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Background: Despite patient selection based on ERBB2 overexpression, response to trastuzumab-based therapy is not always achieved. The reasons for response failure to ERBB2-targeted therapy are still largely unknown. We have investigated whether a gene dosage effect, conferred by an increased number of ERBB2 copies, might provoke increased biological aggressiveness and altered trastuzumab sensitivity. Methods: Vysis PathVysion DNA-based FISH technology was used to measure absolute ERBB2 copy numbers (“CN”) and ERBB2/centromer 17 ratios (“R”) in tumor specimens of 137 patients who had received trastuzumab-based treatment for Her-2/neu over-expressing metastatic breast cancer. Results: An R of > 2.2 was identified as independent negative predictor for time to first metastasis (TTM). Upon trastuzumab-initiation, progressionfree survival (PFS), albeit not overall survival (OS), was significantly longer in patients with R of ≥2.2 (p=0.006 and p=0.123, respectively). Within the amplified patient population a CN > 13 (“high-amplified”) predicted for a significantly shorter TTM and, upon trastuzumab-initiation, a significant longer PFS and showed a trend towards a higher OS (p= 0.020 and p=0.086, respectively; Log Rank test) compared with the low-amplified (CN ≥13) patient population. Multivariate Cox regression analysis revealed that within our patient population higher CN and R were both associated with improved PFS (p=0.003 and p=0.004, respectively) and OS (p=0.004 and p=0.038, respectively). Furthermore, Logistic Regression analysis showed that higher CN and R values were associated with improved overall responses (OR: 1.151, 95% CI: 1.034-1.269 and OR: 1.501, 95% CI 1.169-1.964, respectively). Conclusion: In ERBB2 over-expressing FISH-amplified breast cancers CN can discriminate between two groups of breast cancer patients with different prognosis in the adjuvant setting as well as in the metastatic setting under the influence of trastuzumab-based therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD10-04.

With the objective of discovering novel putative intervention sites for anticancer therapy, we compared transcriptional profiles of breast cancer, lung squamous cell cancer (LSCC), lung adenocarcinoma (LAC), and renal cell cancer (RCC). Each of these tumor types still needs improvement in medical treatment. Our intention was to search for genes not only highly expressed in the majority of patient samples but which also exhibit very low or even absence of expression in a comprehensive panel of 16 critical (vital) normal tissues. To achieve this goal, we combined two powerful technologies, PCR-based cDNA subtraction and cDNA microarrays. Seven subtractive libraries consisting of ∼9250 clones were established and enriched for tumor-specific transcripts. These clones, together with ∼1750 additional tumor-relevant genes, were used for cDNA microarray preparation. Hybridizations were performed using a pool of 16 critical normal tissues as a reference in all experiments. In total, we analyzed 20 samples of breast cancer, 11 of LSCC, 11 of LAC, and 8 of RCC. To select for genes with low or even no expression in normal tissues, expression profiles of 22 different normal tissues were additionally analyzed. Importantly, this tissue-wide expression profiling allowed us to eliminate genes, which exhibit also high expression in normal tissues. Similarly, expression signatures of genes, which are derived from infiltrating cells of the immune system, were eliminated as well. Cluster analysis resulted in the identification of 527 expressed sequence tags specifically up-regulated in these tumors. Gene-wise hierarchical clustering of these clones clearly separated the different tumor types with RCC exhibiting the most homogenous and LAC the most diverse expression profile. In addition to already known tumor-associated genes, the majority of identified genes have not yet been brought into context with tumorigenesis such as genes involved in bone matrix mineralization (OSN, OPN, and OSF-2) in lung, breast, and kidney cancer or genes controlling Ca2+ homeostasis (RCN1,CALCA, S100 protein family). EGLN3, which recently has been shown to be involved in regulation of hypoxia-inducible factor, was found to be highly up-regulated in all RCCs and in half of the LSCCs analyzed. Furthermore, 42 genes, the expression level of which correlated with the overall survival of breast cancer patients, were identified. The gene dendogram clearly separates two groups of genes, those up-regulated such as cyclin B1, TGF-β3, B-Myb, Erg2, VCAM-1, and CD44 and those down-regulated such as MIG-6, Esp15, and CAK in patients with short survival time.

Background:BRCA-1/2 germline mutations are responsible for early onset breast cancer with poor outcome. The underlying causes of the particularly malignant phenotype are not completely understood, but mammary stem cells appear to have a key role in this process.Materials and Methods: We have investigated the presence of mammary stem/progenitor cells in normal tissues and in tumor tissues obtained from women with and without BRCA1/2 germline mutations by utilizing ALDH-1 immunohistochemistry.Results: Isolated ALDH-1 positive cells were found in 15/18 (64%) of breast cancer samples from women with BRCA 1 or 2 mutations and in 33 /51 (65%) of matched sporadic breast cancer cases (p=0.5949, Chi Square test). While mammary stem cells were also detected in non-malignant breast lesions, only 41% of the tissues contained ALDH-1 positive cells (p=0.0371, Chi Square test). In patients with BRCA germline mutations ALDH-1 positive cells were more common in p53 positive (p=0.0028, Chi Square test) tumors, in high grade (p=0.0796), and in larger tumors (p=0.0604), while no such association was seen in sporadic cancer cases. In our patients, the expression of ALDH-1 positive cells in breast cancer was neither associated with disease-free and overall survival, nor time to metastasis.Conclusion: Breast cancers from BRCA mutation carriers do not harbour more ALHD-1 positive cells than sporadic tumors, and their more aggressive phenotype can thus not be explained by an increased stem cell pool. The presence of ALDH-1 in normal breast tissue suggests that additional factors determine the biological behaviour of mammary stem cells. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1156.

Background: Since pathological complete responses (pCR) might be a surrogate for effective eradication of micrometastatic disease leading possibly to prolonged overall survival in primary breast cancer, neoadjuvant treatment of early breast cancer aims at achieving high rates of pCR.Methods: Primary aim of ABCSG-24 is to evaluate the influence of 6 cycles of EDC±T (experimental group) as compared to 6 cycles of ED±T (control group) on the rate of pCR at the time of surgery. 536 patients (pts) (268 pts/group, 5% dropout rate for 510 eligible pts, power=83%,p Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1081.

Abstract #66 LIBERATE, a randomized, placebo controlled, double blind trial studied the effect of tibolone (Livial), a tissue selective hormone replacement therapy (HRT) on breast cancer (BC) recurrence, aiming to demonstrate non-inferiority of treatment compared to placebo. In the LIFT trial of osteoporotic women, tibolone prevented BC development. Design and Method: Women with surgically treated BC (T1-3, N0-2, M0) within the last 5 years complaining of vasomotor symptoms, were randomly assigned to tibolone 2.5mg daily or placebo treatment for a maximum of 5 years. Adequate sample size was estimated to be >1500 in each arm. A bone mineral density (BMD) sub-study of 724 patients (454 Caucasian; 270 Asian) was enrolled utilizing DXA scanning at baseline and 2 years. Results: Between 2002 and 2004, 3,148 women were randomized in 31 countries; 1579 to tibolone and 1569 to placebo. Mean age at randomization was 52.7 years (28.0-75.0) and mean time since surgery was 2.1 years. In total 58% of women recruited were node positive and 78% ER positive. The trial closed prematurely in July 2007, with a median follow-up of 3.1 years (0.01-4.99) per patient, because an increased risk of BC recurrence occurred on tibolone HR 1.40 (1.14-1.70; p Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 66.

Abstract #14 Background: Historically, standard endocrine treatment for postmenopausal women with hormone-sensitive early breast cancer (EBC) was 5 years' tamoxifen. However, the inclusion of an aromatase inhibitor (AI) is now considered standard practice. There is increasing evidence that whether as initial adjuvant treatment or as a switch treatment following 2-3 years of tamoxifen therapy, Ais improve patients' outcomes compared with 5 years' tamoxifen monotherapy. To date, there is limited evidence comparing a prospective sequencing strategy of 2 years of tamoxifen followed by 3 years of an AI compared with 5 years' tamoxifen. Previously presented data from ABCSG Trial 8 (SABCS 2005), at a median follow-up of 55 months, revealed a 24% reduction in the risk of recurrence in favor of a sequencing strategy compared with 5 years' tamoxifen (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.56-1.02), although the difference was not statistically significant (p=0.07). Here we present updated data from ABCSG Trial 8. Methods: Postmenopausal women with histologically verified G1 or G2, locally radically treated invasive or minimally invasive hormone receptor-positive breast cancer were eligible for inclusion. Newly diagnosed patients were randomized to receive 5 years' tamoxifen therapy or 2 years' tamoxifen followed by anastrozole for 3 years. The primary endpoint was event-free survival, including locoregional and distant metastatic recurrences and new contralateral breast cancers. Results: This final analysis will report the data cut-off point, the number of eligible patients, and the median follow-up period of the trial, which will exceed 5 years. The incidence of first events, local recurrences, distant metastases, and contralateral breast cancers for the two treatment arms of the study will be presented. The effect of treatment on the trial endpoint will be analyzed using a Cox proportional hazards model and data will be presented as estimated HRs with two-sided 95% CIs and p-values. Conclusions: The updated analyses of ABCSG Trial 8 will provide evidence regarding 2 years' treatment with tamoxifen followed by 3 years' anastrozole in comparison to 5 years' tamoxifen for postmenopausal women with newly diagnosed hormone-sensitive EBC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 14.