These fundamental observations may assist physicians in evaluating the survival potential of patients and in directing them toward the appropriate therapeutic decision.

Hypoxia stabilizes HIF-1a (Hypoxia Inducible Factor-1a), which then triggers the expression of several genes involved in many aspects of cancer progression, including metabolic adaptation, cell survival and angiogenesis. The aim of our study was to evaluate the impact of HIF-1a and CA IX (carbonic anhydrase IX) (one of its target genes) expression on prognosis and treatment outcome of patients with breast cancer. Because of the extreme O 2 -dependent instability of the protein, we first validated HIF-1a staining using xenograft tumours that were subjected to experimental conditions mimicking surgical clamping or sitting at room temperature under normoxic conditions after surgical excision but before fixation. Afterwards, the immunohistochemical staining of HIF-1a and CA IX was evaluated in 132 invasive breast carcinomas with a 10-year follow-up, and correlated to classical clinicopathological parameters and response to adjuvant therapy. No significant correlation was found between tumour size or nodal status and the expression of HIF-1a or CA IX. Statistically significant association was found between HIF-1a or CA IX staining and the grade, hormonal receptors loss and the presence of carcinoma in situ. Overexpression of HIF-1a and CA IX correlates with a poor prognosis in breast cancer. We show that HIF-1a is an independent prognostic factor for distant metastasis-free survival and disease-free survival in multivariate analysis. Furthermore, overexpression of HIF-1a or CA IX correlates with a poor outcome after conventional adjuvant therapy. CA IX is, however, a weaker prognostic and predictive factor than HIF-1a, and its association with HIF1a does not modify the survival curve neither response to therapy, compared to HIF-1a alone. ' 2007 Wiley-Liss, Inc.

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Purpose: Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are used to determine human epidermal growth factor receptor-2 (HER-2) status and patient eligibility for trastuzumab therapy. Using FISH and IHC, we analyzed the relationship between pathologic complete response to trastuzumab-based neoadjuvant therapy and level of HER-2 amplification in locally advanced breast cancer. Experimental Design: Breastbiopsies from 93 HER-2^positivepatients treatedwithtrastuzumabbased neoadjuvant therapy were centrally collected and analyzed retrospectively for HER-2 amplification using FISH and HER-2 overexpression using IHC. Tumors were classified by FISH as no, low, or high amplification. Biopsies were reassessed centrally by IHC and graded 0, 1+, 2+, or 3+. Results: HER-2 status of tumor samples as assessed by FISH and IHC correlated: 16 no amplification (11 IHC 1+ and 5 IHC 2+), 27 low amplification (26 IHC 3+ and 1 IHC 2+), and 50 high amplification (all IHC 3+). Trastuzumab-based neoadjuvant therapy achieved pathologic complete response in 35 of 93 (37.6%) tumors. Pathologic complete response rate in low-and high-amplification tumors was significantly higher than in no-amplification tumors (44% versus 6%; P < 0.004). Pathologic complete response rate in high-amplification tumors was significantly higher compared with low-amplification tumors (56% versus 22%; P < 0.005). In the subgroup of low-plus high-amplification tumors, no correlation was found between pathologic complete response rate and IHC score, treatment regimen,Tor N stage, tumor grade, or hormonal receptors. Conclusions: This is the first study to show positive correlation between level of HER-2 amplification assessed by FISH and rate of pathologic complete response to trastuzumab-based neoadjuvant treatment.The human epidermal growth factor receptor-2 (HER-2) gene, which plays an important role in tumor formation and growth processes, is amplified in approximately 20% to 30% of all breast cancers (1, 2). Patients whose tumors overexpress HER-2 are more likely to experience a shorter time to relapse and a significantly lower overall survival rate (1, 2). Treatment with trastuzumab (Herceptin), a recombinant monoclonal antibody against HER-2, results in significant clinical benefits in patients diagnosed with HER-2 -positive disease. In phase II/III trials, trastuzumab significantly improved survival by up to 8.5 months when given as first-line treatment in combination with a taxane (3, 4) in women with HER-2 -positive metastatic breast cancer. In five major adjuvant clinical trials involving >13,000 women with HER-2 -positive early breast cancer, trastuzumab significantly reduced the risk of recurrence and improved overall survival by one third (5 -8).In the neoadjuvant setting, primary systemic therapy with trastuzumab-based combination chemotherapy has also shown clinical benefit in terms of both overall response and pathologic complete response rates (9 -13). The goals of primary systemic therapy are to treat occult system...

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In vitro models are required for the study of these cancers, and several cell lines have already been established and characterised (Lafargues & Ozzello, 1958;Soule et al., 1973;Cailleau et al., 1974;Engel et al., 1978;Whitehead et al., 1983;Yamane et al., 1984;Chu et al., 1985;Vandewalle et al., 1987). Nevertheless, owing to the heterogenity and the diversity of mammary cancers, a great number of cell models is necessary to understand the reasons for this diversity and the effect of anticancer drugs on tumour cells.Cytogenetic studies of mammary adenocarcinoma cell lines are essential for comprehension of the pathogenesis of these cancers (Trent, 1985;Gebhart et al., 1986). The implication of chromosomal alterations in these pathologies has opened a new and promising route towards better knowledge of these cancers (Cervenka & Koulischer, 1973). Chromosomal alterations are generally numerous, and markers often demonstrate hyperploidy in these cancers (Sandberg, 1980). Demonstration of the minimum genetic alterations indispensable for cell transformation is difficult, and might be easier on cells with a karyotype closer to normal. Sandberg and Wolman mentioned the existence of such cells, but most of their results concerned karyotype studies without chromosome banding (Sandberg, 1980;Wolman, 1983 [-', hyaluronidase 25 IU for 20 ml, Hepes buffer 4.8 g 1' in distilled water). Cells were then fixed in acetic acid:methanol (1:3) and dropped onto grease-free, cooled slides for chromosome counting and examination. R bands were obtained by heat denaturation of the chromosomes according to the method of Dutrillaux and Lejeune (1971). Xenografted CAL51 cells were plated and studied in vitro in the same manner.

EGFR determination is of limited value as a prognostic indicator in breast cancer.