Search

552 Background: Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase playing an important role as a key mediator for signal transduction. We examined the subtype specific prognostic signifi...

620 Background: The transcription factor IRF4 (interferon regulating factor 4) regulates immunoglobulin class switch recombination as well as plasma cell differentiation. We examined the prognostic significance of IRF4 mRNA expression in node-negative breast cancer. Methods: Microarray based gene-expression data for IRF4 (204562_at) were analysed in four previously published cohorts (Mainz, Rotterdam, Transbig, Yu) of node-negative breast cancer patients not treated with adjuvant therapy (n=824). A meta-analysis of previously published cohorts was performed using a random effects model. Prognostic significance of IRF4 on metastasis-free survival (MFS) was examined in the whole cohort and in different molecular subtypes: luminal A (ER+/HER2-/aurora kinase A [AURKA]low, luminal B (ER+/HER2-/AURKAhigh), basal-like (ER-/HER2-), HER2+. Independent prognostic relevance was analysed using multivariate Cox regression. Results: Higher RNA expression of IRF4 was related to better MFS in a meta-analysis of the whole...

10551 Background: Prediction of late metastasis is of clinical relevance in breast cancer. However, systematic genome-wide studies to identify genes associated with increased risk of metastasis 5 or more years after surgery are scarce. Methods: We examined the natural course of disease in three previously published cohorts (Mainz, Rotterdam, Transbig) including 766 node-negative breast cancer patients with gene array data who did not receive systemic chemotherapy in the adjuvant setting. We established a Cox regression based method adjusted for multiple testing that identified genes predicting late metastasis (5 or more years after surgery). Only those genes were accepted that showed similar results in all three cohorts. Metastasis-free survival (MFS) was analyzed with univariate and multivariate Cox regression. Results: We identified 9 genes [ABCC5 (Hazard Ratio (HR) 2.19, p=0.003), EDDM3B (HR 3.58, p=0.044), RAD23B (HR 0.37, p

10566 Background: Proliferation has an important prognostic impact in breast cancer. We examined the importance of proliferation amongst different molecular subtypes (luminal, basal-like, erbB2-lik...

10616 Background: Immunological defense mechanisms play an important prognostic role in breast cancer. We examined the prognostic impact of immunoglobulin kappa C (IGKC) in 766 node-negative breast...

e22014 Background: Triple-negative breast cancer (TNBC) is characterized by lack of expression of estrogen receptor (ER), progesterone receptor (PR) and HER-2. This makes it one of the most challenging subgroups for clinical decision-making. Methods: We analyzed gene-expression profiles of 200 node-negative breast cancer patients utilizing the Affymetrix HG-U133A array. After performing an unsupervised hierarchical cluster analysis using 2579 genes selected for variable expression within our dataset, we constructed metagenes for five dominant cluster (basal-like, luminal, proliferation, T-cell, B-cell). The interrelation of the median expression of these metagenes between TNBC and those cancer specimens expressing at least one of those receptors was analysed with the Wilcoxon-Mann-Whitney test. An intrinsic gene list was used to define basal-like breast cancer (BLBC). Sensitivity and specificity of TNBC to correctly classify BLBC was calculated. Metastasis-free survival (MFS) at 5 years was calculated according to Kaplan Meier. Results: Of the 200 node-negative breast cancer patients, 33 (16.5%) were triple-negative and 20 (10%) basal-like. Sensitivity of TNBC to correctly predict BLBC was 100%, specificity was 93.1%. TNBC showed an overexpression of the basal-like metagene (P=7.905e-13), an inverse relation with the luminal metagene (p=1.151e-12) and had higher proliferation and higher expression of T-cell (P=6.316e-5) and B-cell (P=3.551e-6) metagene. A higher expression of the B-cell metagene was associated with longer MFS in both TNBC (P=0.048) and BLBC (P=0.041). Conclusions: Characterization of TNBC reveals marked differences in gene-expression. Overexpression of mRNA transcripts related to the humoral immune system might serve as a protective factor in this particular subgroup. No significant financial relationships to disclose.

22057 Background: Topoisomerase II alpha, encoded by TOP2A, is the putative molecular target of anthracycline drug action. Recently, it has been shown that TOP2A gene amplification occurs almost ex...

10585 Background: Recently, we have identified for the first time a new putative phosphodiesterase named edi-3 that correlates with tumorigenesis in endometrial cancer. In the present study we analyzed the prognostic relevance of edi-3 in ovarian cancer. Methods: Edi-3 mRNA expression was measured by quantitative RT-PCR (TaqMan) in 62 patients with primary ovarian cancer. All patients signed informed consent, approved by the Clinical Review Board and Ethics Committee of the Medical University Berlin, Charité, Germany. The tumor specimens were collected according to the Tumor Bank Ovarian Cancer standard operating procedures. A validated systematic intraoperative documentation tool was used for the detailed documentation of all surgical procedures. Using the multivariate proportional hazard model we analyzed whether edi-3 predicts survival independent from FIGO-stage, grading, postoperative residual disease and histological type. Results: Edi-3 expression is associated with survival in the univariate Cox model (hazards ratio [HR]: 1.488, 95% confidence interval [CI]: 1.131 - 1.959, P=0.005). Interestingly, edi-3 was also predictive in the multivariate proportional hazard model adjusted for the conventional clinical factors (HR: 1.521, CI: 1.107 - 2.090, P=0.010). Conclusions: Edi-3 is a new independent prognostic factor in primary ovarian cancer with HR=1.5 (P=0.010). Its function, a possible role in inositol phosphate metabolism, will be further explored in a multi-instutional setting. No significant financial relationships to disclose.

21102 Background: MKI67 and MMP1 mRNA, which might reflect the biological processes of tumor proliferation and matrix degradation, respectively, have been proposed as prognostic marker in invasive carcinoma of the breast. We compared the expression of both genes in invasive lobular versus invasive ductal carcinoma, which represent the most common histological breast cancer subtypes. Methods: MKI67 and MMP1 mRNA expression was determined by microarray analysis of fresh frozen tumor tissue of 118 patients with invasive ductal and 39 patients with invasive lobular carcinoma. We compared the distribution of these markers between both histological subtypes as well as within each subtype between tumors from patients with or without subsequent distant metastasis or local recurrence by two tailed Mann-Whitney test. Results: MKI67 as marker of proliferation and MMP1 as marker of matrix degradation were significantly elevated in invasive ducal versus lobular carcinomas (p = 0.023 and p < 0.0001, respectively). Furthermore, elevation of both markers were significantly associated with the occurrence of metastasis in ductal (p = 0.023 and p = 0.012) but not in lobular carcinomas (p = 0.986 and p = 0.366). In addition, no significant association was found between these markers and development of local recurrence in patients with ductal (p = 0.304 and p = 0.899) or lobular (p = 0.891 and p= 0.153) carcinomas . Conclusions: Our data suggest that differences exist between ductal and lobular carcinoma of the breast regarding both the expression and the prognostic impact of MKI67 and MMP1. Furthermore, the prognostic relevance of proliferation and matrix degradation was more important for the development of distant metastasis than for the development of local recurrence in ductal carcinoma emphasizing differences in the underlying biology of local recurrence and distant metastasis. No significant financial relationships to disclose.

20088 Background: Paclitaxel has an important role in the adjuvant therapy of primary breast cancer. Recently, microtubule-associated protein tau was described as a marker of paclitaxel sensitivity. We attempted to validate these findings in vitro utilizing the ATP tumorchemosensitivity assay (ATP-TCA). Methods: The in vitro drug sensitivity to paclitaxel was evaluated in 48 fresh primary breast cancer specimens using the ATP-TCA. ATP-TCA results were analysed using the area under the curve (AUC) of growth inhibition. These results were correlated with the expression of tau mRNA measured by quantitative RT-PCR (Spearman’s correlation coefficient). Tau was also compared between progesterone receptor (PgR) positive and negative and estrogen receptor (ER) positive and negative tumors, respectively (Wilcoxon test). Results: The correlation of tau with the AUC for paclitaxel was weak (r = −0.20) and disappeared when considering PgR positive and negative tumors separately (r = −0.004 and r = −0.048, respectively). Tau was found to be differentially expressed between PgR positive and negative as well as between ER positive and negative tumors (p < 0.0005 in both tests). Conclusions: The expression of tau does not show independent predictive value for the in vitro paclitaxel sensitivity in primary breast cancer. No significant financial relationships to disclose.

20083 Background: Limitations in the treatment of recurrent disease in cervical carcinoma are for radiation therapy large tumor size and pelvic side wall involvement and for exenteration procedurde previous radiation therapy, bulky disease, and others. Alternative approaches including chemotherapy, chemo-radiation, radiation plus hyperthermia and others are accompanied by a failure rate of 50 to 80%. Recent research has shown that the antineoplastic effect of thalidomide (TD) is due to the inhibition of neo-angiogenesis, a decrease of TNF-a, blocking of nuclear factor κβ-kinase activity, stimulation of the IL-2 and downregulation of cell adhesion molecules. Here, we have studied the effect of TD on a cervical cancer cell line in a murine xenograft model. Methods: We injected 7 × 106 HELA cells s.c. into the dorsal skin of 6–8 week-old male nude mice (cd nu−/nu−; Charles River, Sulzfeld, Germany). The tumor diameter was measured with a caliber rule. The maximum and minimum diameters of the tumor were determined. Tumor volume (V) was calculated by the formula: V = a × b × b/2, where a represents the minimum and b the maximum tumor diameter. As soon as tumors reached a volume of 0.25 cm3 the mice were randomized into a treatment (n = 9) and a control group (n = 9). The mice in the treatment group received 14 daily injections of 300 mg/kg (i.p.) thalidomide for 14 days. Animals were housed under specific pathogen-free conditions. The experiments have been approved by the local animal welfare committee. Results: Thalidomide caused a clear delay in tumor growth. Already 7 days after onset of thalidomide therapy the mean tumor volume was smaller in the treated (0.24 ± 0.03 cm3) compared to the control mice (0.73 ± 0.15 cm3; mean ± standard error; p < 0.01). After 14 days of thalidomide treatment the mean tumor volumes were 0.37 ± 0.05 and 1.05 ± 0.19 cm3 in the treated and in the control mice, respectively (p < 0.01). However, after the end of the 14 days treatment period a new onset of tumor growth was observed. In conclusion, thalidomide delayed tumor growth but did not cause tumor remission. Conclusions: TD is effective in inhibition of tumor growth of a cervical cancer cell line in a mouse xenograft model and might be an alternative drug in patients with recurrent cervical carcinoma without any options for established standard therapy. No significant financial relationships to disclose.