Introduction: Breast cancer subtyping and prognosis have been studied extensively by gene expression profiling, resulting in disparate signatures with little overlap in their constituent genes. Although a previous study demonstrated a prognostic concordance among gene expression signatures, it was limited to only one dataset and did not fully elucidate how the different genes were related to one another nor did it examine the contribution of well-known biological processes of breast cancer tumorigenesis to their prognostic performance.
Method: To address the above issues and to further validate these initial findings, we performed the largest meta-analysis of publicly available breast cancer gene expression and clinical data, which are comprised of 2,833 breast tumors.
In this phase III, multinational, randomized trial, the International Breast Cancer Study Group, Breast International Group, and the National Surgical Adjuvant Breast and Bowel Project will attempt to define the effectiveness of cytotoxic therapy for patients with locoregional recurrence of breast cancer. We will evaluate whether chemotherapy prolongs disease-free survival and, secondarily, whether its use improves overall survival and systemic disease-free survival. Quality of life measurements will be monitored during the first 12 months of the study.
View Article and Find Full Text PDFPurpose: To evaluate the role of microtubule-associated variables as potential predictors of response and clinical outcome in patients with advanced breast cancer receiving single-agent docetaxel or doxorubicin chemotherapy.
Experimental Design: The analysis was done on 173 tumor samples from patients with locally advanced or metastatic breast cancer who have participated in the TAX-303 phase III trial in which patients were randomly assigned to receive docetaxel or doxorubicin. Expression of total alpha- and beta-tubulin, classes II to IV beta-tubulin isotypes, and tau protein was evaluated by immunohistochemistry on formalin-fixed, paraffin-embedded tumors from the primary breast cancer.
Clin Breast Cancer
February 2008
Overexpression of HER2 is encountered in approximately 20% of invasive breast cancers. It is an independent adverse prognostic factor and, more importantly, it is currently the best predictive factor for the activity of trastuzumab, an anti-HER2 monoclonal antibody (MoAb), which has revolutionized the treatment of this breast cancer subgroup. Increasing knowledge of molecular pathways involving the HER family of growth factor receptors has paved the way toward new efficient targeted therapies.
View Article and Find Full Text PDFBackground: Estrogen receptor positive (ER+) breast cancers (BC) are heterogeneous with regard to their clinical behavior and response to therapies. The ER is currently the best predictor of response to the anti-estrogen agent tamoxifen, yet up to 30-40% of ER+BC will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance are required.
View Article and Find Full Text PDFPurpose: To establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety and recommended Phase II dose of ixabepilone, administered weekly as an intravenous (IV) infusion to patients with solid tumors who have failed standard therapy.
Method: This was an open-label, single-arm, Phase I, dose-escalation study.
Results: The MTD of ixabepilone [30-min, weekly IV infusion on a 21-day schedule (N = 33)] was established at 25 mg/m(2).
The microarray technology has enabled scientists to simultaneously investigate the expression of thousands of genes. Regarding breast cancer, this technology has provided a molecular classification into clinically relevant subtypes, new tools to predict disease outcome and response to treatment and new insights into carcinogenesis and metastatic progression pathways. Here we describe the state of the art of gene expression profiling for breast cancer, and we discuss the potential impact on breast cancer patient management considering its limits and promises.
View Article and Find Full Text PDFPurpose: The National Cancer Institute of Canada Clinical Trials Group MA.17 trial examined the efficacy of letrozole (LET) started within 3 months of 5 years of adjuvant tamoxifen in postmenopausal hormone receptor-positive early-stage breast cancer. When the trial was unblinded, patients who received placebo (PLAC) were offered LET.
View Article and Find Full Text PDFPurpose: National Cancer Institute of Canada Clinical Trials Group trial MA.17 randomly assigned 5,187 postmenopausal, hormone-receptor-positive patients with early breast cancer who completed 5 years of tamoxifen to receive either letrozole or placebo. At 30 months median follow-up, letrozole significantly improved disease-free survival (DFS) in all patients and overall survival (OS) in node-positive patients.
View Article and Find Full Text PDFPurpose: The third-generation nonsteroidal aromatase inhibitors (AIs) are increasingly used as adjuvant and first-line advanced therapy for postmenopausal, hormone receptor-positive (HR+) breast cancer. Because many patients subsequently experience progression or relapse, it is important to identify agents with efficacy after AI failure.
Materials And Methods: Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) is a randomized, double-blind, placebo controlled, multicenter phase III trial of fulvestrant versus exemestane in postmenopausal women with HR+ advanced breast cancer (ABC) progressing or recurring after nonsteroidal AI.
Objectives: The prognosis of patients with platinum refractory disease is dismal. We present data from heavily pretreated patients to whom the folinic acid, 5-fluorouracil and oxaliplatin (Folfox) regimen was administered. The objectives were to assess response rate and to evaluate the safety profile.
View Article and Find Full Text PDFPurpose: To investigate the safety and pharmacokinetics (PK) of combined treatment with letrozole and the oral mTOR inhibitor RAD001 in patients with metastatic breast cancer stable or progressing after > or = 4 months on letrozole alone.
Methods: Eighteen patients received letrozole (2.5 mg/day) and RAD001 at 5 mg/day (cohort 1) or 10 mg/day (cohort 2).
The aim of this randomized phase II study was to evaluate the anti-tumor activity and safety of capecitabine and vinorelbine in patients with metastatic breast cancer pretreated with taxanes and anthracyclines. We planned to randomize 72 patients to capecitabine 1250 mg/m(2) orally bid days 1-14 or vinorelbine 30 mg/m(2) i.v.
View Article and Find Full Text PDFHistorically, the selection of adjuvant systemic therapy in early breast cancer has relied on risk assessment embodied by the TNM classification. Since the 2005 International St. Gallen Consensus, treatment selection now involves firstly identifying critical targets and then using risk to assess the trade-off between anticipated toxicity and efficacy.
View Article and Find Full Text PDFThe advent of microarray technology has enabled scientists to simultaneously investigate the expression of thousands of genes. Gene-expression profiling studies have provided a molecular classification of breast cancer into clinically relevant subtypes, new tools to predict disease recurrence and response to different treatments, and new insights into various oncogenic pathways and the process of metastatic progression. Here we describe the state of the art of gene-expression studies in breast cancer, and consider both their current limitations and future promises.
View Article and Find Full Text PDFPurpose: Recently, a 76-gene prognostic signature able to predict distant metastases in lymph node-negative (N(-)) breast cancer patients was reported. The aims of this study conducted by TRANSBIG were to independently validate these results and to compare the outcome with clinical risk assessment.
Experimental Design: Gene expression profiling of frozen samples from 198 N(-) systemically untreated patients was done at the Bordet Institute, blinded to clinical data and independent of Veridex.
Purpose: Controversy exists regarding estrogen (ER) and progesterone (PgR) receptor expression on efficacy of adjuvant endocrine therapy. In the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial, the benefit of anastrozole over tamoxifen was substantially greater in ER+/PgR-than ER+/PgR+ tumors. In BIG 1-98 (Breast International Group), the benefits of letrozole over tamoxifen were the same in ER+ tumors irrespective of PgR.
View Article and Find Full Text PDFOver the last decades, the introduction of several new agents into clinical practice has significantly improved disease control and obtained some, albeit rare, survival benefits in metastatic breast cancer (MBC). Despite these results, the choice of treatment for the majority of patients is still empirically based, since the only two predictive factors with level 1 evidence for clinical use are hormonal receptor status for endocrine therapy and HER-2 status for trastuzumab therapy. Important improvements in the endocrine therapy of both pre- and postmenopausal women with hormone-responsive disease have been achieved.
View Article and Find Full Text PDFPurpose: A number of microarray studies have reported distinct molecular profiles of breast cancers (BC), such as basal-like, ErbB2-like, and two to three luminal-like subtypes. These were associated with different clinical outcomes. However, although the basal and the ErbB2 subtypes are repeatedly recognized, identification of estrogen receptor (ER) -positive subtypes has been inconsistent.
View Article and Find Full Text PDFAim: Trastuzumab (T), a humanised monoclonal antibody against HER-2, is active in HER-2-positive MBC patients. However, nearly 60% of the patients do not benefit from T, stressing the need for additional predictive markers. The following markers could be implicated in response to T: (1) the magnitude of Her-2 gene amplification; (2) the co-expression of the other HER family receptors, possibly responsible for HER-2 trans-activation; (3) the activated status of HER-2; (4) the activated status of downstream effectors as mitogen-activated protein kinases (MAPKs), p38 and p27.
View Article and Find Full Text PDFThe aim of this review article is to examine the available evidence regarding diagnosis and treatment of HER-2 positive breast cancer. This group of breast tumours (up to 30% of the total number of breast cancers) is known for having a more aggressive behaviour. The current recommendations for HER-2 positive tumour diagnosis are discussed since accurate identification of HER-2 amplification or overexpression is key for allowing a correct risk assessment and treatment.
View Article and Find Full Text PDFBackground: Preclinical and clinical studies have shown that the proteasome inhibitor bortezomib (PS341, Velcade) is highly effective when combined with chemotherapeutic agents. The value of trastuzumab (Herceptin) in HER-2-positive (3+ score by immunohistochemistry or fluorescence in situ hybridization positive) breast cancer is also known; however, the response rate is <40% for metastatic breast cancer. These two pharmacologic agents prevent nuclear factor-kappaB (NF-kappaB) activation and induce nuclear accumulation of the cyclin-dependent kinase inhibitor p27(kip1), suggesting that combining bortezomib with trastuzumab could increase trastuzumab efficacy.
View Article and Find Full Text PDFWe have performed a retrospective analysis to evaluate the impact of age, using a 70 year cutoff, on the safety and efficacy of pegylated liposomal doxorubicin (Caelyx) given at 60 mg/m(2) every 6 weeks (treatment A) or 50 mg/m(2) every 4 weeks (treatment B) to 136 metastatic breast cancer patients in two EORTC trials, of whom 65 were 70 years of age or older. No difference in terms of toxicity was observed between younger and older patients treated with the 4-week schedule, while a higher incidence of hematological toxicity, anorexia, asthenia, and stomatitis was observed in older patients when the 6-week schedule was used. Antitumor activity was not affected by age.
View Article and Find Full Text PDFIn a short period of time DNA microarray technology has revolutionized our understanding of human cancer biology. This has been particularly impressive in the field of breast cancer research, where the clinical heterogeneity long observed by physicians seems to be mirrored by different molecular phenotypes exposed by microarray analysis. Gene-expression signatures have been developed to predict prognosis and treatment response and pending adequate validation, are on the verge of entry into the clinical setting.
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