reduction. AIs are effective at BC risk reduction, although long-term follow-up data are required to assess whether this risk reduction will result in reduced mortality. Combination hormone therapy-AI for BC risk reduction is experimental and warrants further investigation.

Clinical management of women at high risk of breast cancer.

This article reviews the evidence that underpins breast cancer screening and prevention strategies for women at high risk of the disease, with a particular focus on evidence published in the last 18 months. The review is timely because the US National Comprehensive Cancer Network, the UK National Institute for Health and Care Excellence and the American Society of Clinical Oncology have recently updated relevant guidelines that inform practice. In the recently published literature, there have been several important findings. A meta-analysis of randomized trials of selective oestrogen receptor modulators (SERMs), along with the first results from the International Breast Cancer Intervention Study II trial, further support the use of SERMs and aromatase inhibitors in the primary prevention of breast cancer. A large observational study has provided evidence that the SERM tamoxifen may be efficacious for breast cancer prevention in women who carry mutations in the breast cancer predisposition genes, BRCA1 and BRCA2. Several observational studies have suggested that contralateral risk-reducing mastectomy, following a diagnosis of breast cancer, may reduce mortality. Evidence regarding the optimal management of women at high risk of breast cancer continues to evolve and needs to be rapidly implemented into clinical practice.

Long-Term Benefit of Tamoxifen Chemoprevention

The prior International Breast Cancer Intervention Study I (IBIS-I) showed that, after a median follow-up of 8 years, tamoxifen reduced the risk for

Mammographic breast density refines Tyrer-Cuzick estimates of breast cancer risk in high-risk women: findings from the placebo arm of the International Breast Cancer Intervention Study I

IntroductionMammographic density is well-established as a risk factor for breast cancer, however, adjustment for age and body mass index (BMI) is vital to its clinical interpretation when assessing individual risk. In this paper we develop a model to adjust mammographic density for age and BMI and show how this adjusted mammographic density measure might be used with existing risk prediction models to identify high-risk women more precisely.MethodsWe explored the association between age, BMI, visually assessed percent dense area and breast cancer risk in a nested case-control study of women from the placebo arm of the International Breast Cancer Intervention Study I (72 cases, 486 controls). Linear regression was used to adjust mammographic density for age and BMI. This adjusted measure was evaluated in a multivariable logistic regression model that included the Tyrer-Cuzick (TC) risk score, which is based on classical breast cancer risk factors.ResultsPercent dense area adjusted for age and BMI (the density residual) was a stronger measure of breast cancer risk than unadjusted percent dense area (odds ratio per standard deviation 1.55 versus 1.38; area under the curve (AUC) 0.62 versus 0.59). Furthermore, in this population at increased risk of breast cancer, the density residual added information beyond that obtained from the TC model alone, with the AUC for the model containing both TC risk and density residual being 0.62 compared to 0.51 for the model containing TC risk alone (P =0.002).Approximately 16% of controls and 19% of cases moved into the highest risk group (8% or more absolute risk of developing breast cancer within 10 years) when the density residual was taken into account. The net reclassification index was +15.7%.ConclusionsIn women at high risk of breast cancer, adjusting percent mammographic density for age and BMI provides additional predictive information to the TC risk score, which already incorporates BMI, age, family history and other classic breast cancer risk factors. Furthermore, simple selection criteria can be developed using mammographic density, age and BMI to identify women at increased risk in a clinical setting.Clinical trial registration numberhttp://www.controlled-trials.com/ISRCTN91879928 (Registered: 1 June 2006).Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0451-5) contains supplementary material, which is available to authorized users.

New Trials Highlight Breast Cancer Therapy and Prevention

Antihormone Therapy for Breast Cancer Prevention Many women who face particularly high odds of developing breast cancer—including those having 2 or more blood relatives with breast cancer, a mother or sister who developed breast cancer before the age of 50 years, or a mother or sister who had breast cancer in bothbreasts—arewilling to take preventive measures. Some have prophylacticmastectomies. Someopt for longterm use of the antihormone therapies tamoxifen or raloxifene, which respectively lower breast cancer risk by 50% and 38% but can cause significant adverse effects such as blood clots and stroke. The phase 3 International Breast Cancer Intervention Study II (IBIS-II) Prevention trial investigatedwhether anastrozole, an alternative antihormone therapy with fewer adverseeffects than tamoxifenor raloxifene, helpspreventbreast cancer in such women. Anastrozole, an aromatase inhibitor that blocks estrogen production, has been used for more than a decade to preventbreast cancer recurrence inpostmenopausal womenwith tumors that are dependent on estrogen. From 2003 to 2012, researchers enrolled 3864 postmenopausal women at increased risk fordevelopingbreast cancer.Of these, 1920were randomlyassigned to take anastrozole for 5 years,while 1944were assigned to take a placebo. The results “were as good as we could havehopedfor,” saidJackCuzick,PhD,chairmanof the IBIS-IISteeringCommitteeanddirector of theWolfson Institute of Preventive Medicine at Queen Mary University of London.Theinvestigatorsfoundthatwomentaking anastrozole were 53% less likely to develop breast cancer than women taking placebo, with 40women in the anastrozole groupdevelopingbreastcancervs85women in theplacebogroup.Women in theanastrozolegroupwerealsosignificantly less likelyto develophigh-gradetumors.Theresultswere recentlypublishedtocoincidewiththeirpresentation at the conference (Cuzick J et al. Lancet.doi:10.1016/S0140-6736[13]62292-8 [published online December 12, 2013]). Mysteriously, the researchers found about a 40% reduction in other cancers as well, especially skin cancers. “This is anotherexcitingpossibility—that thismayhave an effect on other cancers, which we will continue to explore,” said Cuzick. The teamwill continue followingup the IBIS-II Preventionparticipants for at least 10 years to determine if anastrozole continues to influence cancer incidence even after treatment ends, if it reduces deaths from breast cancer, and if it is free from longterm adverse effects. Thestudy results comeshortly after the AmericanSocietyofClinicalOncologyadded exemestane,anotheraromatase inhibitor, to its list of recommended drugs to prevent breast cancer (http://bit.ly/1cRSNbX). That decision, announced in July, was based on the results of an earlier randomized study that showed a 53% reduction over a 3-year period in invasive and noninvasive breast cancer incidence with exemestane compared with placebo (Goss PE et al. N Engl J Med. 2011;364[25]:2381-2391).

Breast cancer chemoprevention: little progress in practice?

Breast cancer chemoprevention: little progress in practice?

Abstract ED05-02: Targeting estrogen receptors for breast cancer prevention

Abstract Before “targeted” therapy was part of the oncology lexicon, the estrogen receptor (ER) was already a much touted target of drug development for breast cancer treatment and prevention. Selective estrogen receptor modulators (SERMs) were developed for the purpose of binding to the ER. Tamoxifen, the first SERM studied for breast cancer treatment and prevention, inhibits the action of the ER in the breast. In the 1980s it elicited improvements in overall and disease-free survival in women with breast cancer and was subsequently tested with a primary endpoint of breast cancer prevention in high-risk women. The Breast Cancer Prevention Trial demonstrated a 49% reduction in new breast cancers in high-risk women, leading to FDA approval of tamoxifen for this purpose in 1998. The was the first FDA approval of an agent for a cancer prevention indication. Subsequently a series of SERMs have been developed for osteoporosis, most notably raloxifene. The Study of Tamoxifen and Raloxifene showed the two SERMs to be equivalent in terms of their ability to target the ER and prevent ER-positive breast cancer, with raloxifene exhibiting overall less toxicity. This agent, already approved for osteoporosis treatment and prevention, was approved for breast cancer prevention in postmenopausal women in 2007. More recently, meta-analyses of these and other studies comparing SERMs to placebo in a variety of disease settings have consistently shown benefits for breast cancer prevention in the SERM arm. The latest approach to targeting the estrogenic effect on breast cancer development involves inhibition of estrogen production, as opposed to estrogen action. The aromatase inhibitors (AIs) prevent the enzyme, aromatase, from converting androgens to estrogens. In postmenopausal women, in whom the majority of AI studies have been carried out, the inhibition of estrogen production is almost complete. The Mammary Prevention 3 trial showed that the AI exemestane decreased the incidence of breast cancer by up to 70% compared to placebo, with different toxicities than tamoxifen. The International Breast Cancer Intervention Study II, which is comparing the AI anastrozole to placebo in high-risk postmenopausal women, is still ongoing. Both the SERM and AI classes of targeted breast cancer prevention agents are effective in preventing ER-positive breast cancers, leaving an urgent need to develop drugs to prevent ER-negative breast cancers. Citation Format: Leslie G. Ford, Barbara K. Dunn. Targeting estrogen receptors for breast cancer prevention. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr ED05-02.

Abstract A07: Lifestyle modifications and use of complementary and alternative medicine in relation to perceived and model-based breast cancer risk among women at high risk of developing breast cancer

Abstract Background: Among women at high risk of breast cancer, there are limited data on the prevalence of use of lifestyle modifications and complementary and alternative medicine (CAM) for the purpose of breast cancer prevention. We examined use of lifestyle modifications and CAM in a diverse cohort of women at high breast cancer risk, including associations between the behaviors and perceived and model-based risk. Methods: We used cross-sectional data from 810 non-Hispanic white and Hispanic women with no personal history of breast cancer enrolled in the Metropolitan New York Registry (MNYR) of Breast Cancer Families, one of six international sites of the National Cancer Institute's Breast Cancer Family Registry. Self-reported current lifestyle modifications (dietary change, exercise), use of CAM (multivitamins, herbal supplements, other dietary supplements, and prayer), perceived breast cancer risk, and breast cancer risk factors were assessed via a computer assisted telephone interview. The International Breast Cancer Intervention Study (IBIS) model, a validated breast cancer risk model for high-risk women, was used to estimate 10-year breast cancer risk. Relative risk regression models were used to examine associations between use of lifestyle modifications and CAM and perceived and model-based risk. Results: The large majority of the sample (92.8%) reported current use of ≥1 lifestyle modification or CAM modality, and 16.4% reported using ≥1 specifically for breast cancer prevention. Among all women, 46.1 % used dietary change, 73.0% used exercise, 55.9% use multivitamins, 17.8% used herbal supplements, 51.5% used dietary supplements, and 44.7% used prayer. Non-Hispanic whites were more likely than Hispanics to use dietary change (p&amp;lt;0.001), exercise (p=0.002), other supplements (p=0.05), and prayer (p&amp;lt;0.001) specifically for breast cancer prevention. Hispanics were more likely than non-Hispanic whites to perceive their risk of breast cancer to be lower than the risk in the general population (p&amp;lt;0.0001). Model-based risk was significantly higher in non-Hispanic whites (7.1% ± 7.9% vs. 5.1% ± 6.5%; p&amp;lt;0.0001). In multivariable analyses, below average perceived risk of breast cancer was associated with prayer (RR: 1.43; 95% CI: 1.05, 1.96) and with the use of a higher number of lifestyle modifications and/or CAM modalities (RR: 1.23; 95% CI: 1.05-1.45) among non-Hispanic whites. Among Hispanics only, higher model-based risk was associated with current exercise (RR: 1.46; 95% CI: 1.02, 2.09). There was no association between perceived risk and current exercise, dietary change, and the use of multivitamins, herbal supplements or other supplements. Model-based risk did not appear to be a significant predictor of dietary change or use of herbal supplements, other supplements, or prayer. Conclusions: Use of lifestyle modifications and CAM modalities is common among women at high risk for breast cancer, but patterns of use differed by ethnicity. Compared to non-Hispanic whites, Hispanic women were less likely to engage in breast cancer prevention behaviors, including dietary change and exercise, and were less likely to accurately perceive their breast cancer risk. Neither perceived risk nor model-based risk appear to be strong predictors of these behaviors. Future research should investigate motivations for the use of these modalities and awareness of evidence-based recommendations among women at high risk of breast cancer. Citation Format: Cristina Valdovinos, Mary Beth Terry, Yuyan Liao, Ann Johnston, Heather Greenlee. Lifestyle modifications and use of complementary and alternative medicine in relation to perceived and model-based breast cancer risk among women at high risk of developing breast cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A07.

Relationships between CYP2D6 phenotype, breast cancer and hot flushes in women at high risk of breast cancer receiving prophylactic tamoxifen: results from the IBIS-I trial

Background:Several studies have reported discordant results regarding the impact of the CYP2D6 phenotype on both the effectiveness and the degree of endocrine symptoms associated with tamoxifen. Other studies have suggested that menopausal symptoms may be a predictive factor to tamoxifen response.Methods:We investigated the relationship between the CYP2D6-predicted phenotype and tamoxifen response in a nested case–control study among women from the International Breast cancer Intervention Study (IBIS-I), which evaluated tamoxifen in the preventive setting.Results:In this retrospective analysis of the tamoxifen-treated women in the IBIS-I study, 9 women (16.6%) who developed oestrogen receptor-positive invasive breast cancer had a 2D6 poor or intermediate metaboliser phenotype compared with 45 (20.6%) controls. Adjusted matched logistic regression revealed no significant difference between cases and controls for extensive vs intermediate metaboliser phenotype (OR=0.81 (0.30–2.23), P=0.7) or extensive vs poor metaboliser phenotype (OR=1.02 (0.31–3.32), P=0.9). Controls in the tamoxifen group with a poor metaboliser phenotype developed nonsignificantly fewer hot flushes compared with those with an extensive metaboliser phenotype (OR=0.40 (0.12–1.31)), but those with the intermediate phenotype developed nonsignificantly more hot flushes (OR=1.38 (0.58–3.29)) in an unadjusted analysis.Conclusion:Data from the preventive IBIS-I study did not support an association between the CYP2D6 phenotype and breast cancer outcome or the development of endocrine symptoms in tamoxifen-treated women.

Tamoxifen, Mammographic Density, and Breast Cancer Prevention

Tamoxifen, Mammographic Density, and Breast Cancer Prevention

Tamoxifen-Induced Reduction in Mammographic Density and Breast Cancer Risk Reduction: A Nested Case-Control Study

Mammographic breast density is a strong risk factor for breast cancer. Tamoxifen, which reduces the risk of breast cancer in women at high risk, also reduces mammographic breast density. However, it is not known if tamoxifen-induced reductions in breast density can be used to identify women who will benefit the most from prophylactic treatment with this drug. We conducted a nested case-control study within the first International Breast Cancer Intervention Study, a randomized prevention trial of tamoxifen vs placebo. Mammographic breast density was assessed visually and expressed as a percentage of the total breast area in 5% increments. Case subjects were 123 women diagnosed with breast cancer at or after their first follow-up mammogram, which took place 12-18 months after trial entry, and control subjects were 942 women without breast cancer. Multivariable logistic regression was used to adjust for other risk factors. All statistical tests were two-sided. In the tamoxifen arm, 46% of women had a 10% or greater reduction in breast density at their 12- to 18-month mammogram. Compared with all women in the placebo group, women in the tamoxifen group who experienced a 10% or greater reduction in breast density had 63% reduction in breast cancer risk (odds ratio = 0.37, 95% confidence interval = 0.20 to 0.69, P = .002), whereas those who took tamoxifen but experienced less than a 10% reduction in breast density had no risk reduction (odds ratio = 1.13, 95% confidence interval = 0.72 to 1.77, P = .60). In the placebo arm, there was no statistically significant difference in breast cancer risk between subjects who experienced less than a 10% reduction in mammographic density and subjects who experienced a greater reduction. The 12- to 18-month change in mammographic breast density is an excellent predictor of response to tamoxifen in the preventive setting.

Evaluation of the Tyrer-Cuzick (International Breast Cancer Intervention Study) Model for Breast Cancer Risk Prediction in Women With Atypical Hyperplasia

Accurate breast cancer risk assessment is vital to personalize screening and risk reduction strategies. Women with atypical hyperplasia have a four-fold higher risk of breast cancer. We evaluated the performance of the Tyrer-Cuzick model, which was designed to predict 10-year risk of breast cancer development, in a well-defined cohort of women with atypia. The Mayo Benign Breast Disease cohort includes 9,376 women who had a benign breast biopsy between 1967 and 1991. Among those, 331 women with atypia were identified by our study pathologists. Risk factor data for the Tyrer-Cuzick model were collated for each woman and used to predict individual risk of developing invasive breast cancer within 10 years. Over a median follow-up of 14.6 years, 64 (19%) of the 331 women developed invasive breast cancer. In the first 10 years after biopsy, 31 women developed invasive breast cancer whereas the Tyrer-Cuzick model predicted 58.9. The observed-to-predicted ratio was 0.53 (95% CI, 0.37 to 0.75). The concordance statistic was 0.540, revealing that the Tyrer-Cuzick model did not accurately distinguish, on an individual level, between women who developed invasive breast cancer and those who did not. The Tyrer-Cuzick model significantly overestimated risk of breast cancer for women with atypia, and individual risk estimates showed poor concordance between predicted risk and invasive breast cancer development. Thus, we cannot recommend the use of the Tyrer-Cuzick model to predict 10-year breast cancer risk in women with atypical hyperplasia.

Breast cancer risk assessment in a mammography screening program and participation in the IBIS-II chemoprevention trial

It has been shown in several studies that antihormonal compounds can offer effective prophylactic treatment to prevent breast cancer. In view of the low participation rates in chemoprevention trials, the purpose of this study was to identify the characteristics of women taking part in a population-based mammography screening program who wished to obtain information about the risk of breast cancer and then participate in the the International Breast Cancer Intervention Study II (IBIS-II) trial, a randomized double-blind controlled chemoprevention trial comparing anastrozole with placebo. A paper-based survey was conducted in a population-based mammography screening program in Germany between 2007 and 2009. All women who met the criteria for the mammography screening program were invited to complete a questionnaire. A total of 2,524 women completed the questionnaire, and 17.7% (n = 446) met the eligibility criteria for the IBIS-II trial after risk assessment. The women who wished to receive further information about chemoprevention were significantly younger (P < 0.01) and had significantly more children (P = 0.03) and significantly more relatives with breast cancer (P < 0.001). There were no significant differences between the participants with regard to body mass index or hormone replacement therapy. Normal mammographic findings at screening were the main reason (42%) for declining to participate in the IBIS-II trial or attend risk counseling. The ultimate rate of recruitment to the IBIS-II trial was very low (three women). Offering chemoprevention to women within a mammography screening unit as part of a paper-based survey resulted in low participation rates for both, the survey and the final participation in the IBIS-II trial. More individualized approaches and communication of breast cancer risk at the time of the risk assessment might be helpful to increase the participation and the understanding of chemopreventive approaches.