Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor.

PURPOSE: Entinostat is an oral isoform selective histone deacetylase inhibitor that targets resistance to hormonal therapies in estrogen receptor-positive (ER+) breast cancer. This randomized, placebo-controlled, phase II study evaluated entinostat combined with the aromatase inhibitor exemestane versus exemestane alone. PATIENTS AND METHODS: Postmenopausal women with ER+ advanced breast cancer progressing on a nonsteroidal aromatase inhibitor were randomly assigned to exemestane 25 mg daily plus entinostat 5 mg once per week (EE) or exemestane plus placebo (EP). The primary end point was progression-free survival (PFS). Blood was collected in a subset of patients for evaluation of protein lysine acetylation as a biomarker of entinostat activity. RESULTS: One hundred thirty patients were randomly assigned (EE group, n = 64; EP group, n = 66). Based on intent-to-treat analysis, treatment with EE improved median PFS to 4.3 months versus 2.3 months with EP (hazard ratio [HR], 0.73; 95% CI, 0.50 to 1.07; one-sided P = .055; two-sided P = .11 [predefined significance level of .10, one-sided]). Median overall survival was an exploratory end point and improved to 28.1 months with EE versus 19.8 months with EP (HR, 0.59; 95% CI, 0.36 to 0.97; P = .036). Fatigue and neutropenia were the most frequent grade 3/4 toxicities. Treatment discontinuation because of adverse events was higher in the EE group versus the EP group (11% v 2%). Protein lysine hyperacetylation in the EE biomarker subset was associated with prolonged PFS. CONCLUSION: Entinostat added to exemestane is generally well tolerated and demonstrated activity in patients with ER+ advanced breast cancer in this signal-finding phase II study. Acetylation changes may provide an opportunity to maximize clinical benefit with entinostat. Plans for a confirmatory study are underway.

Efficacy and safety of erlotinib in patients with locally advanced or metastatic breast cancer.

PURPOSE: To evaluate the efficacy and safety of erlotinib in advanced breast cancer. Experimental design Multicenter, phase II study of erlotinib (150 mg orally daily). Cohort 1: progression after anthracyclines, taxanes, and capecitabine (n = 47). Cohort 2: progression after >1 chemotherapy for advanced-stage disease (n = 22). Primary endpoint was response rate (World Health Organization criteria). Secondary endpoints were safety, time to progression, and survival. RESULTS: One patient in each cohort (n = 2, 3.0%) had a partial response. Response duration was 17 weeks for the Cohort 1 patient and 32 weeks for the Cohort 2 patient. Median time to progression was 43 days for Cohort 1 (range 1-204) and 43 days for Cohort 2 (range 25-419). Common adverse events were diarrhea, rash, dry skin, asthenia, nausea, anorexia. CONCLUSION: Erlotinib had minimal activity in unselected previously treated women with advanced breast cancer. Predictive factors are needed to identify breast cancer patients who may derive benefit from erlotinib treatment.

Concordance between central and local laboratory HER2 testing from a community-based clinical study.

BACKGROUND: Women with HER2-overexpressing breast cancer have an unfavorable prognosis. Trastuzumab improves survival when combined with chemotherapy in the first-line treatment of patients with HER2-overexpressing metastatic breast cancer and decreases the rate of disease relapse by 52% and the rate of death by 33% in women with HER2-overexpressing early-stage breast cancer. HER2 testing can be performed using immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) and can be performed at local pathology laboratories or at central/reference laboratories. Because of the significant benefit seen with trastuzumab, it is critical to accurately identify women most likely to benefit. The method and the location of HER2 testing contribute to the accuracy of test results. PATIENTS AND METHODS: HER-First, a prospective, community-based, phase IV study of first-line trastuzumab/taxane therapy, enrolled patients with HER2-overexpressing metastatic breast cancer. Retesting of all tumor specimens by HER2 IHC and FISH at a high-volume, experienced laboratory was required. RESULTS: Concordance between local and central laboratory HER2 IHC testing was highest for local IHC 3+ samples (n = 377; 77%) and lowest for IHC 2+ samples (n = 184; 26%). Thirty-three percent of samples testing IHC 2+ at a local laboratory tested FISH-positive at the central laboratory. Concordance between HER2 IHC and FISH results was higher when both tests were performed at the central laboratory. CONCLUSION: Accurate HER2 test results are critical to identify patients who are appropriate candidates for trastuzumab, a therapy with significant clinical benefits in HER2-overexpressing breast cancer. These data show that HER2 testing is most accurate when performed at a high-volume reference laboratory.

Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.

BACKGROUND: We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer. METHODS: The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclitaxel. RESULTS: By March 15, 2005, 394 events (recurrent, second primary cancer, or death before recurrence) had been reported, triggering the first scheduled interim analysis. Of these, 133 were in the trastuzumab group and 261 in the control group (hazard ratio, 0.48; P<0.0001). This result crossed the early stopping boundary. The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years. Trastuzumab therapy was associated with a 33 percent reduction in the risk of death (P=0.015). The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831. CONCLUSIONS: Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer. (ClinicalTrials.gov numbers, NCT00004067 and NCT00005970.)

Trastuzumab and cardiac dysfunction: update on preclinical studies.

Trastuzumab, a humanized, recombinant antibody directed against HER2, can significantly improve survival in women with HER2-positive metastatic breast cancer. Treatment with trastuzumab has been associated with cardiac toxicity, most commonly manifested as asymptomatic decreases in left ventricular ejection fraction on multiple gated acquisition scans. These asymptomatic decreases appear to be reversible, and their clinical significance is not well understood. Fortunately, studies are beginning to show that the majority of women with decreases in left ventricular ejection fraction never develop clinical evidence of cardiac dysfunction. Although cardiotoxicity has been difficult to study, in part because of the small number of actual clinical events, preliminary evidence appears to indicate that the mechanism of trastuzumab-related cardiotoxicity is different than that induced by anthracyclines. The development of animal models may yield further understanding of the mechanism(s) of trastuzumab-associated cardiac dysfunction, and may provide a focus for clinical trials of treatment or prevention. Current investigations with rodent and primate models of cardiac dysfunction are briefly discussed in this article.

Development of the breast cancer education and risk assessment program.

PURPOSE/OBJECTIVES: To provide a description of the inception and evolution of the Breast Cancer Education and Risk Assessment Program. DATA SOURCES: Computerized database (e.g., Personal Family History Risk Assessment Model, Knowledge Assessment Tool, risk perception, evaluation form) and author experience. DATA SYNTHESIS: A total of 749 women participated in the group education and risk-assessment program from March 1999 through March 2002. Advanced practice nurses provided information about calculated risks, corrected misperceptions among participants, and highlighted options available to decrease breast cancer risk. Knowledge scores improved, and, in general, participants were very satisfied with the content and comprehensibility of the educational session. CONCLUSIONS: Results from the evaluation of the Breast Cancer Education and Risk Assessment Program suggest that group education is a viable and acceptable way to bring new advances in breast cancer prevention to large groups of women. The data sources support the conclusion that women can be effectively taught general breast cancer risk information in a group setting and be placed into specific risk categories to streamline discussion of risk-management options and relevant research studies. IMPLICATIONS FOR NURSING: Advanced practice nurses are a vital link in the assessment of women at high risk for breast cancer, education, and appropriate referrals for management options and relevant clinical trials.

Lavage and nipple aspiration of breast ductal fluids: a source of biomarkers for environmental mutagenesis.

The acquisition of breast ductal fluid by nipple aspiration and ductal lavage are simple noninvasive procedures to sample breast tissue. Nipple aspiration fluid (NAF) obtained with gentle suction and a simple syringe-adapted apparatus may evaluate the secretory components that bathe the ductal epithelial cells. Evaluations have included the quantification of soluble markers (carcinoembryonic antigen and prostatic-specific antigen), DNA amplification, protein gel electrophoresis, and mutagenesis assays. It has been suggested that environmental mutagens in the breast ductal system may contribute to carcinogenesis. The feasibility of mutagenesis assays on NAF has been limited by the small size of the samples obtained. Three small clinical studies detected mutagens in 6-14% of the samples using the Salmonella Ames assay. Ductal lavage collects more of a cellular aspirate from the ductal system utilizing a microcatheter. Early studies on ductal lavage fluid have included cytology and methylation-specific PCR. Ductal lavage in a high-risk group has identified cellular atypia in 21% of those sampled. Samples obtained through the nipple, by aspiration or lavage, are the proteinaceous secretions from the ductal system and ductal epithelial cells. The fluid represents the cellular events and the dynamic secretory process of the breast and may include potential initiators of the carcinogenesis process in the cellular microenvironment. Fluid obtained by ductal lavage may allow for more detailed studies of the role of mutagens in breast cancer.