Citations

Abstract Background: Epigenetic alterations in the genome, including abnormal DNA methylation and histone hypoacetylation, initiate and promote cancerous changes via several mechanisms, including inactivation of tumor suppressor genes. Preclinical investigations in breast cancer suggest that use of epigenetic modifiers results in re-expression of aberrantly silenced genes and proteins that represent important therapeutic targets (e.g. estrogen receptor alpha, ER). Combination therapy with a DNA methyltransferase inhibitor (DNMTI) and a histone deacetylase inhibitor (HDACI) has yielded superior ER reexpression and greater restoration of tamoxifen responsiveness than with HDACI alone. We hypothesize that clinically tolerable doses of the DNMTI 5-azacitidine (5-AZA) and the HDACI entinostat may not only effect changes in DNA methylation and gene expression, but also yield objective disease responses in women with advanced breast cancer. Trial design: This multicenter phase II study (NCT01349959) is enrolling patients with advanced human epidermal growth factor receptor 2 (HER2)-negative breast cancer with triple negative (ER/progesterone receptor [PR]/HER2−negative, Cohort A) or hormone-resistant (Cohort B) disease. Patients will receive 5-AZA 40 mg/m2 subcutaneously days 1–5 and 8–10 and entinostat 7 mg orally days 3 and 10 every 28 days. Because of the potential for re-expression of the ER with epigenetic agents, patients will be offered continuation of 5-AZA and entinostat at progression with the addition of hormonal therapy (investigator discretion). Mandatory tumor biopsies will be performed at baseline and after 8 weeks of therapy to evaluate correlative biomarkers. Eligibility Criteria: Eligible patients must be ≥ 18 years, have measurable locally advanced/metastatic triple-negative (at least one prior chemotherapy received adjuvant/metastatic setting) or hormone-resistant (must have received two prior hormonal agents and one prior chemotherapy) disease, adequate organ function and ECOG PS ≤ 2. Specific Aims: 1. Objective response rate (ORR) by RECIST 1.1 criteria. 2. Safety and tolerability 3. Progression-free survival, overall survival and clinical benefit rate. 4. Safety and toxicity data, feasibility and response rate where hormonal therapy is added to the combination under investigation at the time of progressive disease. 5. Pharmacokinetics, cytidine deaminase, changes from baseline of candidate gene methylation and expression in circulating deoxyribonucleic acid (DNA) and malignant tissue. Statistical Methods: Using a two-stage three-outcome design to assess the efficacy of the combination, a maximum of 30 patients (requiring 27 evaluable) will be accrued to each cohort unless undue toxicity is encountered for a maximum sample size of 60 patients. The study design tests the null hypothesis that the ORR is at most 5% against the alternative hypothesis that it is at least 20% with a type I error of 4% and power of 90%. Present and Targeted Accrual: This study has just opened to patient enrollment. We anticipate a rapid accrual of 60 patients within 1 year.br](Funding from Stand Up to Cancer and CTEP). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-06.

Abstract Background: Analyses of adjuvant endocrine therapy suggest that the appearance of new vasomotor or joint symptoms within 3 months of initiating either tamoxifen or aromatase inhibitor therapy predict for lower subsequent recurrence. We hypothesized that new vasomotor or joint symptoms may predict outcomes with anastrozole or exemestane in participants in the ongoing NCIC CTG Trial MA.27. We performed a pooled analysis across treatment arms of the MA.27 trial, to examine the effects of early onset new or worsening symptoms on relapse-free survival (RFS).Methods: 7576 postmenopausal women with early breast cancer were accrued to MA.27, a randomized adjuvant trial of exemestane and anastrozole. The second interim analysis data with a 3 year median follow-up was used for this analysis. The trial's primary endpoint is event-free survival, but for this investigational analysis is RFS, which excludes non-breast cancer deaths. All 7118 participants known to be hormone receptor-positive who received trial therapy, and had no relapse in the first 3 months, were included. The association of vasomotor and joint symptoms with patient characteristics was examined with chi-square tests. Stratified log-rank and stratified univariate and multivariate Cox modeling were used to examine the association of early vasomotor and joint symptoms on disease outcomes.Results: Of 4749 women who were asymptomatic at baseline, 230 (5%) experienced vasomotor or joint symptoms at 3 months. The RFS stratified univariate Cox hazard ratio (HR) for vasomotor or joint-related symptoms was 1.184 (95% CI, 0.675-2.079). When all 7118 women were included, 361 (5%) developed new or worsening symptoms at 3 months. RFS was not statistically significant between the women with or without new symptoms (HR 1.129, 95% CI, 0.708-1.800). Higher T stage was the only factor included in the multivariate Cox RFS model that was associated with new or worsening symptoms (p<0.001).Conclusions: In contrast to prior findings, we did not observe a correlation between early emergence of symptoms and improved RFS. Longer follow-up and analysis by treatment arm and at different time points are required. Additional symptoms and time points will be added to the analysis prior to the meeting. Until further data are available, clinicians should not use treatment-emergent symptoms to counsel their patient whether to continue or change their prescribed medication. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 14.

Purpose We performed a case-control genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with musculoskeletal adverse events (MS-AEs) in women treated with aromatase inhibitors (AIs) for early breast cancer. Patients and Methods A nested case-control design was used to select patients enrolled onto the MA.27 phase III trial comparing anastrozole with exemestane. Cases were matched to two controls and were defined as patients with grade 3 or 4 MS-AEs (according to the National Cancer Institute's Common Terminology Criteria for Adverse Events v3.0) or those who discontinued treatment for any grade of MS-AE within the first 2 years. Genotyping was performed with the Illumina Human610-Quad BeadChip. Results The GWAS included 293 cases and 585 controls. A total of 551,358 SNPs were analyzed, followed by imputation and fine mapping of a region of interest on chromosome 14. Four SNPs on chromosome 14 had the lowest P values (2.23E-06 to 6.67E-07). T-cell leukemia 1A (TCL1A) was the gene closest (926-7000 bp) to the four SNPs. Functional genomic studies revealed that one of these SNPs (rs11849538) created an estrogen response element and that TCL1A expression was estrogen dependent, was associated with the variant SNP genotypes in estradiol-treated lymphoblastoid cells transfected with estrogen receptor alpha and was directly related to interleukin 17 receptor A (IL17RA) expression. Conclusion This GWAS identified SNPs associated with MS-AEs in women treated with AIs and with a gene (TCL1A) which, in turn, was related to a cytokine (IL17). These findings provide a focus for further research to identify patients at risk for MS-AEs and to explore the mechanisms for these adverse events.

Purpose Nonhormonal treatment options have been investigated as treatments for hot flashes, a major clinical problem in many women. Starting in 2000, a series of 10 individual double-blind placebo-controlled studies has evaluated newer antidepressants and gabapentin for treating hot flashes. This current project was developed to conduct an individual patient pooled analysis of the data from these published clinical trials. Patients and Methods Individual patient data were collected from the various study investigators who published their study results between 2000 and 2007. Between-study heterogeneity for study characteristics and patient populations was tested via χ2 tests before a pooled analysis. The primary end point, the change in hot flash activity from baseline to week 4, for each agent was calculated via both weighted and unweighted approaches, using the size of the study as the weight. Basic summary statistics were produced for hot flash score and frequency using the following three statistics: raw change, percent reduction, and whether or not a 50% reduction was achieved. Results This study included seven trials of newer antidepressants and three trials of gabapentin. The optimal doses (defined by individual study results) of the newer antidepressants paroxetine, venlafaxine, fluoxetine, and sertraline decreased hot flash scores by 41%, 33%, 13%, and 3% to 18% compared with the corresponding placebo arms, respectively. The three gabapentin trials decreased hot flashes by 35% to 38% compared with the corresponding placebo arms. Conclusion Some newer antidepressants and gabapentin, within 4 weeks of therapy initiation, decrease hot flashes more than placebo.