Incidence Of Invasive Breast Cancer Research Articles

Study protocol: Randomized controlled trial of web-based decision support tools for high-risk women and healthcare providers to increase breast cancer chemoprevention

BackgroundChemoprevention using selective estrogen receptor modulators and aromatase inhibitors has been shown to reduce invasive breast cancer incidence in high-risk women. Despite this evidence, few high-risk women who are eligible for chemoprevention utilize it as a risk-reducing strategy. Reasons for low uptake include inadequate knowledge about chemoprevention among patients and healthcare providers, concerns about side effects, time constraints during the clinical encounter, and competing comorbidities. Methods/designWe describe the study design of a randomized controlled trial examining the effect of two web-based decision support tools on chemoprevention decision antecedents and quality, referral for specialized counseling, and chemoprevention uptake among women at an increased risk for breast cancer. The trial is being conducted at a large, urban medical center. A total of 300 patients and 50 healthcare providers will be recruited and randomized to standard educational materials alone or in combination with the decision support tools. Patient reported outcomes will be assessed at baseline, one and six months after randomization, and after their clinic visit with their healthcare provider. DiscussionWe are conducting this trial to provide evidence on how best to support personalized breast cancer risk assessment and informed and shared decision-making for chemoprevention. We propose to integrate the decision support tools into clinical workflow, which can potentially expand quality decision-making and chemoprevention uptake. Trial registrationNCT03069742.

Pre-diagnosis alcohol consumption and mortality risk among black women and white women with invasive breast cancer

BackgroundAlcohol consumption is associated with increased risk of breast cancer; however, its association with subsequent risk of breast cancer death is unclear.MethodsWe followed 4523 women with complete information on relevant risk factors for mortality; these women were 35 to 64 years of age when diagnosed with incident invasive breast cancer between 1994 and 1998. During follow up (median, 8.6 years), 1055 women died; 824 died from breast cancer. The information on alcohol consumption before diagnosis was collected shortly after breast cancer diagnosis (average: 5.1 months) during an in-person interview which used a structured questionnaire. Multivariable Cox proportional hazards regression models provided hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer-specific mortality, mortality due to causes other than breast cancer, and all-cause mortality associated with alcohol consumption from age 15 years until breast cancer diagnosis and during recent periods of time prior to breast cancer diagnosis.ResultsAverage weekly alcohol consumption from age 15 years until breast cancer diagnosis was inversely associated with breast cancer-specific mortality (Ptrend = 0.01). Compared to non-drinkers, women in the highest average weekly alcohol consumption category (≥7 drinks/week) had 25% lower risk of breast cancer-specific mortality (HR = 0.75, 95% CI = 0.56–1.00). Breast cancer mortality risk was also reduced among women in the highest average weekly alcohol consumption category in two recent time periods (5-year period ending 2-years prior to breast cancer diagnosis, HR = 0.74, 95% CI = 0.57–0.95; 2-year period immediately prior to breast cancer diagnosis: HR = 0.73, 95% CI = 0.56–0.95). Furthermore, analyses of average weekly alcohol consumption by beverage type from age 15 years until breast cancer diagnosis suggested that wine consumption was inversely associated with breast cancer-specific mortality risk (wine Ptrend = 0.06, beer Ptrend = 0.24, liquor Ptrend = 0.74). No association with any of these alcohol consumption variables was observed for mortality risk due to causes other than breast cancer.ConclusionsOverall, we found no evidence that alcohol consumption before breast cancer diagnosis increases subsequent risk of death from breast cancer.

Association between meat consumption and risk of breast cancer: Findings from the Sister Study.

Meat consumption has been postulated to increase the risk of breast cancer, but this association has not been consistently seen. We examined the association between consumption of different types of meat, meat mutagens and incident invasive breast cancer. Information on consumption of different meat categories and meat cooking practice behaviors was obtained from 42,012 Sister Study participants who completed a Block 1998 Food Frequency Questionnaire at enrollment (2003-2009) and satisfied eligibility criteria. Exposure to meat type and meat mutagens was calculated, and associations with invasive breast cancer risk were estimated using multivariable Cox proportional hazards regression. During follow-up (mean, 7.6 years), 1,536 invasive breast cancers were diagnosed at least 1 year after enrollment. Increasing consumption of red meat was associated with increased risk of invasive breast cancer (HRhighest vs. lowest quartile :1.23, 95% CI: 1.02-1.48, ptrend = 0.01). Conversely, increasing consumption of poultry was associated with decreased invasive breast cancer risk (HR highest vs. lowest quartile : 0.85; 95% CI: 0.72-1.00; ptrend = 0.03). In a substitution model with combined red meat and poultry consumption held constant, substituting poultry for red meat was associated with decreased invasive breast cancer risk (HR highest vs. lowest quartile of poultry consumption: 0.72, 95% CI: 0.58-0.89). No associations were observed for cooking practices, estimated heterocyclic amines or heme iron from red meat consumption with breast cancer risk. Red meat consumption may increase the risk of invasive breast cancer, whereas poultry consumption may be associated with reduced risk. Substituting poultry for red meat could reduce breast cancer risk.

Adherence to quality breast cancer survivorship care in four Canadian provinces: a CanIMPACT retrospective cohort study

BackgroundIn order to maximize later health, there are established components and guidelines for quality follow-up care of breast cancer survivors. However, adherence to quality follow-up in Canada may not be optimal, and may vary by province. We determined and compared the proportion of patients in each province who received adherent and non-adherent surveillance for recurrence, new cancers and late effects, recommended preventive care, and recommended physician visits for comorbidities.MethodsCohorts consisted of all adult women diagnosed with incident invasive breast cancer between 2007 and 2010/2012 in four Canadian provinces (British Columbia (BC) N = 9338; Manitoba N = 2688; Ontario N = 23,700; Nova Scotia (NS) N = 2735), identified from provincial cancer registries, alive and cancer-free at 30 months post-diagnosis. Their healthcare utilization was determined from one to 5 years post-treatment, using linked administrative databases. Adherence, underuse, and overuse of recommended services were evaluated yearly and compared using descriptive statistics.ResultsIn all provinces and follow-up years, the majority of survivors had more than the recommended number of visits to either an oncologist or primary care physician (range 53.8% NS Year 3; 85.8% Ontario Year 4). The proportion of patients with the guideline-recommended number of oncologist visits varied by province (range 29.8% BC Year 5; 74.8% Ontario Year 5), and the proportion of patients with less than the recommended number of specified breast cancer-related visits with either an oncologist or primary care physician ranged from 32.6% (Ontario Year 2) to 84.4% (NS Year 3). Underuse of surveillance breast imaging was identified in NS and BC. The proportion of patients receiving imaging for metastatic disease (not recommended in the guidelines) in BC, Manitoba, and Ontario (not reported in NS) ranged from 20.3% (BC Year 5) to 53.3% (Ontario Year 2). Compliance with recommended physician visits for patients with several chronic conditions was high in Ontario and NS. Preventive care was less than optimal in all provinces with available data.ConclusionsQuality of breast cancer survivor follow-up care varies among provinces. Results point to exploration of factors affecting differences, province-specific opportunities for care improvement, and the value of administrative datasets for health system assessment.

Abstract 966: Coffee consumption and invasive breast cancer incidence among postmenopausal women in the Cancer Prevention Study II Nutrition Cohort

Abstract Accumulating evidence suggests that coffee consumption may be inversely associated with breast cancer risk among postmenopausal women, with growing evidence of a stronger association for caffeinated than for decaffeinated coffee. However, few studies have examined this association by hormone receptor status or minimized confounding due to cigarette smoking. Recently, we found that caffeinated, but not decaffeinated coffee consumption was inversely associated with breast cancer mortality among nonsmoking women enrolled in the Cancer Prevention Study-II (CPS-II). Subsequently, the 2018 WCRF/AICR Diet, Nutrition, Physical Activity and Cancer Third Expert Report drew no conclusion regarding the association between coffee consumption and breast cancer risk. To provide further evidence, we examined total, caffeinated and decaffeinated coffee consumption in relation to postmenopausal invasive breast cancer incidence, overall, among nonsmokers and by estrogen and/or progesterone receptor (ER/PR) status among women enrolled in the CPS-II Nutrition Cohort, a subcohort of CPS-II. This analysis included 57,120 postmenopausal women who were cancer-free and reported coffee intake in 1999, and who were followed for cancer incidence through June 2013. During follow-up, 2,848 (2,349 ER or PR positive, and 252 ER and PR negative) women with a verified invasive breast cancer were identified. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI). Neither total nor decaffeinated coffee consumption was associated with risk of invasive breast cancer among all women or in any subgroup. For caffeinated coffee consumption, the HR (95% CI) for consumption of 2 or more cups/day, compared to less than 1 cup/month, was 0.90 (0.82-1.00) among all women, and 0.88 (0.80-0.98) among nonsmokers. Similarly, caffeinated coffee consumption was associated with a statistically significantly lower risk of ER+ or PR+ breast cancer (HR=0.88, 95% CI 0.79-0.99) and a nonsignificant lower risk of ER- and PR- breast cancer (HR=0.83, 95% CI 0.59-1.16) among all women. These findings underscore the importance of stratifying on type of coffee in studies examining the association between coffee consumption and risk of invasive postmenopausal breast cancer. Additionally, to better understand the role of caffeinated vs. decaffeinated coffee in breast cancer etiology we will examine the potential mediating effects of coffee metabolites on this association. Citation Format: Susan M. Gapstur, Marjorie L. McCullough, Rebecca A. Hodge, Ying Wang, Caroline Y. Um, Terryl J. Hartman, Mia M. Gaudet. Coffee consumption and invasive breast cancer incidence among postmenopausal women in the Cancer Prevention Study II Nutrition Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 966.

Abstract LB-140: Myoepithelial-immune cell crosstalk in the transition from non-invasive to invasive breast cancer

Abstract The incidence of ductal carcinoma in situ (DCIS), a pre-invasive malignancy of the breast, has increased in the U.S. since the 1980s, from 3% to 20% of all breast cancer diagnoses. This increase is largely attributed to mammographic screening. Common treatments of DCIS are breast-conserving surgery followed by adjuvant radiation therapy or mastectomy. Further, despite efforts to detect and treat early stage cancer, the incidence of invasive breast cancer (IBC) has not declined, suggesting that many women with DCIS are over treated. Thus, prognostic markers that predict risk of DCIS progression are needed. Genomic studies have yet to find tumor intrinsic alterations that predict DCIS progression to IBC. In contrast, genetic changes in the myoepithelium are found at the transition from DCIS to IBC, suggesting myoepithelial cells may play a role in progression. To investigate the myoepithelium for potential biomarkers, we advanced a non-surgical intraductal tumor cell delivery model in mice using human DCIS.com cells. We reported a progressive loss in myoepithelial differentiation markers p63, calponin, and smooth muscle actin (SMA) prior to transition to IBC, observations that were confirmed in human DCIS. Thus, compromise in the myoepithelium may be an early warning for DCIS at high risk for progression. Here, we hypothesize that the myoepithelial differentiation state informs immune response, and that DCIS lesions with loss of myoepithelial Calponin and SMA will be associated with a pro-tumorigenic immune milieu. This hypothesis is based on observations by us and others showing lymphocyte infiltration in areas where the DCIS myoepithelium has been focally compromised. To address this, we analyzed the expression of 10 myoepithelial and lymphoid biomarkers using multiplex immunohistochemistry to analyze the relationship between myoepithelial cell integrity and immune cells (N=36 cases). DCIS in the background of IBC (mixed DCIS) is assumed to be high-risk DCIS. We find compromised myoepithelial calponin in mixed compared to pure DCIS. Mixed lesions also show reduced infiltration of immune and T-cells, consistent with reduced immune surveillance. However, calponin loss in pure DCIS cases was associated with a decrease in Foxp3+ T-regulatory cells and increase in CD8+PD-1+ T-cells. Next we found that DCIS areas with focal loss of the myoepithelium and micro-invasion showed an increase in immune infiltration, increased T-cells, and increased PD-1+CD8+ T-cells. These data suggest that early compromise in the myoepithelial layer may associate with activation of cytotoxic effectors, consistent with increased immune surveillance. However, since we find T-cell numbers are reduced in mixed DCIS, effective immune surveillance may be dampened with progression. These data support an unreported relationship between myoepithelial cell integrity and the activation state of local immune cells. Citation Format: Elizabeth Mitchell, Sonali Jindal, Tiffany Chan, Jayasri Narasimhan, Sheila Weinmann, Pepper Schedin. Myoepithelial-immune cell crosstalk in the transition from non-invasive to invasive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-140.

Abstract 963: The interplay between lifestyle-related factors and genetics with risk of invasive breast cancer among postmenopausal women from the UK Biobank

Abstract Background: Many genetic variants have been associated with increased risk of breast cancer. In contrast, an overall healthy lifestyle has been associated with a reduced risk. However, the degree to which an overall healthy lifestyle may attenuate the impact of genetic variants on risk of breast cancer remains equivocal. In this study, we examined the association of a healthy lifestyle index (HLI) with risk of breast cancer by genetic risk groups. Methods: The study included 106,814 postmenopausal women of white descent aged 40 to 70 years who were enrolled in the UK Biobank cohort between 2006 and 2010. The HLI was based on a combination of diet, physical activity, smoking, alcohol consumption and anthropometry (ranging from 0 to 20, with the higher scores representing more favorable lifestyle). A polygenic risk score (categorized as low, intermediate and high) was generated as the sum of risk alleles weighted by the logOR of 117 breast cancer associated single nucleotide polymorphisms. A total of 1,949 incident invasive breast cancer cases were ascertained after a median follow-up of 5.7 years. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the association of a healthy lifestyle risk score with risk of breast cancer by genetic risk groups. Results: Compared to women with an unfavorable lifestyle (lowest quartile), women with a favorable lifestyle (highest quartile) had a 32% reduced risk of invasive breast cancer (HR: 0.68: 0.59, 0.79). Women with high genetic risk (highest tertile) had an 86% increased risk of invasive breast cancer (1.86: 1.66, 2.08) compared to those with low genetic risk (lowest tertile). Compared with women who had an unfavorable lifestyle, a favorable lifestyle did not significantly reduce risk of invasive breast cancer among women with low genetic risk (0.80: 0.63-1.02), while women with a favorable lifestyle had 32% and 43% reduced risk of invasive breast cancer in the intermediate and high genetic risk categories, respectively (0.68: 0.53, 0.86 and 0.57; 0.44, 0.74, respectively). However, interaction between the genetic score and the lifestyle score did not achieve statistical significance (pinteraction=0.162). Conclusion: This study suggests that an overall healthy lifestyle may attenuate the impact of genetics on risk of breast cancer, particularly among women with intermediate and high genetic risk. Citation Format: Rhonda S. Arthur, Tao Wang, Thomas Rohan. The interplay between lifestyle-related factors and genetics with risk of invasive breast cancer among postmenopausal women from the UK Biobank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 963.

Comparison of Questionnaire-Based Breast Cancer Prediction Models in the Nurses' Health Study.

The Gail model and the model developed by Tyrer and Cuzick are two questionnaire-based approaches with demonstrated ability to predict development of breast cancer in a general population. We compared calibration, discrimination, and net reclassification of these models, using data from questionnaires sent every 2 years to 76,922 participants in the Nurses' Health Study between 1980 and 2006, with 4,384 incident invasive breast cancers identified by 2008 (median follow-up, 24 years; range, 1-28 years). In a random one third sample of women, we also compared the performance of these models with predictions from the Rosner-Colditz model estimated from the remaining participants. Both the Gail and Tyrer-Cuzick models showed evidence of miscalibration (Hosmer-Lemeshow P < 0.001 for each) with notable (P < 0.01) overprediction in higher-risk women (2-year risk above about 1%) and underprediction in lower-risk women (risk below about 0.25%). The Tyrer-Cuzick model had slightly higher C-statistics both overall (P < 0.001) and in age-specific comparisons than the Gail model (overall C, 0.63 for Tyrer-Cuzick vs. 0.61 for the Gail model). Evaluation of net reclassification did not favor either model. In the one third sample, the Rosner-Colditz model had better calibration and discrimination than the other two models. All models had C-statistics <0.60 among women ages ≥70 years. Both the Gail and Tyrer-Cuzick models had some ability to discriminate breast cancer cases and noncases, but have limitations in their model fit. Refinements may be needed to questionnaire-based approaches to predict breast cancer in older and higher-risk women.

Effect modifiers in a randomized phase III trial of low-dose tamoxifen in breast preinvasive disease.

1500 Background: Low-dose tamoxifen (babytam) at 5 mg/day for 3 years decreases local or contralateral recurrence by 52% in women with hormone sensitive breast pre-invasive neoplasia after surgery (DeCensi et al JCO 2019). Here we report the results of exploratory analyses to assess whether the benefit of babytam varies among subgroups of patients defined by individual characteristics. Methods: Post-hoc subgroup analyses were performed according to a mixed approach based on the test for interaction and biological plausibility. Incidence of invasive breast cancer or DCIS was the primary endpoint. HRs were estimated using Cox proportional-hazards modeling. Results: Age at menopause, smoking status and Ki-67 exhibited a significant interaction with treatment. Specifically, the effect of babytam was greater in women aged &gt; 50y (n = 293, HR = 0.27, 95%CI: 0.10-0.73) than in women aged ≤50y (n = 207, HR = 0.86, 0.35-2.07), p-interaction = .09. Never smokers (n = 307) had a greater benefit than former (n = 68) or current smokers (n = 97): HR = 0.28, 0.11-0.70 vs HR = 0.57, 0.09-3.45 vs HR = 1.51, 0.41-5.64, respectively (p = .05). Tumors with Ki-67 above the median level of 10% (n = 133) had a greater effect (HR = 0.27, 0.09-0.81) than Ki-67 ≤10% (n = 145, HR = 1.58, 0.45-5.60, p = .04). Weaker statistical interactions (p &gt; .1) were also found for waist circumference and hot flashes (HF) at baseline. Women with waist circumference ≥89 cm (metabolic syndrome, n = 208) had a greater effect (HR = 0.22, 0.07-0.78) than women &lt; 89 cm (n = 228, HR = 0.61, 0.25-1.46). Compared with placebo and no HF, babytam effect was stronger in women with HF (HR = 0.13, 0.02-0.96) than in women on babytam and no HF (HR = 0.50, 0.24-1.03) or placebo and HF (HR = 0.72, 0.31-1.69, log-rank p-trend = .004). Additional subgroups according to obesity, family history of breast or ovarian cancer, alcohol use, extent of surgery, radiotherapy for DCIS, ER and HER2 expression, positive margins and treatment compliance showed no significant heterogeneity of treatment. Conclusions: Exploratory analyses showed a trend to a higher effect of babytam in women aged 50 or older, never smokers, women with hot flashes or abdominal obesity and tumors with Ki-67 above 10%. Our results provide insight into the efficacy of babytam towards a personalized preventive approach. Clinical trial information: NCT01357772.

Dietary index scores and invasive breast cancer risk among women with a family history of breast cancer

Many epidemiologic studies have analyzed the relations of individual foods and nutrients and breast cancer risk with inconsistent results. Few studies have examined recommendation-based dietary indices and breast cancer risk. The aim of this study was to determine associations between recommendation-based dietary index scores and incident invasive breast cancer. The Sister Study is a prospective cohort of 50,884 US women (baseline: 2003-2009) who had a sister with breast cancer but no prior breast cancer themselves. We created scores for the Dietary Approaches to Stop Hypertension (DASH) diet, Alternative Mediterranean Diet (AMED), and Alternative Healthy Eating Index-2010 (AHEI-2010) from dietary intakes estimated by a baseline-validated Block food-frequency questionnaire (FFQ). We used Cox regression to estimate multivariable-adjusted HRs and 95% CIs for total invasive breast cancer risk and by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status. We documented 1,700 invasive breast cancer cases through 2015 (mean follow-up, 7.6 y). Individuals in the highest quartile of DASH scores had a lower risk of invasive breast cancer compared with those in the lowest quartile (HR: 0.78; 95% CI: 0.67, 0.90; P-trend=0.001), with stronger associations for ER- (HR: 0.61; 95% CI: 0.40, 0.94; P-trend=0.006) as well as ER-/PR- and ER-/PR-/HER2- subtypes. AHEI-2010 (HR for highest compared with lowest quartile: 0.90; 95% CI: 0.78, 1.03; P-trend=0.15) and AMED (HR for highest compared with lowest quartile: 0.90; 95% CI: 0.77, 1.06; P-trend=0.07) were weakly and nonsignificantly associated with breast cancer risk, but after excluding alcohol, AHEI-2010 was inversely associated with risk of ER-/PR- (HR: 0.64; 95% CI: 0.42, 0.98; P-trend=0.04) and ER-/PR-/HER2- subtypes. We did not observe any significant interactions by menopausal status or other participant characteristics. DASH scores were inversely associated with breast cancer risk; DASH and AHEI-2010 scores excluding alcohol were particularly inversely associated with risk of ER-/PR- and ER-/PR-/HER2- breast cancers. This trial was registered at clinicaltrials.gov as NCT00047970.

Regular use of aspirin and other non-steroidal anti-inflammatory drugs and breast cancer risk for women at familial or genetic risk: a cohort study

BackgroundThe use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced breast cancer risk, but it is not known if this association extends to women at familial or genetic risk. We examined the association between regular NSAID use and breast cancer risk using a large cohort of women selected for breast cancer family history, including 1054 BRCA1 or BRCA2 mutation carriers.MethodsWe analyzed a prospective cohort (N = 5606) and a larger combined, retrospective and prospective, cohort (N = 8233) of women who were aged 18 to 79 years, enrolled before June 30, 2011, with follow-up questionnaire data on medication history. The prospective cohort was further restricted to women without breast cancer when medication history was asked by questionnaire. Women were recruited from seven study centers in the United States, Canada, and Australia. Associations were estimated using multivariable Cox proportional hazards regression models adjusted for demographics, lifestyle factors, family history, and other medication use. Women were classified as regular or non-regular users of aspirin, COX-2 inhibitors, ibuprofen and other NSAIDs, and acetaminophen (control) based on self-report at follow-up of ever using the medication for at least twice a week for ≥1 month prior to breast cancer diagnosis. The main outcome was incident invasive breast cancer, based on self- or relative-report (81% confirmed pathologically).ResultsFrom fully adjusted analyses, regular aspirin use was associated with a 39% and 37% reduced risk of breast cancer in the prospective (HR = 0.61; 95% CI = 0.33–1.14) and combined cohorts (HR = 0.63; 95% CI = 0.57–0.71), respectively. Regular use of COX-2 inhibitors was associated with a 61% and 71% reduced risk of breast cancer (prospective HR = 0.39; 95% CI = 0.15–0.97; combined HR = 0.29; 95% CI = 0.23–0.38). Other NSAIDs and acetaminophen were not associated with breast cancer risk in either cohort. Associations were not modified by familial risk, and consistent patterns were found by BRCA1 and BRCA2 carrier status, estrogen receptor status, and attained age.ConclusionRegular use of aspirin and COX-2 inhibitors might reduce breast cancer risk for women at familial or genetic risk.

Diabetes and differences in detection of incident invasive breast cancer.

Many women diagnosed with breast cancer have chronic conditions such as diabetes that may impact other health behaviors. Our purpose was to determine if breast cancer screening and detection differs among women with and without diabetes. We conducted a cross-sectional analysis of a retrospective cohort of women aged 52-74years diagnosed with incident stages I-III breast cancer enrolled in an integrated health plan between 1999 and 2014 with linkage to the Surveillance, Epidemiology and End Results registry (n = 2040). Screening data were taken from electronic health records. We used multivariable modified Poisson regression models with robust standard errors to estimate relative risks (RR) and 95% confidence intervals (CI) for outcomes of (i) receipt of screening in the 2 years prior to diagnosis; (ii) symptom-detected breast cancer; and (iii) diagnosis of locally advanced stage III breast cancer. Compared to women without diabetes, women with diabetes were similar with respect to receipt of screening mammography (78% and 77%), symptom-detected breast cancer (46% and 49%), and stage III diagnosis (7% and 7%). In multivariable models adjusting for age and year of diagnosis, race, BMI, Charlson comorbidity score and depression diagnosis no differences were observed in the outcomes by presence of diabetes. Further investigation is warranted to determine how diabetes acts as a mediating factor in adverse breast cancer outcomes.

Validation of the breast cancer surveillance consortium model of breast cancer risk.

In order to use a breast cancer prediction model in clinical practice to guide screening and prevention, it must be well calibrated and validated in samples independent from the one used for development. We assessed the accuracy of the breast cancer surveillance consortium (BCSC) model in a racially diverse population followed for up to 10years. The BCSC model combines breast density with other risk factors to estimate a woman's 5- and 10-year risk of invasive breast cancer. We validated the model in an independent cohort of 252,997 women in the Chicago area. 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). In an independent cohort of 252,997 women (median age 50 years, 26% non-Hispanic Black), the BCSC model was well calibrated (E/O = 0.94, 95% confidence interval [CI] 0.90-0.98), but underestimated the incidence of invasive breast cancer in younger women and in women with low mammographic density. The AUROC was 0.633, similar to that observed in prior validation studies. The BCSC model is a well-validated risk assessment tool for breast cancer that may be particularly useful when assessing the utility of supplemental screening in women with dense breasts.

Abstract P4-10-02: Impact of raloxifene adherence in breast cancer risk

Abstract BACKGROUND: Raloxifene is a selective estrogen receptor modulator that has demonstrated to reduce breast cancer risk and reduce the incidence of vertebral fractures. Based on these effects, raloxifene is used as a risk reduction agent and to prevent osteoporosis in postmenopausal women. Little is known about the raloxifene adherence rates or the relationship between adherence and breast cancer incidence. METHODS: Women 60 years or older without a breast cancer history were identified in the MarketScan database (2008-2015). We identified women who received raloxifene by searching for prescription claims. Proportion of days covered (PDC) were calculated, adherence was defined as a PDC &amp;gt;80% in the first year after initial prescription claim. We identified factors associated with adherence. ICD-9 codes were used to identify incident cases of invasive breast cancer and cumulative incidence rates were calculated. A multivariable Cox model with propensity score method (matching variables included year of claim, age, comorbidities and family history of breast cancer) was used to evaluate the association between raloxifene adherence and breast cancer risk. All statistical tests were two-sided. RESULTS: A total of 16,179 women were included in the analysis. We identified that during the first year of treatment 6,716 (40.2%) women had a PDC &amp;gt;80% and thus were considered to be adherent. Factors associated with increased adherence included the use of generic drug, mail order of 90 days supply and family history of breast cancer (all p&amp;lt;0.001). Using propensity score matching, the 5 year-cumulative incidence of invasive breast cancer was 1.5% among those not adherent and 0.9% among those adherent to raloxifene (p=0.01). Similarly, the 9 year-cumulative rates were 3.6% and 1.9% respectively (p=0.01). After adjusting for potential confounders, patients that were adherent to raloxifene during the first year of treatment had a lower risk of invasive breast cancer compared to those that were non-adherent (HR=0.64; 95%CI 0.04-0.9). CONCLUSIONS: Among women 60 years of age or older receiving raloxifene, adherence to therapy was associated with lower risk of invasive breast cancer. Efforts to ensure adherence and compliance are crucial so patients can receive full benefit from this therapy. Citation Format: Chavez-MacGregor M, Lei X, Zhao H, Bevers TB, Brewster A, Giordano SH. Impact of raloxifene adherence in breast cancer risk [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-10-02.

Abstract P3-05-01: Age-related methylation signals of breast cancer risk in blood

Abstract BACKGROUND: Age is the biggest risk factor for developing breast cancer, which suggests that the biological aging process is a direct driver of cancer etiology. In all normal tissues, DNA methylation status changes systematically with age and is believed to mediate the biological consequences of aging. DNA methylation patterns, commonly referred to as 'Epigenetic Clocks', can be used as measures of aging. However, the chronologic and epigenetic ages can have subtle differences in different individuals. We hypothesize that accelerated epigenetic aging (i.e. DNA methylation indicating an older age than the chronologic age of the individual) is a risk factor for breast cancer development. METHODS: We used DNA methylation data from blood samples and clinical data from n=2,107 participants in the Women's Health Initiative (WHI) and tested the association between breast cancer risk and two of the most commonly used epigenetic clocks by Horvath (based on 353 CpGs) and Hannum et al. (based on 71 CpGs). DNA methylation in whole blood was measured using the Illumina HumanMethylation450 BeadChip. We used Cox proportional hazard models to assess the association between two epigenetic age predictors (calculated using the algorithms by Horvath and Hannum et al.) and subsequent risk of breast cancer. The model was adjusted for several breast cancer risk factors including: chronologic age at the time of blood sampling, observational vs. clinical trial, clinical trial arm, race/ethnicity, education, BMI, waist-hip ratio, smoking, alcohol, age at menopause, age at menarche, number of pregnancies, age at first birth, previous mastectomy, months breastfed, and cell count estimates. Family history data and BRCA mutation status was incomplete in the WHI and therefore could not be included in our analysis. RESULTS: Increased epigenetic age determined by the Horvath clock relative to chronological age was associated with increased future incidence of invasive breast cancer, even after adjusting for known risk factors (HR=1.04, P=0.03). Utilizing the Hannum clock, we found no significant association between epigenetic age and breast cancer risk (HR=1.01, P=0.568). When we included both age predictors as independent variables in a single model, the strength of the association between the Horvath epigenetic age and breast cancer risk increased (Horvath HR=1.09, P=6.3e-5; Hannum HR=0.95, p=0.077), such that every one year increase in epigenetic age relative to chronological age was associated with a 9% increased risk of future breast cancer. These results suggest that the aging signal in the Horvath clock that is unique from that captured by Hannum is what drives the specific association with breast cancer. CONCLUSIONS: Our results support the hypothesis that “accelerated” epigenetic aging measured in the blood increases breast cancer risk. We also demonstrate that the two epigenetic clocks capture different aspects of aging, only some of which have implications for breast cancer risk. Epigenetic clocks may assist in targeting breast cancer screening to higher risk populations in the future, and understanding the biological mechanisms that are altered by the epigenetic changes may lead to new risk reduction strategies. Citation Format: Hofstatter EW, Levine M, Hatzis C, Pusztai L. Age-related methylation signals of breast cancer risk in blood [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-05-01.

Abstract P1-08-11: The impact of existing comorbidities on survival disparities among women diagnosed with invasive breast cancer

Abstract Missouri is one of many states in the US burdened by high rates of mortality from female breast cancer (BC) as well as comorbidities such as Type-2 diabetes, cardiovascular disease (CVD), and hypertension. These comorbidity rates are higher among vulnerable populations including individuals in poverty and/or living in rural areas, African Americans, and the elderly. There is evidence that women with comorbidities at the time of BC diagnosis have a worse prognosis. We hypothesize that the co-existence of comorbidities is likely to impact survival and may contribute to survival disparities observed among women diagnosed with BC from these vulnerable populations. Objective: To examine whether the number and/or type of comorbidity at BC diagnosis is associated with higher BC and all-cause mortality among women diagnosed with invasive BC in Missouri between 2004 and 2012. Methods: Women age 18+ diagnosed with BC in Missouri during 2004–2012 were identified from the Missouri Cancer Registry. These data were then merged with hospital discharge data from the Missouri Patient Abstract System. Associations were evaluated in all women and by race, neighborhood poverty level, rural/urban residence, and age at diagnosis. A comorbidity score was constructed to account for the number of comorbidities (Type-2 diabetes, hypertension, and CVD) identified for each individual. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression models, adjusting for age at diagnosis, race, tumor hormone receptor status, stage, BC treatment, and rural/urban residence. Models were further stratified by race, poverty level, rural/urban residence, and age group. Results: A total of 31,133 women with incident invasive BC and with comorbidity data at the time of BC diagnosis were included in the analysis. After a median follow-up time of 79 months, 9,912 deaths occurred, of which 4,900 deaths were due to BC. Increasing number of comorbidities was significantly associated with BC mortality (ptrend &amp;lt; 0.001). BC mortality (HR, 1.33; 95% CI 1.19-1.49) and all-cause mortality (HR, 1.51; 90% CI 1.32-1.61) were significantly higher in women with ≥2 comorbidities. CVD accounted for the largest increase in BC mortality (HR, 1.36; 95% CI 1.19-1.55). In stratified analyses, we did not observe significant differences in associations by race, poverty, rural/urban residence, or age; however, there was a statistically significant interaction with age when modeled as a continuous measure, comorbidity score, and risk of mortality outcomes (p&amp;lt; 0.001). White women with all 3 comorbidities had the highest risk of death (BC-specific: HR, 1.95; all-cause: HR, 2.28). Women in rural areas with ≥2 comorbidities were 1.78 times more likely to die of BC while women living in the metro with all 3 comorbidities were almost 2 times more likely to die of any cause. Conclusion: Our results demonstrate the negative impact that comorbidities such as diabetes, CVD, and hypertension can have on BC and overall mortality in a diverse group of BC patients diagnosed and treated in Missouri. The data produced from this study can be utilized to identify and implement targeted preventive strategies to improve the quality of life and survival of BC patients. Citation Format: Connor AE, May B, Schmaltz CL, Jackson-Thompson J, Visvanathan K. The impact of existing comorbidities on survival disparities among women diagnosed with invasive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-11.

Abstract P4-09-02: Validation of iPrevent using the prospective family study cohort (ProF-SC)

Abstract Background: iPrevent (https://www.petermac.org/iprevent) provides women with highly-tailored risk management information after first estimating their breast cancer (BC) risk using the established risk prediction models, IBIS and BOADICEA. iPrevent has an internal switching algorithm that governs which model is used for each woman, depending on her risk factor data (i.e. LCIS/atypical hyperplasia status, BRCA status, and cancer family history). This study assessed the calibration and discriminatory accuracy of the 10-year BC risk estimates provided by iPrevent. Methods: Subjects were 16,574 women in the ProF-SC, aged 18-70 years and without BC or bilateral mastectomy at recruitment. After 10 years follow-up, 655 women (4%) were diagnosed with invasive BC. A “batch mode” for iPrevent is not available, so the iPrevent-assigned cumulative 10-year invasive BC risks were calculated by entering self-reported risk factors at cohort entry into either the IBIS (10,169 women) or BOADICEA (6,405 women) software packages (according to the iPrevent switching algorithm). To assess calibration, the mean iPrevent-assigned risk was compared with the mean 10-year observed invasive BC incidence, using a chi-squared goodness-of-fit statistic for the whole cohort, and by quartiles of risk. To evaluate discriminatory accuracy, the overall area under the receiver operating characteristic curve (AUC) for the development of invasive BC within 10 years was computed. Data were censored at date of invasive or in situ BC diagnosis, bilateral mastectomy, death, loss to follow-up, or at 10 years of follow-up. Results: For the whole cohort, iPrevent assigned risk was well-calibrated – 690 expected BCs (E) 655 observed (O) (E/O=1.05, 95% CI: 0.98-1.14), although for women in the highest risk quartile, i.e. &amp;gt;6% 10-year risk, E/O=1.19, 95% CI: 1.07-1.32. The AUC was 0.70, 95% CI: 0.68-0.72. Conclusions: iPrevent is well calibrated overall and has good discriminatory accuracy for predicting 10-year BC risk, thus justifying its clinical use. Citation Format: Phillips K-A, Liao Y, Collins IM, Buchsbaum R, Weideman P, Bickerstaffe A, MacInnis RJ, kConFab Investigators, Cuzick J, Antoniou A, Andrulis IL, John EM, Daly MB, Buys SS, Hopper JL, Terry MB. Validation of iPrevent using the prospective family study cohort (ProF-SC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-09-02.

Disparities in breast cancer diagnosis for immigrant women in Ontario and BC: results from the CanIMPACT study

BackgroundIn Canada, clinical practice guidelines recommend breast cancer screening, but there are gaps in adherence to recommendations for screening, particularly among certain hard-to-reach populations, that may differ by province. We compared stage of diagnosis, proportion of screen-detected breast cancers, and length of diagnostic interval for immigrant women versus long-term residents of BC and Ontario.MethodsWe conducted a retrospective cohort study using linked administrative databases in BC and Ontario. We identified all women residing in either province who were diagnosed with incident invasive breast cancer between 2007 and 2011, and determined who was foreign-born using the Immigration Refugee and Citizenship Canada database. We used descriptive statistics and bivariate analyses to describe the sample and study outcomes. We conducted multivariate analyses (modified Poisson regression and quantile regression) to control for potential confounders.ResultsThere were 14,198 BC women and 46,952 Ontario women included in the study population, of which 11.8 and 11.7% were foreign-born respectively. In both provinces, immigrants and long-term residents had similar primary care access. In both provinces, immigrant women were significantly less likely to have a screen-detected breast cancer (adjusted relative risk 0.88 [0.79–0.96] in BC, 0.88 [0.84–0.93] in Ontario) and had a significantly longer median diagnostic interval (2 [0.2–3.8] days in BC, 5.5 [4.4–6.6] days in Ontario) than long-term residents. Women from East Asia and the Pacific were less likely to have a screen-detected cancer and had a longer diagnostic interval, but were diagnosed at an earlier stage than long-term residents. In Ontario, women from Latin America and the Caribbean and from South Asia were less likely to have a screen-detected cancer, had a longer median diagnostic interval, and were diagnosed at a later stage than long-term residents. These findings were not explained by access to primary care.ConclusionsThere are inequalities in breast cancer diagnosis for Canadian immigrant women. We have identified particular immigrant groups (women from Latin America and the Caribbean and from South Asia) that appear to be subject to disparities in the diagnostic process that need to be addressed in order to effectively reduce gaps in care.

Risks of breast or ovarian cancer in BRCA1 or BRCA2 predictive test negatives: findings from the EMBRACE study

PurposeBRCA1/BRCA2 predictive test negatives are proven noncarriers of a BRCA1/BRCA2 mutation that is carried by their relatives. The risk of developing breast cancer (BC) or epithelial ovarian cancer (EOC) in these women is uncertain. The study aimed to estimate risks of invasive BC and EOC in a large cohort of BRCA1/BRCA2 predictive test negatives. MethodsWe used cohort analysis to estimate incidences, cumulative risks, and standardized incidence ratios (SIRs). ResultsA total of 1,895 unaffected women were eligible for inclusion in the BC risk analysis and 1,736 in the EOC risk analysis. There were 23 incident invasive BCs and 2 EOCs. The cumulative risk of invasive BC was 9.4% (95% confidence interval (CI) 5.9–15%) by age 85 years and the corresponding risk of EOC was 0.6% (95% CI 0.2–2.6%). The SIR for invasive BC was 0.93 (95% CI 0.62–1.40) in the overall cohort, 0.85 (95% CI 0.48–1.50) in noncarriers from BRCA1 families, and 1.03 (95% CI 0.57–1.87) in noncarriers from BRCA2 families. The SIR for EOC was 0.79 (95% CI 0.20–3.17) in the overall cohort. ConclusionOur results did not provide evidence for elevated risks of invasive BC or EOC in BRCA1/BRCA2 predictive test negatives.

Receptor activator of nuclear factor kB ligand, osteoprotegerin, and risk of death following a breast cancer diagnosis: results from the EPIC cohort

BackgroundReceptor activator of nuclear factor kappa-B (RANK)-signaling is involved in tumor growth and spread in experimental models. Binding of RANK ligand (RANKL) to RANK activates signaling, which is inhibited by osteoprotegerin (OPG). We have previously shown that circulating soluble RANKL (sRANKL) and OPG are associated with breast cancer risk. Here we extend these findings to provide the first data on pre-diagnosis concentrations of sRANKL and OPG and risk of breast cancer-specific and overall mortality after a breast cancer diagnosis.MethodsTwo thousand six pre- and postmenopausal women with incident invasive breast cancer (1620 (81%) with ER+ disease) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were followed-up for mortality. Pre-diagnosis concentrations of sRANKL and OPG were quantified in baseline serum samples using an enzyme-linked immunosorbent assay and electrochemiluminescent assay, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer-specific and overall mortality were calculated using Cox proportional hazards regression models.ResultsEspecially in women with ER+ disease, higher circulating OPG concentrations were associated with higher risk of breast cancer-specific (quintile 5 vs 1 HR 1.77 [CI 1.03, 3.04]; ptrend 0.10) and overall mortality (q5 vs 1 HR 1.39 [CI 0.94, 2.05]; ptrend 0.02). sRANKL and the sRANKL/OPG ratio were not associated with mortality following a breast cancer diagnosis.ConclusionsHigh pre-diagnosis endogenous concentrations of OPG, the decoy receptor for RANKL, were associated with increased risk of death after a breast cancer diagnosis, especially in those with ER+ disease. These results need to be confirmed in well-characterized patient cohorts.