Incidence of Fatty Liver and Liver Function Changes in Hormone Receptor-Positive Breast Cancer Patients upon Receiving Long-Term Postoperative Tamoxifen Therapy

Introduction: Obesity is an independent risk factor for the development of breast cancer and has been associated with poor breast cancer outcomes. But, this association usually depend on hormone-receptor positivity and ovarian activity. Obesity was confirmed as an adverse prognostic factor in patients treated with aromatase inhibitors, but the adverse effects in patients treated with tamoxifen was not known exactly. Thus, we aimed to examine the efficacy of adjuvant tamoxifen in hormone receptor-positive premenopausal breast cancer patients according to the body mass index (BMI). Material-Methods: Newly diagnosed hormone receptor-positive breast cancer patients who were premenopausal and non-metastatic were enrolled to the study. Patients with BMI ranging between 18.5 and 24.9 kg/m2 as normal weight patients (Arm A, n = 408), and patients with a BMI ranging ≥ 25 kg/m2 were overweight and obese patients (Arm B, n = 418). Results: The median follow-up time for this analysis was 36 (6-327) months. The median age was 39.5 (22-57) and 43 (20-56) in Arm A and Arm B, respectively (P<0.0001). The mean BMI was 22.1 ± 1.8 kg/m2 and 29.2 ± 3.3 kg/m2 of Arm A and Arm B, respectively ( P = <0.001). In both normal weight and overweight patients, the other baseline clinico-pathologic properties and the treatment history with radiotherapy and chemotherapy were similar and not statistically significant. In overweight and obese patients the history of diabetes mellitus and hypertension was significantly higher compared to normal weight patients. In patients with normal weight patients DFS rate was 88.5% and 78.2% whereas in overweight and obese patients DFS rate was 87.2% and 70.9% in the third and fifth years respectively (Figure 1) ( P = 0.43). In patients with normal weight patients OS rate was 98.5% and 93.2% whereas in overweight and obese patients OS rate was 94.6% and 87.4% in the third and fifth years respectively (Figure 2) ( P = 0.02). Conclusion: Our study showed that BMI have no worse effect on recurrence risk in patients treated with tamoxifen in hormone-receptor positive premenopausal breast cancer. Poor survival outcome was observed in overweight and obese patients can be due to dose limitations of chemotherapeutic agents and higher rate of comorbid diseases. Citation Format: Kadri Altundag, Mehmet AN Sendur, Sercan Aksoy, Taner Babacan, Yavuz Ozisik. Efficacy of adjuvant tamoxifen in hormone receptor-positive premenopausal breast cancer patients according to the body mass index [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-16.

OBJECTIVES/SPECIFIC AIMS: (1) To evaluate the association of patient and clinical factors with adherence to adjuvant hormone therapy (HT). (2) To examine the association of HT-related symptoms and the extent of remediation with early discontinuation of hormone therapy. METHODS/STUDY POPULATION: Retrospective cohort study of risk factors for interruption and early discontinuation of adjuvant hormone therapy in hormone receptor-positive nonmetastatic breast cancer patients diagnosed between 2009 and 2015. This study will include incident hormone receptor-positive breast cancer patients who initiated their HT and were followed at Tufts MC until Dec 31, 2016. Primary data source is electronic medical records (EMRs) RESULTS/ANTICIPATED RESULTS: The primary outcome of this study is early discontinuation to HT, defined as the first treatment gap of greater than or equal to 180 days following the initiation of HT. Treatment interruption, defined as any patient- or provider-initiated treatment gap of ≥ 2 weeks, will be examined as the secondary endpoint. Any HT-related symptoms occurred during a follow-up interval will be captured and categorized into five major types (i.e., vasomotor, neuropsychological, gastrointestinal, gynecological, and musculoskeletal symptoms). Onset and duration of a HT-related symptom will be recorded. Severity of the symptoms will also be rated by clinical oncologists. Remediations in response to HT- related symptoms will be collected and categorized into to two groups (pharmacological or non-pharmacological) and whether they were patient- or provider-initiated. Response to a remediation is defined as complete relief, partial relied, no relief, or with worsening symptoms. Response to a treatment change (i.e., HT switch or hold) was collected separately but using the same criteria. Analyses will be performed on the association between patient and clinical factors with rates of nonadherence (unplanned treatment interruption and/or early discontinuation) of hormone therapy, respectively. We also will explore whether patients with elevated symptoms and/or incomplete remediation will have earlier discontinuation of hormone therapy. DISCUSSION/SIGNIFICANCE OF IMPACT: Through formal chart review, we will establish a dataset that contains highly detailed information about treatment-emergent symptoms and remediations, which will enable us to quantitatively assess the impact of these treatment factors on adherence to hormone therapy for breast cancer. The in-depth analysis of risk factors associated with nonadherence to hormone therapy will inform development of interventions to improve cancer outcomes.

BackgroundMammalian enabled (MENA) protein is a member of the enabled/vasodilator stimulated phosphoprotein (Ena/VASP) protein family, which regulates cytoplasmic actin network assembly. It plays a significant role in breast cancer invasion, migration, and resistance against targeted therapy and chemotherapy. However, its role in the efficacy of endocrine therapy for the hormone receptor-positive (HR+) breast cancer patients is not known. This study investigated the role of MENA in the resistance against tamoxifen therapy in patients with HR+ breast cancer and the underlying mechanisms.MethodsMENA expression levels in the clinical HR+ breast cancer samples (n = 119) were estimated using immunohistochemistry (IHC) to determine its association with the clinicopathological features, tamoxifen resistance, and survival outcomes. Western blotting (WB) and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) analysis was performed to estimate the MENA protein and mRNA levels in the tamoxifen-sensitive and -resistant HR+ breast cancer cell lines. Furthermore, CCK8, colony formation, and the transwell invasion and migration assays were used to analyze the effects of MENA knockdown on the biological behavior and tamoxifen sensitivity of the HR+ breast cancer cell lines. Xenograft tumor experiments were performed in the nude mice to determine the tumor growth rates and tamoxifen sensitivity of the control and MENA knockdown HR+ breast cancer cells in the presence and absence of tamoxifen treatment. Furthermore, we estimated the growth rates of organoids derived from the HR+ breast cancer patients (n = 10) with high and low MENA expression levels when treated with tamoxifen.ResultsHR+ breast cancer patients with low MENA expression demonstrated tamoxifen resistance and poorer prognosis compared to those with high MENA expression. Univariate and multivariate Cox regression analysis demonstrated that MENA expression was an independent predictor of tamoxifen resistance in patients with HR+ breast cancer. MENA knockdown HR+ breast cancer cells showed significantly reduced tamoxifen sensitivity in the in vitro experiments and the in vivo xenograft tumor mouse model compared with the corresponding controls. Furthermore, MENA knockdown increased the in vitro invasion and migration of the HR+ breast cancer cells. HR+ breast cancer organoids with low MENA expression demonstrated reduced tamoxifen sensitivity than those with higher MENA expression. Mechanistically, P-AKT levels were significantly upregulated in the MENA-knockdown HR + breast cancer cells treated with or without 4-OHT compared with the corresponding controls.ConclusionsThis study demonstrated that downregulation of MENA promoted tamoxifen resistance in the HR+ breast cancer tissues and cells by enhancing the AKT signaling pathway. Therefore, MENA is a promising prediction biomarker for determining tamoxifen sensitivity in patients with HR+ breast cancer.

Background:Increased adiposity may trigger signalling pathways that induce aromatase expression. As aromatase inhibitors exert their effects by blocking the aromatase enzyme, higher body mass index (BMI) can reduce the effect of aromatase inhibitors. Thus, we aimed to investigate retrospectively the effect of BMI on the efficacy of aromatase inhibitors in hormone receptor-positive postmenopausal patients with breast cancer.Methods:Newly diagnosed hormone receptor-positive breast cancer patients who were postmenopausal and non-metastatic were enrolled to the study. Patients with BMI ranging between 18.5 and 24.9 kg m−2 were considered as normal weight patients (Arm A, n=102), and patients with a BMI ranging ⩾25 kg m−2 were grouped as overweight and obese patients (Arm B, n=399).Results:In both normal weight and overweight patients, the baseline clinico-pathologic properties and the treatment history with radiotherapy and chemotherapy were similar, and with no statistically significant difference. In normal weight patients disease-free survival (DFS) rate was 93.7% and 77.6%, whereas in overweight and obese patients DFS rate was 96.8% and 85.5% in the first and third years, respectively, (P=0.08). Three year survival rate in Arm A patients was 98.3%, whereas in Arm B was 98.0% (P=0.57). When anastrozole was compared with letrozole in the subgroup analysis no difference with regard to DFS and overall survival was detected.Conclusion:These results, contradictory to the prior results, show that BMI has no worse effect on outcomes of aromatase inhibitors in postmenopausal hormone receptor-positive breast cancer patients. In the subgroup analysis, letrozole and anastrozole had similar survival outcomes.

535 Background: Endocrine therapy has greatly improved the clinical outcomes of hormone receptor-positive breast cancer patients. However, there was an unmet need to identify the potentially best regimen of initial adjuvant endocrine therapy. Therefore, in this network meta-analysis, we synthesized the latest evidence to indirectly compare the efficacy and safety among different 5 years of regimens of initial adjuvant endocrine therapy. Methods: We conducted a systematic search of the PubMed, Web of Science, and EMBASE in January 2022. Randomized clinical trials assessing the efficacy and safety of initial 5 years of adjuvant endocrine therapy were included. The primary outcomes were disease-free survival (DFS) and overall survival (OS) and the secondary outcome was severe adverse effects (SAEs). A Bayesian network meta-analysis was carried out to indirectly compare all regimens and the SUCRA values were used to obtain rankings. Results: Eleven studies with 49,987 subjects were included. For DFS, exemestane (EXE) (hazard ratio [HR] 0.91, 95% confidence interval [95%CI] 0.87-0.96), anastrozole (ANA) (0.94, 0.90-0.97), letrozole (LET) (0.93, 0.89-0.97), tamoxifen (TAM) followed by EXE (0.91, 0.87-0.96), and TAM followed by ANA (0.92, 0.87-0.98) were more favorable than TAM, with TAM followed by EXE ranking as the first of SUCRA. For OS, only TAM followed by ANA showed significant superiority than TAM (HR 0.91, 95%CI 0.86-0.97) and ranked as the first of SUCRA. For SAEs, EXE (HR 1.72, 95%CI 1.04-2.98), ANA (1.58, 1.03-2.43), and LET (1.63, 1.02-2.57) showed greater associations with bone fracture than TAM. However, no significant difference in the incidences of cardiac events, thromboembolic events, and cerebrovascular events was found among all comparisons. Conclusions: The sequential use of aromatase inhibitors may be the optimal treatment mode for hormone receptor-positive postmenopausal early breast cancer patients. In addition, the three kinds of aromatase inhibitors achieved roughly equal efficacy, but caused different types of SAEs.

1 ) Objective: This study was conducted to investigate the incidence rate of fatty liver and it's related factors based on a three year follow up of multiphasic health screening participants. M e t h o d s: 671 male workers who had participated in both initial and second multiphasic health screening were selected. Initial screening was performed during the year of 1996 to 1997 and second screening was performed during the year of 1999 to 2000. Among them, four hun- dred and thirty workers who didn't initially have a fatty liver were selected as the final study subjects. They were classified into 2 categories according to the initial and second hepatic ultra - sonographic findings; stationary normal (307, 71.4%), and fatty liver incident (123, 28.6%). The incidence rate was calculated using the incidence density method. Results: The incidence rate of fatty liver among the male workers was 9.73 per 100 person- years. The white collar workers had a higher incidence rate (10.66) than the blue collar workers (8.14). The incidence density ratio of alcohol drinking to fatty liver incidence was 1.41, and the incidence density ratio of low vegetable diet was 1.63. The incidence density ratio of obesity was 1.78 for the 100-109% obesity index group, 2.83 for the 110-119% obesity index group, 4.25 for the ≥120% obesity index group over <100%. Smoking, regular exercise, salty food preference, and taking food supplement had no significant effect on the incidence of fatty liver. The fatty liver incident group had higher initial blood pressure, GPT, γ GTP, fasting blood sugar, HbA1c, uric acid, total cholesterol and triglyceride levels than the stationary normal group. However, there were no differences in the GOT, HDL-cholesterol or LDL-cholesterol levels. In the multiple logistic regression analysis, obesity index and serum triglyceride were found to be major factors in the incidence of fatty liver after controlling age, alcohol drinking, vegetable diet, daily coffee intake, blood pressure, HbA1c, total cholesterol, and uric acid levels. Conclusions: The incidence rate of fatty liver among the male workers was 9.73 per 100 per - son-years. The lifestyles which gave rise to an increasing incidence of fatty liver were those involving excessive alcohol drinking, obesity, and low vegetable diet. Moreover, many cardio - vascular disorder related health indices such as blood pressure, and the blood sugar, blood lipid and uric acid levels, were related to the incidence of fatty liver.

Background: CDK4/6 inhibitors benefit a limited percentage of hormone receptor-positive breast cancer (HRPBC) patients in the adjuvant setting: according to the MonarchE study, from all patients treated with the endocrine plus CDK4/6 inhibitor combination, 84% were adequately treated with endocrine therapy alone, ~5% experienced benefit from the combination, and 11% were not rescued from relapse by abemaciclib. Given the side effects and the cost, biomarkers to guide treatment decisions in this setting are appealing. We found that the p27Kip1 V109G SNP was enriched in HRPBC patients experiencing relapse despite endocrine treatment. p27Kip1 binds to cyclins and CDKs, restraining cells from cycling by inhibiting the formation of CDK/cyclin complexes and their kinase activity, resulting in less phosphorylation of Rb. A functionally impaired p27Kip1 could render tumor cells insensitive to endocrine therapy, while being rescued by CDK4/6 inhibitors. Thus, this SNP could narrow down the patient population that requires adjuvant CDK4/6 inhibitors. Methods: Isogenic HRPBC cell lines, wild-type or polymorphic homozygous for the p27Kip1 V109G SNP were generated with CRISPR-Cas9. Cell cycle and cell viability were assessed with BRDU incorporation and colony assays. Immunoprecipitation coupled with western blot (WB) was used to measure the formation of CDK/Cyclin complexes; Rb phosphorylation was assessed by WB. An in vitro kinase assay was set up to measure the CDK4 activity of p27Kip1/CDK/Cyclin complexes. Patients (n=115) with metastatic, HRPBC receiving endocrine monotherapy or in combination with CDK4/6 inhibitors were genotyped for the p27Kip1 V109G SNP, and PFS by genotype and therapy compared with the Kaplan-Meier method. All statistical tests were two-sided. Results: three isogenic polymorphic clones were generated from the wild-type T47-D hormone-positive cell line. The three clones were resistant to hormonal deprivation compared to wild-type cells. The relative plating efficiency (RPE) in the colony assays of the polymorphic clones exposed to hormonal deprivation compared to that of deprived T47-D cells was 550% (clone C1), 165% (clone E1) and 100% (Clone F5); P&amp;lt; 0.005. The three clones were also resistant to fulvestrant (Fulv) (300%, 170% and 180%, respectively); P&amp;lt; 0.005. Cell cycle (positive BRDU cells) decreased ~3 fold in wild type cells (18% to 6.5%) when exposed to hormonal deprivation or Fulv, but remained unaltered in the polymorphic clones. However, when palbociclib was added to hormonal deprivation or Fulv, the effects in RPE increased and were similar in polymorphic clones and parental cells (&amp;gt;5% RPE compared to vehicle, both in polymorphic and wild-type cells). The p27Kip1 V109G SNP was found in homozygosity in ~15% of metastatic HRPBC patients. When patients received endocrine monotherapy in the first-line setting, polymorphic patients experience rapid failure (N=51) compared to wild-type/heterozygous patients (4.3 vs. 21.1 months; P &amp;lt; 0.0001). However, when patients received hormonal plus CDK4/6 inhibitors, the differences disappeared (18.3 vs. 24.3 months; P=0.85). Mechanistically, we observed that the formation of CDK2/CyclinA, CDK2/CyclinE and CDK4/Cyclin D1 complexes was &amp;gt;200% higher in polymorphic than in wild-type cells (P&amp;lt; 0.05). Regarding CDK4 kinase activity of p27Kip1/CDK/Cyclin complexes, as opposed to wild-type p27Kip1, p27Kip1 V109G was unable to suppress the kinase activity of CDK4 in presence of Fulv or hormonal deprivation. However, palbociclib was able to fully suppress CDK4 kinase activity regardless of the p27Kip1 genotype. Conclusion: Germline p27Kip1 genotyping can constitute a tool for treatment selection: whereas wild-type patients are adequately treated with endocrine monotherapy, polymorphic patients are inherently resistant, but are rescued with CDK4/6 inhibitors. Thus, hormonal+CDK4/6 inhibitor combos could be reserved for the polymorphic patients. Citation Format: Miguel Quintela-Fandino, Silvana Mouron, Maria J. Bueno, Manuel Muñoz, Raul Torres, Sandra Rodriguez, Rodrigo Sánchez-Bayona, Luis Manso, Jorge Silva, Marcos Malumbres. p27Kip1 V109G single-nucleotide polymorphism (SNP): pinpointing the hormone-receptor positive breast cancer subpopulation that requires CDK4/6 inhibitors in addition to endocrine therapy. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-28.

In this study, we evaluated if PITX2 DNA methylation is a marker for disease recurrence in lymph node-negative (LNN), steroid hormone receptor-positive (HR+) breast cancer patients. In addition, we studied the association between PITX2 DNA methylation and PITX2 gene expression. PITX2 DNA-methylation was measured in tumor tissue from 412 LNN/HR+ breast cancer patients who had not received any adjuvant systemic treatment. In addition, PITX2 DNA-methylation and mRNA expression was evaluated in 32 breast cancer cell lines. In univariate Cox regression analysis, DNA-methylation of PITX2 as a continuous variable was associated with early distant metastasis (HR = 1.71; P < 0.01) and poor overall survival (HR = 1.71; P < 0.01). In multivariate analysis together with the established prognostic factors age, tumor size and tumor grade, and steroid hormone receptor levels, both associations retained their significance (for MFS, HR = 1.74; P < 0.01; for OS, HR = 1.46; P = 0.02). In the breast cancer cell lines, PITX2 DNA methylation was inversely association with PITX2A and PITX2B mRNA expression (P < 0.01). Hypermethylation of PITX2 is, in cell lines, negatively associated with PITX2 mRNA expression and, in clinical specimens, positively associated with breast cancer disease progression.

Atrophic vaginitis represents a major barrier to compliance with aromatase inhibitor (AI) therapy in breast cancer (BC) survivors. While local estrogen therapy is effective for postmenopausal vaginal dryness, the efficacy of such therapies has not been evaluated systematically in hormone receptor-positive (HR+) BC patients on AI therapy. Furthermore, the potential risk of breast cancer recurrence with vaginal estrogen therapy represents a long-term safety concern for the patients with HR+BC. Unfortunately, there is no standardized assay to measure very low concentrations of estradiol (E2) in these women being treated with AI therapy. This makes it difficult to evaluate even indirectly the potential risk of BC recurrence with vaginal estrogen therapy in HR+BC patients on AI therapy. In this review, we describe available assays to measure very low concentrations of E2, discuss the Food and Drug Administration-approved vaginal estrogen products on the market, and summarize published and ongoing clinical trials evaluating the safety and efficacy of vaginal estrogen in HR+BC patients on AI therapy. In the absence of any randomized controlled clinical trials, this review serves as a summary of available clinical data and ongoing studies to aid clinicians in selecting the best available option for their patients.

4MO Prognostic implication of 21-gene expression assay in luminal B type hormone receptor-positive breast cancer patients younger than 40 years

To examine (1) the trend and associated factors of Oncotype DX (ODX) use among hormone receptor-positive (HR+) breast cancer (BC) patients in 2004-2015; (2) the trend of reported chemotherapy by Recurrence Score (RS); and (3) the survival differences associated with ODX use. ODX data from Genomic Health Inc. were linked with 17 SEER registries data. HR + BC cases with lymph node negative (N0) or 1-3 positive LNs (N1) from 2004-2015 were analyzed. The Cochrane-Armitage trend test, logistic regression, Kaplan-Meier survival curve, and stratified Cox model were performed. Survival analysis was restricted to HR+/HER2- patients from 2010 to 2014, matched on propensity score. ODX use increased substantially from 2004 to 2015 (N0: 2.0% to 42.7%; N1: 0.3% to 27.9%). Non-Hispanic black and Medicaid insured patients had lower odds of receiving ODX. N0 patients with moderately differentiated or 2.1-5.0cm tumor and N1 patients with well-differentiated or < 2.0cm tumor had higher odds of using ODX. The reported chemotherapy use decreased significantly with low and intermediate RS, and increased for high RS among N0 patients. ODX use was associated with better breast cancer-specific survival [hazard ratio (95% CI) N0 1.96 (1.60-2.41), N1 1.90 (1.42-2.54)] and overall survival [N0 2.06 (1.83-2.31), N1 1.72 (1.42-2.09)], especially in the first 36months. ODX use has increased significantly since 2004, nonetheless disparities remain, especially for racial/ethnic minorities and Medicaid insured patients. Administering chemotherapy based on ODX results has been improved among N0 patients. Patients receiving ODX had better survival than those not.

SummaryA chronic vitamin B complex deficiency in dogs on a 41% casein diet produced a marked decrease in voluntary food intake, but liver function tests remained normal and liver sections showed no increase in fat. A similar chronic B complex deficiency using dogs on a 20% casein diet produced an abnormal liver function and fatty changes in liver biopsy specimens. These findings were absent in the inanition and normal control dogs. Therapy with yeast extract restored the liver function to normal and the fatty change in the liver decreased, even though protein and caloric intake were restricted.

Tamoxifen can reduce the occurrence of breast cancer by a half in high-risk women. Recently, a genome-wide association study identified two single-nucleotide polymorphisms (SNPs) nearor in the CTSO and ZNF423 genes that were associated with breast cancer risk during tamoxifen therapy. We hypothesized that these two SNPs could be associated with increased recurrence in breast cancer patients who received adjuvant tamoxifen therapy. A total of 586 breast carcinomas were available for SNP genotyping assays. TaqMan pre-designed SNP genotyping assays were used to identify the presence of CTSO rs10030044 and ZNF423 rs8060157. We then investigated the relationship between CTSO rs10030044 genotypes and mRNA expression levels of CTSO and BRCA1 in 290 breast cancer patients. We found a positive correlation between the variant GG genotype of CTSO rs10030044 and shorter disease-free survival, or overall survival in hormone receptor-positive breast cancer patients receiving adjuvant tamoxifen therapy. In contrast, this genotype was not associated with prognosis in hormone receptor-negative breast cancer patients. Multivariate Cox regression analysis revealed that this genotype was an independent factor indicating a poor prognosis in hormone receptor-positive breast cancer patients receiving adjuvant tamoxifen therapy. No association was found between CTSO genotype and mRNA expression of CTSO and BRCA1. ZNF423 rs8060157 genotype was not associated with prognosis in this study. We show that a SNP near the CTSO gene is a poor prognostic factor in breast cancer although further research might help to reveal the factors linking this genotype and prognosis.

Tamoxifen is associated with an increased risk of developing fatty liver. The aim of this systematic review and meta-analysis was to evaluate the prevalence and incidence of fatty liver developed after tamoxifen treatment in breast cancer patients. A systematic search of PubMed (Medline), EMBASE, OVID Medline, the Cochrane Library and other databases was performed for this review. The abstracts obtained from the search were reviewed by two investigators who chose manuscripts for full-text review. The event rates were calculated with a random-effects model and quality-effects model. The search yielded 165 references. Of these, 24 were included in the quantitative summary. We analysed the data of a total of 6,962 patients treated with tamoxifen and 975 patients not treated with tamoxifen. The prevalence of fatty liver among patients with breast cancer taking tamoxifen was 40.25 per 100 patients and the incidence rate was 12.37 per 100 person-years. The incidence of fatty liver was much higher in the tamoxifen group than in the control group [incidence rate ratio: 3.12, 95% CI (confidence interval): 2.05-4.75, I2 =61%], regardless of region. The main risk factors were body mass index (BMI) [hazard ratio (HR): 1.15, 95% CI: 1.09-1.22] and hypercholesterolaemia (HR: 1.01, 95% CI: 1.00-1.02). The use of tamoxifen was associated with increased risks in the incidence and prevalence of fatty liver, especially in patients with high BMI and hypercholesterolaemia.

Background: Radium-223 dichloride (Ra-223), a first-in-class α-emitter with a potent, targeted antitumor effect on bone metastases (mets), was well tolerated and reduced baseline bone biomarker levels in a phase 2 study in metastatic breast cancer (MBC) patients (pts) with bone-dominant disease (Coleman et al. Breast Cancer Res Treat 2014). Adding everolimus (EVE) to exemestane (EXE) significantly improved progression-free survival (PFS) versus EXE alone in human epidermal growth factor receptor 2–negative (HER2-), hormone receptor–positive (HR+) MBC pts with advanced disease. This trial will evaluate efficacy and safety of Ra-223 with EXE and EVE in pts with HER2-, HR+ breast cancer and bone mets (NCT02258451). Trial design: Pts scheduled to receive EXE (25 mg PO once daily) and EVE (10 mg PO once daily) will be randomized 1:1 to Ra-223 (50 kBq/kg IV) or placebo × 6 cycles q4wk. EXE and EVE treatment (tx) will continue until disease progression, unacceptable toxicity, or the pt can no longer travel to the clinic to receive study medication. Stratification will be by geographic region, previous lines of hormone therapy, and presence of visceral disease. Safety and efficacy will be assessed at each 4-week clinic visit during tx. Long-term safety will be assessed until study termination (ie, pt death, pt loss to follow-up, or pt reaching required number of events). Main eligibility criteria: Eligible pts are pre- or postmenopausal with estrogen receptor–positive and HER2- bone lesion–related asymptomatic or mildly symptomatic MBC not amenable to cure by surgery or radiotherapy, and with ≥2 bone mets visible on bone scan. Pts must have measurable disease per RECIST v1.1, ≥1 prior line of hormonal therapy in the metastatic setting, and 1-2 skeletal related events before study entry; be on bisphosphonates or denosumab for ≥1 mo before study entry; and have ECOG performance status of 0-1, adequate hematologic, renal, and liver function, and life expectancy ≥6 mo. Pts may not have prior or current need for chemotherapy in the metastatic setting, unresolved spinal cord compression, and prior or current EVE tx. Specific aims: The primary endpoint is symptomatic skeletal event (SSE)–free survival. Secondary endpoints are overall survival, time to opiate use for cancer pain, time to pain progression, time to cytotoxic chemotherapy, radiologic PFS (rPFS), and acute and long-term safety. Exploratory endpoints include time to first on-study SSE, time to bone alkaline phosphatase (bALP) progression, bALP response at wk 12 and end of tx, bone-specific rPFS, resource utilization, biomarker assessments, and time to visceral mets onset. Statistical methods: Assuming a one-sided α of 0.1, power of 90%, ∼160 SSEs will be required at the time of analysis. A stratified log-rank test will be used to analyze efficacy (intent-to-treat population). Safety analysis will be descriptive. Present and target accrual: This trial is now enrolling pts. Target accrual is 311. Citation Format: Rugo HS, Huang L, Petrenciuc O, Zaccarini P, Coleman RE. A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in human epidermal growth factor receptor 2–negative, hormone receptor–positive breast cancer patients with bone metastases. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-11.