Risk Of Invasive Breast Cancer Research Articles

Abstract IA027: DCIS or cancer? Why all the confusion?

Abstract Many women diagnosed with DCIS in the United States report they are confused about their chances of developing an invasive breast cancer or metastatic cancer. They are told that DCIS is not cancer but it holds the possibility of becoming a cancer. Nevertheless, DCIS is treated in much the same way as a small invasive cancer. Surgical options include lumpectomy alone, lumpectomy with radiotherapy, unilateral or bilateral mastectomy. Much of the confusion is generated by the current paradigm that separates DCIS and invasive cancer into distinct conditions. The mortality of DCIS is 3% over 20 years and that prevention of local invasive recurrence post-DCIS does not reduce breast cancer mortality. If the invasive recurrence were the real cancer then preventing it would reduce the risk of dying but this has not been shown. Further, the risk of an invasive in-breast recurrence following DCIS is the same as the risk of an invasive in-breast recurrence following invasive breast cancer. In the Banting database, the 15-year risk of invasive local recurrence following DCIS was 15.6%, following stage I breast cancer was 15.3% and following stage II breast cancer was 15.9%. In the Banting database, the 15-year risk of ipsilateral invasive recurrence was 14% for DCIS patients who receives radiotherapy and was 29% for DCIS patients who did not received radiotherapy – a difference of 15%. In the Banting database, the 15-year risk of ipsilateral invasive recurrence was 14% for Stage I/II patients who received radiotherapy and was 27% for Stage I/II patients who did not receive radiotherapy – a difference of 13%. The benefit of radiotherapy is the same in both groups. Similarly, the benefit of unilateral mastectomy versus lumpectomy on preventing local invasive recurrence is the same for DCIS patients as it is for early-stage invasive breast cancer patients. In our SEER-based analysis of 812,851 women with breast cancer, the 25-year actuarial risk of contralateral invasive breast cancer was 10.1% for patients with DCIS and was 9.9% for patients with invasive breast cancer. Based on this finding, the benefit of performing a contralateral mastectomy at the time of diagnosis is the same for both groups. We accept lumpectomy as standard of care for invasive breast cancer even though the risk of invasive ipsilateral recurrence is much higher after lumpectomy than after mastectomy. We consider contralateral mastectomy as an option for women with invasive cancer, but as overtreatment for women with DCIS even though the risk of contralateral breast cancer is almost exactly the same. The benefit of radiotherapy is the same for patients with DCIS and stage I/II breast cancer, but we are more likely to consider it overtreatment for DCIS patients. Much of the confusion can be resolved if we consider both types of cancer to be different points on the spectrum. Breast cancer is heterogeneous; DCIS is one end of the spectrum. Accepting this fact will make the rationale behind treatment decisions easier to explain. Citation Format: Steven A. Narod. DCIS or cancer? Why all the confusion? [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr IA027.

A common IGF1R gene variant predicts later life breast cancer risk in women with preeclampsia

PurposePreeclampsia has been inconsistently associated with altered later life risk of cancer. This study utilizes the Nurses’ Health Study 2 (NHS2) to determine if the future risk of breast and non-breast cancers in women who experience preeclampsia is modified by carrying a protective variant of rs2016347, a functional insulin-like growth factor receptor-1 (IGF1R) single nucleotide polymorphism.MethodsThis retrospective cohort study completed within the NHS2 evaluated participants enrolled in 1989 and followed them through 2015, with a study population of 86,751 after exclusions. Cox proportional hazards models both with and without the impact of rs2016347 genotype were used to assess the risk of invasive breast cancer, hormone receptor-positive (HR+) breast cancer, and non-breast cancers.ResultsWomen with preeclampsia had no change in risk of all breast, HR+ breast, or non-breast cancers when not considering genotype. However, women carrying at least one T allele of rs2016347 had a lower risk of HR+ breast cancer, HR 0.67, 95% CI: 0.47–0.97, P = 0.04, with interaction term P = 0.06. For non-breast cancers as a group, women carrying a T allele had an HR 0.76, 95% CI: 0.53–1.08, P = 0.12, with interaction term P = 0.26.ConclusionsThis retrospective cohort study found that women with preeclampsia who carry a T allele of IGF1R rs2016347 had a reduced future risk of developing HR+ breast cancer, and a reduced but not statistically significant decreased risk of non-breast cancers suggesting a possible role for the IGF-1 axis in the development of cancer in these women.

Ductal Carcinoma In Situ (DCIS) Diagnosed by MRI-Guided Biopsy among BRCA1/BRCA2 Mutation Carriers.

While BRCA1/BRCA2 pathogenic sequence variants (PSVs) clearly confer an increased risk for invasive breast cancer, the extent to which these mutant alleles increase DCIS risk is less clear. To assess the rate of detection over a 5-year period, and MRI imaging features of pure noncalcified DCIS in a cohort of Israeli BRCA1/BRCA2 PSV carriers attending a high-risk clinic from 2015 to 2020. All female BRCA1/BRCA2 PSV-carriers followed at the Meirav High-risk clinic from 2015 to 2020 were eligible if they underwent semiannual breast imaging (MRI/mammography) and MRI-guided biopsy-proven pure DCIS. Clinical data, pathology information, and imaging characteristics were retrieved from the computerized archiving system. 18/121 (15.2%) participating BRCA1 PSV carriers and 8/81 (10.1%) BRCA2 PSV-carriers who underwent MRI-guided biopsy were diagnosed with DCIS. The median age of BRCA1 carriers and BRCA2 carriers was 49.8 years and 60.6 years, respectively (p = 0.55). Negative estrogen-receptor tumors were diagnosed in 13/18 (72%) BRCA1 and 2/8 (25%) BRCA2 PSV carriers (p < 0.05). Thirteen (13/18-72%) BRCA1 carriers had intermediate to high-grade or high-grade DCIS compared with 4/8 (50%) of BRCA2 carriers (p = 0.03). Over the 5-year study period, 29/1100 (2.6%) BRCA1/BRCA2 PSV carriers were diagnosed with DCIS seen on MRI only. MRI-detected noncalcified DCIS is more frequent in BRCA1 PSV carriers compared with BRCA2 carriers, unlike the BRCA2 predominance in mammography-detected calcified DCIS. BRCA1-related DCIS is diagnosed earlier, more likely to be estrogen receptor-negative and of higher grade compared with BRCA2-related DCIS. Future prospective studies should validate these results and assess the actual impact they might have on clinical management of BRCA PSV carriers.

Validation of the Nigerian Breast Cancer Study Model for Predicting Individual Breast Cancer Risk in Cameroon and Uganda.

The Nigerian Breast Cancer Study (NBCS) model is a new risk assessment tool developed for predicting risk of invasive breast cancer in Nigeria. Its applicability outside of Nigeria remains uncertain as it has not been validated in other sub-Saharan Africa populations. We conducted a case-control study among women with breast cancer and controls ascertained in Cameroon and Uganda from 2011 to 2016. Structured questionnaire interviews were performed to collect risk factor characteristics. The NBCS model, the Gail model, the Gail model for Black population, and the Black Women's Health Study model were applied to the Cameroon and Uganda samples separately. Nigerian as well as local incidence rates were incorporated into the models. Receiver-Operating Characteristic analyses were performed to indicate discriminating capacity. The study included 550 cases (mean age 46.8 ± 11.9) and 509 controls (mean age 46.3 ± 11.7). Compared with the other three models, the NBCS model performed best in both countries. The discriminating accuracy of the NBCS model in Cameroon (age-adjusted C-index = 0.602; 95% CI, 0.542-0.661) was better than in Uganda (age-adjusted C-index = 0.531; 95% CI, 0.459-0.603). These findings demonstrate the potential clinical utility of the NBCS model for risk assessment in Cameroon. All currently available models performed poorly in Uganda, which suggests that the NBCS model may need further calibration before use in other regions of Africa. Differences in risk profiles across the African diaspora underscores the need for larger studies and may require development of region-specific risk assessment tools for breast cancer.

Breast Cancer Risk and Screening Mammography Frequency Among Multiethnic Women

In 2009, the U.S. Preventive Services Task Force updated recommended mammography screening frequency from annual to biennial for average-risk women aged 50-74 years. The association between estimated breast cancer risk and mammography screening frequency was evaluated. A single-center retrospective cohort study was conducted among racially/ethnically diverse women, aged 50-74 years, who underwent screening mammography from 2014 to 2018. Data on age, race/ethnicity, first-degree family history of breast cancer, previous benign breast biopsies, and mammographic density were extracted from the electronic health record to calculate Breast Cancer Surveillance Consortium 5-year risk of invasive breast cancer, with a 5-year risk ≥1.67% defined as high risk. Multivariable analyses were conducted to determine the association between breast cancer risk factors and mammography screening frequency (annual versus biennial). Data were analyzed from 2020 to 2022. Among 12,929 women with a mean age of 61±6.9 years, 82.7% underwent annual screening mammography, and 30.7% met high-risk criteria for breast cancer. Hispanic women were more likely to screen annually than non-Hispanic Whites (85.0% vs 79.8%, respectively), despite fewer meeting high-risk criteria. In multivariable analyses adjusting for breast cancer risk factors, high- versus low/average-risk women (OR=1.17; 95% CI=1.04, 1.32) and Hispanic versus non-Hispanic White women (OR=1.46; 95% CI=1.29, 1.65) were more likely to undergo annual mammography. A majority of women continue to undergo annual screening mammography despite only a minority meeting high-risk criteria, and Hispanic women were more likely to screen annually despite lower overall breast cancer risk. Future studies should focus on the implementation of risk-stratified breast cancer screening strategies.

Physical activity from menarche-to-first pregnancy and risk of breast cancer: the California teachers study.

A longer menarche-to-first pregnancy window of susceptibility (WOS) is associated with increased breast cancer risk. Whether physical activity, an established preventive risk factor, during the menarche-to-first pregnancy WOS offsets breast cancer risk overall or for specific molecular subtypes is unclear. We examined the prospective association between physical activity during the menarche-to-first pregnancy WOS and breast cancer risk in the California Teachers Study (N = 78,940). Recreational physical activity at multiple timepoints were recalled at cohort entry, and converted to metabolic equivalent of task hours per week (MET-hrs/wk). We used multivariable Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). We observed 5,157 invasive breast cancer cases over 21.6years of follow-up. Longer menarche-to-first pregnancy WOS (≥ 20 vs. < 15years) was associated with higher breast cancer risk (HR = 1.23, 95% CI = 1.13-1.34). Women with higher physical activity level during menarche-to-first pregnancy had lower risk of invasive breast cancer (≥ 40 vs. < 9 MET-hrs/wk: HR = 0.89, 95% CI = 0.83-0.97) and triple-negative subtype (≥ 40 vs. < 9 MET-hrs/wk: HR = 0.53, 95% CI = 0.32-0.87). No association was observed for luminal A-like and luminal B-like subtypes. Higher physical activity level was associated with lower breast cancer risk among women with moderate (15-19years) menarche-to-first pregnancy intervals (≥ 40 vs. < 9 MET-hrs/wk: HR = 0.80, 95% CI = 0.69-0.92), but not with short (< 15years) or long (≥ 20years) intervals. Physical activity during a WOS was associated with lower breast cancer risk in our cohort. Understanding timing of physical activity throughout the life course in relationship with breast cancer risk maybe important for cancer prevention strategies.

Qualitative analysis of shared decision-making for chemoprevention in the primary care setting: provider-related barriers

BackgroundChemoprevention with anti-estrogens, such as tamoxifen, raloxifene or aromatase inhibitors, have been shown to reduce breast cancer risk in randomized controlled trials; however, uptake among women at high-risk for developing breast cancer remains low. The aim of this study is to identify provider-related barriers to shared decision-making (SDM) for chemoprevention in the primary care setting.MethodsPrimary care providers (PCPs) and high-risk women eligible for chemoprevention were enrolled in a pilot study and a randomized clinical trial of web-based decision support tools to increase chemoprevention uptake. PCPs included internists, family practitioners, and gynecologists, whereas patients were high-risk women, age 35–75 years, who had a 5-year invasive breast cancer risk ≥ 1.67%, according to the Gail model. Seven clinical encounters of high-risk women and their PCPs who were given access to these decision support tools were included in this study. Audio-recordings of the clinical encounters were transcribed verbatim and analyzed using grounded theory methodology.ResultsSix primary care providers, of which four were males (mean age 36 [SD 6.5]) and two were females (mean age 39, [SD 11.5]) and seven racially/ethnically diverse high-risk female patients participated in this study. Qualitative analysis revealed three themes: (1) Competing demands during clinical encounters; (2) lack of knowledge among providers about chemoprevention; and (3) limited risk communication during clinical encounters.ConclusionsCritical barriers to SDM about chemoprevention were identified among PCPs. Providers need education and resources through decision support tools to engage in risk communication and SDM with their high-risk patients, and to gain confidence in prescribing chemoprevention in the primary care setting.

Comprehensive multiplexed immune profiling of the ductal carcinoma in situ immune microenvironment regarding subsequent ipsilateral invasive breast cancer risk

BackgroundDuctal carcinoma in situ (DCIS) is treated to prevent subsequent ipsilateral invasive breast cancer (iIBC). However, many DCIS lesions will never become invasive. To prevent overtreatment, we need to distinguish harmless from potentially hazardous DCIS. We investigated whether the immune microenvironment (IME) in DCIS correlates with transition to iIBC.MethodsPatients were derived from a Dutch population-based cohort of 10,090 women with pure DCIS with a median follow-up time of 12 years. Density, composition and proximity to the closest DCIS cell of CD20+ B-cells, CD3+CD8+ T-cells, CD3+CD8− T-cells, CD3+FOXP3+ regulatory T-cells, CD68+ cells, and CD8+Ki67+ T-cells was assessed with multiplex immunofluorescence (mIF) with digital whole-slide analysis and compared between primary DCIS lesions of 77 women with subsequent iIBC (cases) and 64 without (controls).ResultsHigher stromal density of analysed immune cell subsets was significantly associated with higher grade, ER negativity, HER-2 positivity, Ki67 ≥ 14%, periductal fibrosis and comedonecrosis (P < 0.05). Density, composition and proximity to the closest DCIS cell of all analysed immune cell subsets did not differ between cases and controls.ConclusionIME features analysed by mIF in 141 patients from a well-annotated cohort of pure DCIS with long-term follow-up are no predictors of subsequent iIBC, but do correlate with other factors (grade, ER, HER2 status, Ki-67) known to be associated with invasive recurrences.

Abstract 686: Subsequent invasive breast cancer risk after DCIS treatment in multinational PRECISION consortium cohorts comprising 48,576 patients

Abstract Background: Although DCIS is a precursor of invasive breast cancer (IBC), most DCIS lesions never will progress. As we cannot distinguish reliably progressive from harmless DCIS yet, almost all women with DCIS are treated extensively with surgery and often adjuvant radiotherapy or endocrine treatment, implying overtreatment of many thousands of women with harmless DCIS. PRECISION aims to reduce such overtreatment by identifying factors associated with subsequent ipsilateral IBC. Many factors have been implicated in subsequent DCIS and IBC risk, but most studies relied on small series with limited prognostic power. To overcome this, we conducted pooled analyses of four large cohorts with DCIS from three different countries. Methods: Cohorts were pooled with data of 48,804 women with DCIS: a population-based cohort (NL, n=18,996), prospective, a population-based, screening cohort (Sloane, UK, n=8,462), a single center cohort (MDACC, USA, n=2,363), and a representative DCIS patient series from the National Cancer Database Special Study (USA, n=18,983). Patients with missing data on treatment and follow-up or follow-up shorter than six months were excluded from analyses. Risk of a subsequent ipsilateral invasive breast cancer (iIBC) was assessed in three DCIS lesion size groups (&amp;lt;20mm, 20-50mm and ≥50mm) and in patients who had clear surgical margins (&amp;lt;2mm) after final breast conserving surgery (BCS) versus patients who did not. Cox proportional hazards models were used to assess differences in risk of IBC, with a focus on DCIS size and margin status. Results: In final analyses, 48,576 patients, diagnosed between 1999 and 2017, were included. Median follow-up was 7.6 years (range 0.5-21.1). In multivariable analyses, patients with smaller size of DCIS (&amp;lt;20mm) had a decreased risk of iIBC compared with women with larger lesion size (HR 0.81; 95% CI 0.68-0.97). In 33,091 BCS treated patients, patients with clear surgical margins had a decreased risk of iIBC (HR 0.68; 95% CI 0.52-0.90). Conclusion: In our quest to reduce overtreatment for women with DCIS, we have identified free surgical margins and smaller lesion size as independent factors reducing the risk of subsequent ipsilateral invasive breast cancer, irrespective of the treatment received. Knowledge of these, and additional, factors could aid in selecting patients suitable for less invasive management strategies such as active surveillance or omitting radiotherapy. This work was supported by Cancer Research UK and by KWF Dutch Cancer Society (ref.C38317/A24043); Web site: https://cancergrandchallenges.org/teams/precision Citation Format: Renee S. Schmitz, Alexandra W. van den Belt-Dusebout, Karen Clements, Yi Ren, Chiara Cresta, Jasmine Timbres, Yat-Hee Liu, Danalyn Byng, Thomas Lynch, Brian Menegaz, Deborah Collyar, Terry Hyslop, Michael Schaapveld, Elinor Sawyer, Shelley E. Hwang, Alastair Thompson, Marc D. Ryser, Jelle Wesseling, Esther H. Lips, Marjanka K. Schmidt, Grand Challenge PRECISION Consortium. Subsequent invasive breast cancer risk after DCIS treatment in multinational PRECISION consortium cohorts comprising 48,576 patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 686.

Abstract SY25-02: Double-edged “soil”: Stromal microenvironment in breast cancer development

Abstract SY25-02: Double-edged “soil”: Stromal microenvironment in breast cancer development

Association of Screening With Digital Breast Tomosynthesis vs Digital Mammography With Risk of Interval Invasive and Advanced Breast Cancer

Digital breast tomosynthesis (DBT) was developed with the expectation of improving cancer detection in women with dense breasts. Studies are needed to evaluate interval invasive and advanced breast cancer rates, intermediary outcomes related to breast cancer mortality, by breast density and breast cancer risk. To evaluate whether DBT screening is associated with a lower likelihood of interval invasive cancer and advanced breast cancer compared with digital mammography by extent of breast density and breast cancer risk. Cohort study of 504 427 women aged 40 to 79 years who underwent 1 003 900 screening digital mammography and 375 189 screening DBT examinations from 2011 through 2018 at 44 US Breast Cancer Surveillance Consortium (BCSC) facilities with follow-up for cancer diagnoses through 2019 by linkage to state or regional cancer registries. Breast Imaging Reporting and Data System (BI-RADS) breast density; BCSC 5-year breast cancer risk. Rates per 1000 examinations of interval invasive cancer within 12 months of screening mammography and advanced breast cancer (prognostic pathologic stage II or higher) within 12 months of screening mammography, both estimated with inverse probability weighting. Among 504 427 women in the study population, the median age at time of mammography was 58 years (IQR, 50-65 years). Interval invasive cancer rates per 1000 examinations were not significantly different for DBT vs digital mammography (overall, 0.57 vs 0.61, respectively; difference, -0.04; 95% CI, -0.14 to 0.06; P = .43) or among all the 836 250 examinations with BCSC 5-year risk less than 1.67% (low to average-risk) or all the 413 061 examinations with BCSC 5-year risk of 1.67% or higher (high risk) across breast density categories. Advanced cancer rates were not significantly different for DBT vs digital mammography among women at low to average risk or at high risk with almost entirely fatty, scattered fibroglandular densities, or heterogeneously dense breasts. Advanced cancer rates per 1000 examinations were significantly lower for DBT vs digital mammography for the 3.6% of women with extremely dense breasts and at high risk of breast cancer (13 291 examinations in the DBT group and 31 300 in the digital mammography group; 0.27 vs 0.80 per 1000 examinations; difference, -0.53; 95% CI, -0.97 to -0.10) but not for women at low to average risk (10 611 examinations in the DBT group and 37 796 in the digital mammography group; 0.54 vs 0.42 per 1000 examinations; difference, 0.12; 95% CI, -0.09 to 0.32). Screening with DBT vs digital mammography was not associated with a significant difference in risk of interval invasive cancer and was associated with a significantly lower risk of advanced breast cancer among the 3.6% of women with extremely dense breasts and at high risk of breast cancer. No significant difference was observed in the 96.4% of women with nondense breasts, heterogeneously dense breasts, or with extremely dense breasts not at high risk.

Urinary concentration of endocrine-disrupting phthalates and breast cancer risk in Indian women: A case-control study with a focus on mutations in phthalate-responsive genes

BackgroundPhthalates are known endocrine-disrupting chemicals used indiscriminately as constituents in consumer products including food processing, and packaging, cosmetics, personal care and household items. Although, few studies have assessed the risk of breast cancer on exposure to phthalates, their association with breast cancer risk in Indian women have not yet been evaluated. MethodsWe conducted a case-control study involving 171 participants. Urinary concentrations of six phthalate dieters; DMP (Dimethyl phthalate), DEP (Diethyl phthalate), DBP (Dibutyl phthalate), BBP (benzyl butyl phthalate), DEHP (Di-2-ethyl-hexyl phthalate), DINOP (Di-n-octyl phthalate) were estimated by GC-MS and geometric means were calculated. Univariate and multivariable logistic regression was performed to assess breast cancer risk on exposure to phthalates. Genes responsive to phthalates were identified through literature search and matched with NGS data, and gene-enrichment analysis was performed. ResultsSignificant associations were observed between urinary phthalate concentrations and increased risk of breast cancer for di-butyl phthalate (OR=1.5, 95% CI; 1.06, 2.11, p = 0.002) and di-2-ethyl-hexyl phthalate (>median vs ≤ median; OR=2.97, 95% CI; 1.18, 7.47, p = 0.005) in multivariable analyses. We also found several phthalate-responsive gene mutations in paired breast tumor tissues, which include PTPRD (76.19%), AR (42.86%), CYP1A1 (42.86%), CYP19A1 (23.81%), AHRR (19.05%), PIK3CA (19.05%), CYP1B1 (9.52%), RB1 (9.52%) and MMP9 (9.52%). Gene-enrichment analysis revealed that these genes form a major part of ER/PR, PPAR and HIF-1α-TGF-β signaling cascades involved in breast cancer ConclusionAlthough the sample size is small, in this first case-control study from India, DBP and DEHP were found to be associated with increased risk of invasive breast cancer and tumor tissues revealed mutations in several phthalate-responsive genes. It is, therefore suggested that human biomonitoring in India and larger studies evaluating the early life genetic and epigenetic alterations on phthalates exposure are required to establish their role in breast carcinogenesis.

Low-dose tamoxifen for breast cancer prevention in patients with ductal carcinoma in situ (DCIS) and atypical lesions: A real-world experience.

e12537 Background: Patients diagnosed with non-invasive breast lesions such as DCIS and lobular carcinoma in situ (LCIS) and atypical breast lesions such as atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH) are at increased risk of developing invasive breast cancer (BC). Tamoxifen 20mg daily for 5 years has shown to be effective for BC prevention in these at-risk patients but its use can be limited by its adverse effects. The recent Tam01 study found that low dose tamoxifen (5mg daily for 3 years) in patients with DCIS, ALH, and ADH resulted in an approximate 50% risk reduction in BC events compared to placebo with a slight increase in hot flashes but no increases in uterine cancer or venous thromboembolism within the tamoxifen group (PMID: 30973790). The objective of this study was to evaluate the use of low dose tamoxifen at our institution and determine how many patients preferred this option. Methods: We performed a retrospective chart review of women who were diagnosed with DCIS, LCIS, ADH, and/or ALH at our institution from January 2019 to December 2021 and subsequently started adjuvant tamoxifen. Patients with history of invasive BC were excluded. Patients were categorized as being on standard dose (20mg daily) or low dose (5mg daily or 10mg every other day) tamoxifen. Fisher’s exact test was used to compare rates of standard and low dose tamoxifen use in the entire cohort as well as in pathology-based subgroups. Results: We included 130 women diagnosed with DCIS, LCIS, ADH and/or ALH and who started adjuvant tamoxifen. The median age at diagnosis was 50 years and 68% were premenopausal. Overall, 62% (n = 80) of women started standard dose tamoxifen and 38% (n = 50) low dose tamoxifen. Among 63 patients who were offered both standard and low dose options, 76% (n = 48) initiated low dose tamoxifen (p &lt; 0.0001). Twenty women were noted to be hesitant to start standard dose tamoxifen due to concern for side effects or preexisting menopausal symptoms but were agreeable to the low dose option. Of the 86 patients with DCIS, a preference for standard dose tamoxifen was observed (74% vs 26%, p = 0.0016). Among 44 patients with LCIS, ADH, and/or ALH, more patients were on low dose tamoxifen (64% vs 36%, p = 0.282). Nine percent (n = 7) of patients on standard dose tamoxifen switched to low dose due to adverse effects including hot flashes, mood changes, and insomnia. Conclusions: At our institution, in patients offered both low dose and standard dose tamoxifen, more than 75% started low dose tamoxifen. The low dose option was more frequently used for atypical lesions such as ADH, ALH and LCIS. In women at higher risk of invasive BC who may be reluctant to start standard dose tamoxifen or intolerant of it, low dose tamoxifen should be considered and offered.

Accuracy of the Breast Cancer Surveillance Consortium Model Among Women with LCIS.

The Breast Cancer Surveillance Consortium (BCSC) model predicts risk of invasive breast cancer risk based on age, race, family history, breast density, and history of benign breast disease, including lobular carcinoma in situ (LCIS). However, validation studies for this model included few women with LCIS. We sought to evaluate the accuracy of the BCSC model among this cohort. Women with LCIS diagnosed between 1983 and 2017 were identified from a prospectively maintained database. The BCSC score was calculated; those with prior breast cancer, unknown breast density, age < 35 years or > 74 years, or with history of chemoprevention use were excluded. The Kaplan-Meier method was used to estimate incidence rates. Time-dependent receiver operating characteristic (ROC) analysis was used to analyze the discriminative capacity of the model. 1302 women with LCIS were included. At a median follow-up of 7years, 152 women (12%) developed invasive cancer (6 with bilateral disease). Cumulative incidences of invasive breast cancer were 7.1% (95% CI 5.6-8.7) and 13.3% (95% CI 10.9-15.6), respectively, and the median BCSC risk scores were 4.9 and 10.4, respectively, at 5 and 10years. The median 10-year BCSC score was significantly lower than the 10-year Tyrer-Cuzick score (10.4 vs 20.8, p < 0.001). The ROC curve scores (AUC) for BCSC at 5 and 10years were 0.59 (95% CI 0.52-0.66) and 0.58 (95% CI 0.52-0.64), respectively. The BCSC model has moderate accuracy in predicting invasive breast cancer risk among women with LCIS with fair discrimination for risk prediction between individuals.

Associations of coffee/caffeine consumption with postmenopausal breast cancer risk and their interactions with postmenopausal hormone use.

We investigated the association of coffee and caffeine with breast cancer (BCa) risk, overall and by ER/PR status. We also examined potential interactions of coffee and caffeine with postmenopausal hormone use. Our study included 77,688 postmenopausal participants from the Women's Health Initiative observational study cohort without a history of any cancer at baseline (except non-melanoma skin) and with valid Food Frequency Questionnaire data and complete data on dietary caffeine. Regular coffee (none, 1, 2-3, 4-5, and ≥ 6 cups/day) and caffeine (tertiles) were assessed at baseline. Information on BCa risk factors was collected at baseline. The associations were examined using survival analysis, accounting for death as a competing risk. The median follow-up time for our cohort was 18.3years. During the follow-up, 5005 women developed invasive breast cancer. In multivariable analysis, coffee was not associated with the overall invasive BCa risk. Higher caffeine intake was mildly associated with increased BCa risk (2nd vs. 1st tertile SHR = 1.10, 95% CI 1.03-1.18, 3rd vs. 1st tertile SHR-1.05, 95% CI 0.98-1.13, overall p = 0.03). We found no interaction of coffee/caffeine with postmenopausal hormone use (p interaction = 0.44 and 0.42, respectively). In the exploratory analysis by ER/PR status, we found a positive association of caffeine with ER+ /PR+ BCa (2nd vs. 1st tertile SHR = 1.17, 95% CI 1.07-1.28, 3rd vs. 1st tertile SHR = 1.13, 95% CI 1.03-1.24, overall p = 0.002); no associations were observed for ER-/PR- tumors. Coffee was not associated with the risk of ER+ /PR+ or ER-/PR- tumors. We found no associations of coffee with BCa risk, overall and for ER/PR-defined tumor subtypes. The higher caffeine consumption was mildly and positively associated with the overall BCa risk and with ER+ /PR+ tumors.

Healthy lifestyle index and the risk of ductal carcinoma in situ of the breast in the Women's Health Initiative.

A relatively high healthy lifestyle index (HLI) score, representing a healthy diet, participation in moderate to vigorous physical exercise, no smoking, low to no alcohol intake and a normal body mass index, has been associated with a reduced risk of invasive breast cancer. However, no study has shown an association between the HLI and the risk of ductal carcinoma in situ of the breast (DCIS), which is considered to be a nonobligate precursor of invasive breast cancer. We evaluated this association in a prospective cohort of 132 230 postmenopausal women, aged 50 to 79 years, recruited between 1993 and 1998 across the United States and enrolled in the Women's Health Initiative study. The HLI score was created and categorized into quartiles. During an average follow-up of 15.4 years, 2035 DCIS cases were ascertained. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of HLI with the risk of DCIS. Women in the highest HLI quartile had a lower DCIS risk than those in the lowest quartile (HR4thQT = 0.80, 95% CI, 0.70-0.92) and this association was stronger in women with a family history of breast cancer (HR4thQT = 0.70, 95% CI, 0.52-0.93), and for ER+/PR+ DCIS (HR4thQT = 0.66, 95% CI, 0.52-0.83). These findings suggest that there is an inverse association between HLI and risk of DCIS, and suggest that the adoption of a healthy lifestyle might lower the risk of DCIS.

QbD-based optimization of raloxifene-loaded cubosomal formulation for transdemal delivery: ex vivo permeability and in vivo pharmacokinetic studies.

Raloxifene (RLX) is a drug that is commonly recommended to postmenopausal women at high risk of invasive breast cancer and to prevent osteoporosis. However, limited water solubility (0.000512mg/ml) and low oral bioavailability (2%) of RLX limit its therapeutic utility. The objective of the present study was to develop an alternative transdermal delivery of RLX to improve its absorption, bypass first pass metabolism, and subsequently improve bioavailability. RLX-loaded cubosomes were prepared using the ethanol injection method followed by microfluidization technique and optimized using the QbD-based 23 factorial design. The average particle size, entrapment efficiency, and zeta potential of the optimized formulation were found to be 110.6nm, 98.23%, and 26.2mV, respectively. In vitro dissolution study indicated that the RLX-loaded cubosomes released 98.26% of the drug compared to pure RLX dispersion (58.6%). Histopathological examination revealed no sign of inflammation, indicating the safety of the developed formulation. Accelerated stability study as per ICH guidelines displayed no significant change in the formulation characteristics and drug-related performance of the developed formulation. Ex vivo permeability studies demonstrated a prolonged release from cubosomal formulation. In vivo pharmacokinetic studies revealed that the relative bioavailability of the optimized transdermal RLX-loaded cubosomes increased by 2.33-fold and 1.22-fold when compared with the oral RLX dispersion and transdermal RLX hydro-ethanolic solution respectively. IVIVC showed level C correlation with linear regression. Thus, the developed RLX-loaded cubosomes may have potential to overcome the problems associated with the existing marketed oral dosage forms of RLX.

Association of Prediagnostic Serum Levels of Vitamin D with Risk of Ductal Carcinoma In Situ of the Breast in the UK Biobank Cohort Study.

Higher circulating levels of vitamin D [25(OH)D] have been associated with reduced risk of developing invasive breast cancer. However, their association with risk of ductal carcinoma in situ (DCIS) of the breast has received little attention. We examined the association of serum vitamin D with risk of DCIS in 231,203 women, aged 40 to 69 years at enrollment in the UK Biobank cohort study. Multivariable Cox proportional hazards models were used to estimate HRs and 95% confidence intervals for the association of vitamin D with DCIS risk. There was no association between serum 25(OH)D levels and risk of DCIS overall, or by menopausal status. The association was not modified by body mass index category, family history of breast cancer, or current use of menopausal hormone therapy. In this large prospective cohort study, we did not observe an association between circulating serum levels of vitamin D and risk of DCIS. While previous studies have suggested that serum vitamin D has an inverse association with risk of invasive breast cancer, the present results do not provide evidence for an association with DCIS, a non-obligate precursor of invasive disease.

Strategies to Identify and Recruit Women at High Risk for Breast Cancer to a Randomized Controlled Trial of Web-based Decision Support Tools.

We describe five strategies to identify and successfully recruit a large cohort of racially/ethnically diverse high-risk women from multiple sources to a randomized controlled trial evaluating interventions to increase chemoprevention uptake. Findings could inform recruitment efforts for future breast cancer prevention trials to increase recruitment yield of high-risk women.

Alcohol consumption, smoking, and invasive breast cancer risk after ductal carcinoma in situ.

Alcohol is an established risk factor for invasive breast cancer, and women with a prior ductal carcinoma in situ diagnosis are at higher risk of invasive breast cancer than the general population. However, for women with a prior ductal carcinoma in situ diagnosis, few studies have evaluated the association between alcohol and smoking and risk of subsequent invasive breast cancer. Utilizing a population-based case-control design nested among women diagnosed with a ductal carcinoma in situ between 1995 and 2013, we compared 243 cases diagnosed with a subsequent invasive breast cancer and 423 individually matched controls never diagnosed with a subsequent breast cancer. Compared with never to occasional drinkers, drinkers consuming at least 7 alcoholic drinks per week on average at ductal carcinoma in situ diagnosis had a higher risk of invasive breast cancer that was borderline significant (OR 1.79, 95% CI 1.01-3.17, P value = 0.04). Smoking was not significantly associated with risk of developing an invasive breast cancer after adjustment for alcohol consumption. These findings suggest that consuming at least one alcoholic drink per day on average is positively associated with invasive breast cancer for women with a prior ductal carcinoma in situ diagnosis. If confirmed, modulating alcohol consumption could be one strategy for women with a history of ductal carcinoma in situ to impact their risk of invasive breast cancer.