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Fulvestrant was as effective as anastrozole. These data confirm that fulvestrant is an additional, effective, and well-tolerated treatment for advanced breast cancer in postmenopausal women whose disease progressed on prior endocrine therapy.

Exemestane modestly enhanced bone loss from the femoral neck without significant influence on lumbar bone loss. Except for a 6% to 9% drop in plasma high-density lipoprotein cholesterol, no major effects on serum lipids, coagulation factors, or homocysteine were recorded. Bone mineral density should be assessed according to the US Preventive Services Task Force guidelines.

Coamplification of HER-2/neu and TOP2A may define a subgroup of high-risk breast cancer patients who benefit from individually tailored and dose-escalated adjuvant anthracyclines.

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Amplification and overexpression of the receptor tyrosine kinase ErbB2 occur in up to 30% of human breast cancers, and high ErbB2 levels are correlated with poor prognosis for breast cancer patients. In contrast to the epithelial growth factor receptor (ErbB1), ErbB2 is not downregulated by ligand-induced mechanisms. Here we show that flotillins are involved in the stabilization of ErbB2 at the plasma membrane. In SKBR3 breast cancer cells and breast cancer tissue, a positive correlation between flotillin and ErbB2 expression levels could be demonstrated. Moreover, the tissue microarray analyses of biopsies from 194 patients diagnosed with carcinomas of the breast showed that flotillin-2 emerged as a potential predictor of prognosis in breast cancer. Depletion of flotillin-1 and flotillin-2 leads to internalization and degradation of ErbB2. Furthermore, flotillin-1 and -2 were found to be in a molecular complex with ErbB2 and Hsp90. The depletion of one of these proteins results in disruption of this complex, followed by destabilization of ErbB2 at the membrane, and its internalization and degradation. As a consequence, ErbB2-triggered downstream signalling is inhibited. Our data demonstrate a novel mechanism for interfering with ErbB2 signalling, which potentially can have clinical impact.

We present a general method for rigorously identifying correlations between variations in large-scale molecular profiles and outcomes and apply it to chromosomal comparative genomic hybridization data from a set of 52 breast tumors. We identify two loci where copy number abnormalities are correlated with poor survival outcome (gain at 8q24 and loss at 9q13). We also identify a relationship between abnormalities at two loci and the mutational status of p53. Gain at 8q24 and loss at 5q15-5q21 are linked with mutant p53. The 9q and 5q losses suggest the possibility of gene products involved in breast cancer progression. The analytical techniques are general and also are applicable to the analysis of array-based expression data.T echniques for in vitro genomic and proteomic analysis are generating vast amounts of quantitative biological data. As an example, high-density DNA microarrays are capable of producing 30,000 measurements from a single sample of RNA (1). In the area of cancer, such data offer fertile ground for systematic computational analyses to help identify new cancer targets or potential therapeutics. Chromosomal comparative genomic hybridization (CGH) has been applied extensively to human tumor specimens, and array-based CGH methods are beginning to generate higher-density data (2, 3). For such techniques to be most useful, computational methods must generate conclusions that are supportable quantitatively in a rigorous statistical sense, and not provide just a means of visualization.The challenge arises when the ratio between the number of measurements to the number of experimental samples is high. In this case, false patterns often emerge. For example, suppose we measure expression levels for several thousand mRNAs in 10 cell lines, 5 of which exhibit phenotype A and 5 that exhibit phenotype B. The expression ratios for each gene will show some variation regardless of correlation with phenotype. The apparent correlation to cell-line phenotype resulting from a naïve computation of correlation over all genes will be distributed approximately normally, and some genes may show an apparently significant correlation. In fact, because there are only 252 [10!͞(5!(10-5)!)] ways of labeling 10 cell lines with 5 each of phenotypes A and B, it is extremely likely that many genes of the several thousand will show an apparently perfect correlation with phenotype, even if there is no true relationship between any observed genes' expression and phenotype.We present a method for rigorously identifying correlations between large-scale multivariate measurements and outcomes and apply it to chromosomal CGH data from a set of 52 human breast tumors. We identify two loci (8q24 and 9q13) where copy number abnormalities are correlated with poor survival outcome and also identify a relationship between two loci (8q24 and 5q15-5q21) and the mutational status of p53. The techniques are applicable generally and also are used easily in the analysis of array-based expression data. Materials and MethodsTumor Specimens. Fifty-two s...