Targeting the IKKβ/mTOR/VEGF signaling pathway as a potential therapeutic strategy for obesity-related breast cancer.

Clinical correlation studies have clearly shown that obesity is associated with breast cancer risk and patient survival. Although several potential mechanisms linking obesity and cancers have been proposed, the detailed molecular mechanism of obesity-mediated breast tumorigenesis has not yet been critically evaluated. In this study, we evaluated the effects of obesity on mammary tumor initiation and progression using mice with genetic and diet-induced obesity bearing mammary tumor xenografts and mouse mammary tumor virus-neu transgenic mice that were fed a high-fat diet.

Frequency of mesenchymal-epithelial transition factor gene (MET) and the catalytic subunit of phosphoinositide-3-kinase (PIK3CA) copy number elevation and correlation with outcome in patients with early stage breast cancer.

Background: The current study was conducted to determine the frequency and association between recurrence-free survival (RFS) and MET and catalytic subunit of phosphoinositide-3-kinase (PIK3CA) copy number elevations in patients with early stage breast cancer.

Methods: Tumor DNA was extracted from 971 formalin-fixed, paraffin-embedded early breast cancers for molecular inversion probes arrays. Data were segmented using the single-nucleotide polymorphism (SNP)-FASST2 segmentation algorithm.

Decline in the use of anthracyclines for breast cancer.

Purpose: To determine the patterns of use of anthracycline- and taxane-based chemotherapy for breast cancer treatment.

Methods: Claims from a 5% national Medicare sample and from a nationally representative claims database (Marketscan) from 1998 to 2009 were used. Patients with International Classification of Diseases (ICD), ninth revision, codes indicating breast cancer, ICD and Common Procedural Terminology codes indicating breast surgery, and claims for chemotherapy between 3 months before and 12 months after surgery comprised the study cohort.

Relationship between lymphocytopenia and circulating tumor cells as prognostic factors for overall survival in metastatic breast cancer.

Introduction: Lymphocytopenia and circulating tumor cells (CTCs) have been reported as independent prognostic factors for overall survival (OS) in metastatic breast cancer (MBC), and both have been associated with bone metastases. Our objective was to compare the prognostic significance of lymphocytopenia, CTC count, and extensive bone metastases (> 2 lesions) assessed by fluorine-18 ((18)F) fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in patients with MBC.

Patients And Methods: This is a retrospective study that included patients with MBC who were starting a new line of systemic therapy.

Ganglioside GD2 identifies breast cancer stem cells and promotes tumorigenesis.

Cancer stem cells (CSCs) are a small subpopulation of cancer cells that have increased resistance to conventional therapies and are capable of establishing metastasis. However, only a few biomarkers of CSCs have been identified. Here, we report that ganglioside GD2 (a glycosphingolipid) identifies a small fraction of cells in human breast cancer cell lines and patient samples that are capable of forming mammospheres and initiating tumors with as few as 10 GD2+ cells.

Inflammatory breast cancer: what we know and what we need to learn.

Purpose: We review the current status of multidisciplinary care for patients with inflammatory breast cancer (IBC) and discuss what further research is needed to advance the care of patients with this disease.

Design: We performed a comprehensive review of the English-language literature on IBC through computerized literature searches.

Results: Significant advances in imaging, including digital mammography, high-resolution ultrasonography with Doppler capabilities, magnetic resonance imaging, and positron emission tomography-computed tomography, have improved the diagnosis and staging of IBC.

High ERK protein expression levels correlate with shorter survival in triple-negative breast cancer patients.

The mitogen-activated protein kinase (MAPK) signaling pathway is known to be activated in triple-negative breast cancer (TNBC). Extracellular signal-related kinase (ERK), a member of the MAPK pathway, promotes cell proliferation, angiogenesis, cell differentiation, and cell survival. To assess the prognostic impact of ERK in TNBC patients, relative quantities of ERK (ERK-2 and pMAPK) and direct targets of the ERK pathway (MAPK/ERK kinase 1, phospho-enriched protein in astrocytes [PEA]-15, phosphorylated (p)PEA-15, tuberous sclerosis protein 2, p70S6 kinase, and p27) were measured using reverse-phase protein arrays in tumor tissue from patients with TNBC (n = 97) and non-TNBC (n = 223).

Mutation profiling identifies numerous rare drug targets and distinct mutation patterns in different clinical subtypes of breast cancers.

The mutation pattern of breast cancer molecular subtypes is incompletely understood. The purpose of this study was to identify mutations in genes that may be targeted with currently available investigational drugs in the three major breast cancer subtypes (ER+/HER2-, HER2+, and Triple Negative). We extracted DNA from fine needle aspirations of 267 stage I-III breast cancers.

Toward individualized breast cancer therapy: translating biological concepts to the bedside.

The management of breast cancer has changed dramatically over the past 20 years. Based on gene expression profiles, or proteomics of three or four biomarkers, it is apparent that there are multiple subtypes with different clinical characteristics, clinical courses, and sensitivities to existing therapies. This manuscript reviews the management of hormone receptor-positive, human epidermal growth factor receptor 2-positive, and triple-negative breast cancers, emphasizing changes that have occurred in recent years and focusing on potential mechanisms of drug resistance.

Ixabepilone-associated peripheral neuropathy: data from across the phase II and III clinical trials.

Purpose: Dose-limiting neuropathy is a major adverse event associated with most of the microtubule-stabilizing agent-based chemotherapy regimens. Ixabepilone, a semisynthetic analogue of the natural epothilone B, has activity against a wide range of tumor types. Peripheral neuropathy (PN), associated with ixabepilone treatment, is usually mild to moderate, predominantly sensory and cumulative.

cMET and phospho-cMET protein levels in breast cancers and survival outcomes.

Purpose: To evaluate cMET (mesenchymal-epithelial transition factor gene) and phospho-cMET (p-cMET) levels in breast cancer subtypes and its impact on survival outcomes.

Experimental Design: We measured protein levels of cMET and p-cMET in 257 breast cancers using reverse phase protein array. Regression tree method and Martingale residual plots were applied to find best cutoff point for high and low levels.

Anthracycline regimen adherence in older patients with early breast cancer.

Background: Rates of anthracycline adherence in breast cancer (BC) patients are unknown, but noncompletion of chemotherapy is associated with worse outcomes.

Methods: Using the Surveillance, Epidemiology, and End Results-Medicare database, we obtained demographics, comorbidities, tumor characteristics, and treatment and hospitalization data from stage I-III BC patients diagnosed at age ≥66 years in 1996-2005 treated with surgery who had anthracycline claims. We compared variables between patients with claims for less than four cycles, considered nonadherent cases, and those with claims for four or more cycles using logistic regression analyses.

Incidence of brain metastases as a first site of recurrence among women with triple receptor-negative breast cancer.

Background: This retrospective study sought to define the incidence of brain metastases as a first site of recurrence among women with triple receptor-negative breast cancer (TNBC).

Methods: A total of 2448 patients with stage I through III TNBC who were diagnosed between 1990 and 2010 were identified. We computed the cumulative incidence of developing brain metastases as a first site of recurrence at 2 and 5 years.

Phase III trial evaluating weekly paclitaxel versus docetaxel in combination with capecitabine in operable breast cancer.

Purpose: We investigated whether capecitabine and docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide (FEC) or weekly paclitaxel (WP) followed by FEC would improve relapse-free survival (RFS) in operable breast cancer.

Patients And Methods: In this single-institution study, patients with clinical stages I to IIIC breast cancer were randomly assigned on a 1:1 basis to WP 80 mg/m(2) for 12 weeks followed by fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2) (FEC-100) every 3 weeks for four cycles or docetaxel 75 mg/m(2) on day 1 and capecitabine (XT) 1,500 mg/m(2) on days 1 through 14 every 3 weeks for four cycles followed by FEC for four cycles and stratified by timing of chemotherapy (preoperative v adjuvant). Accrual was stopped short of 930 patients on the basis of a Bayesian predictive calculation that additional accrual would be unlikely to change the qualitative comparison of the two regimens.

Estrogen receptor (ER) mRNA and ER-related gene expression in breast cancers that are 1% to 10% ER-positive by immunohistochemistry.

Purpose: We examined borderline estrogen receptor (ER) -positive cancers, defined as having 1% to 10% positivity by immunohistochemistry (IHC), to determine whether they show the same global gene-expression pattern and high ESR1 mRNA expression as ER-positive cancers or if they are more similar to ER-negative cancers.

Patients And Methods: ER status was determined by IHC in 465 primary breast cancers and with the Affymetrix U133A gene chip. We compared expressions of ESR1 mRNA and a 106 probe set ER-associated gene signature score between ER-negative (n = 183), 1% to 9% (n = 25), 10% (n = 6), and more than 10% (n = 251) ER-positive cancers.

An open-label, phase 2 trial of RPI.4610 (Angiozyme) in the treatment of metastatic breast cancer.

Background: Serum and plasma levels of vascular endothelial growth factor (VEGF) correlate with prognosis in patients with metastatic breast cancer (MBC). VEGF binds to 2 receptors on endothelial cells, VEGFR-1 and VEGFR-2. RPI.

Phase II trial of simple oral therapy with capecitabine and cyclophosphamide in patients with metastatic breast cancer: SWOG S0430.

Background: Interest in oral agents for the treatment of metastatic breast cancer (MBC) has increased because many patients prefer oral to i.v. regimens.

Epithelial-mesenchymal transition induced by TNF-α requires NF-κB-mediated transcriptional upregulation of Twist1.

Proinflammatory cytokines produced in the tumor microenvironment facilitate tumor development and metastatic progression. In particular, TNF-α promotes cancer invasion and angiogenesis associated with epithelial-mesenchymal transition (EMT); however, the mechanisms underlying its induction of EMT in cancer cells remain unclear. Here we show that EMT and cancer stemness properties induced by chronic treatment with TNF-α are mediated by the upregulation of the transcriptional repressor Twist1.

Aromatase inhibitors and breast cancer prevention.

Introduction: Endocrine therapy with selective estrogen receptor modulators (SERMs) has been the mainstay of breast cancer prevention trials to date. The aromatase inhibitors, which inhibit the final chemical conversion of androgens to estrogens, have shown increased disease-free survival benefit over tamoxifen in patients with primary hormone receptor-positive breast cancer, as well as reducing the risk of developing contralateral breast cancers. The aromatase inhibitors are being actively evaluated as prevention agents for women with a history of ductal carcinoma in situ as well as for women who are considered to be at high risk for developing primary invasive breast cancer.

Gene expression, molecular class changes, and pathway analysis after neoadjuvant systemic therapy for breast cancer.

Purpose: To examine gene expression differences between pre- and post-neoadjuvant systemic therapy (NST) specimens of breast cancers and identify biologic changers that may lead to new therapeutic insights.

Methods: Gene expression data from prechemotherapy fine needle aspiration specimens were compared with resected residual cancers in 21 patients after 4 to 6 months of NST. We removed stroma-associated genes to minimize confounding effects.

Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.

Background: Resistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. In early studies, the mTOR inhibitor everolimus added to endocrine therapy showed antitumor activity.

Methods: In this phase 3, randomized trial, we compared everolimus and exemestane versus exemestane and placebo (randomly assigned in a 2:1 ratio) in 724 patients with hormone-receptor-positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease (or both).

Retrospective analysis of antitumor effects of zoledronic acid in breast cancer patients with bone-only metastases.

Background: Bisphosphonates have been used successfully in the treatment of hypercalcemia and to reduce skeletal complications of bone metastasis, but have not been shown to prevent bone metastasis or to prolong survival time in metastatic breast cancer patients. The aim of this study was to determine whether the progression-free survival (PFS) and overall survival (OS) of patients with bone-only breast cancer metastasis differed based on whether patients received zoledronic acid, pamidronate, or no bisphosphonate upon diagnosis of their metastases.

Patients And Methods: We retrospectively identified 314 patients diagnosed with bone-only metastasis at the time of initial staging or who developed bone metastasis as the first recurrence site during follow-up from January 1, 1997 to December 31, 2008, at The MD Anderson Cancer Center.