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Introduction: Reliable predictive and prognostic markers for routine diagnostic purposes are needed for breast cancer patients treated with neoadjuvant chemotherapy. We evaluated protein biomarkers in a cohort of 116 participants of the GeparDuo study on anthracycline/taxane-based neoadjuvant chemotherapy for operable breast cancer to test for associations with pathological complete response (pCR) and disease-free survival (DFS). Particularly, we evaluated if interactions between hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression might lead to a different clinical behavior of HR+/HER2+ coexpressing and HR+/HER2- tumors and whether subgroups of triple negative tumors might be identified by the help of Ki67 labeling index, cytokeratin 5/6 (CK5/6), as well as cyclooxygenase-2 (COX-2), and Y-box binding protein 1 (YB-1) expression. Methods: Expression analysis was performed using immunohistochemistry and silver-enhanced in situ hybridization on tissue microarrays (TMAs) of pretherapeutic core biopsies. Results: pCR rates were significantly different between the biology-based tumor types (P = 0.044) with HR+/HER2+ and HR-/HER2- tumors having higher pCR rates than HR+/HER2-tumors. Ki67 labeling index, confirmed as significant predictor of pCR in the whole cohort (P = 0.001), identified HR-/HER- (triple negative) carcinomas with a higher chance for a pCR (P = 0.006). Biology-based tumor type (P = 0.046 for HR+/HER2+vs. HR+/HER2-), Ki67 labeling index (P = 0.028), and treatment arm (P = 0.036) were independent predictors of pCR in a multivariate model. DFS was different in the biology-based tumor types (P < 0.0001) with HR+/HER2- and HR+/HER2+ tumors having the best prognosis and HR-/HER2+ tumors showing the worst outcome. Biology-based tumor type was an independent prognostic factor for DFS in multivariate analysis (P < 0.001). Conclusions: Our data demonstrate that a biology-based breast cancer classification using estrogen receptor (ER), progesterone receptor (PgR), and HER2 bears independent predictive and prognostic potential. The HR+/HER2+ coexpressing carcinomas emerged as a group of tumors with a good response rate to neoadjuvant chemotherapy and a favorable prognosis. HR+/HER2- tumors had a good prognosis irrespective of a pCR, whereas patients with HR-/HER- and HR-/HER+ tumors, especially if they had not achieved a pCR, had an unfavorable prognosis and are in need of additional treatment options. Trial registration ClinicalTrials.gov identifier: NCT00793377
The three-dimensional quantification of small scale processes in the upper troposphere and lower stratosphere is one of the challenges of current atmospheric research and requires the development of new measurement strategies. This work presents first results from the newly developed Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) obtained during the ESSenCe and TACTS/ESMVal aircraft campaigns. The focus of this work is on the so-called dynamics mode data characterized by a medium spectral and a very high spatial resolution. The retrieval strategy for the derivation of two- and three-dimensional constituent fields in the upper troposphere and lower stratosphere is presented. Uncertainties of the main retrieval targets (temperature, O3, HNO3 and CFC-12) and their spatial resolution are discussed. During ESSenCe, high resolution two-dimensional cross-sections have been obtained. Comparisons to collocated remote-sensing and in-situ data indicate a good agreement between the data sets. During TACTS/ESMVal a tomographic flight pattern to sense an intrusion of stratospheric air deep into the troposphere has been performed. This filament could be reconstructed with an unprecedented spatial resolution of better than 500 m vertically and 20 km × 20 km horizontally.
The three-dimensional quantification of small-scale processes in the upper troposphere and lower stratosphere is one of the challenges of current atmospheric research and requires the development of new measurement strategies. This work presents the first results from the newly developed Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) obtained during the ESSenCe (ESa Sounder Campaign) and TACTS/ESMVal (TACTS: Transport and composition in the upper troposphere/lowermost stratosphere, ESMVal: Earth System Model Validation) aircraft campaigns. The focus of this work is on the so-called dynamics-mode data characterized by a medium-spectral and a very-high-spatial resolution. The retrieval strategy for the derivation of two- and three-dimensional constituent fields in the upper troposphere and lower stratosphere is presented. Uncertainties of the main retrieval targets (temperature, O3, HNO3, and CFC-12) and their spatial resolution are discussed. During ESSenCe, high-resolution two-dimensional cross-sections have been obtained. Comparisons to collocated remote-sensing and in situ data indicate a good agreement between the data sets. During TACTS/ESMVal, a tomographic flight pattern to sense an intrusion of stratospheric air deep into the troposphere was performed. It was possible to reconstruct this filament at an unprecedented spatial resolution of better than 500 m vertically and 20 × 20 km horizontally.
The proliferative stimulus of the epidermal growth factor (EGF) in human epithelial cells is mediated by its binding to the external domain of the EGF receptor (EGF-R). The purpose of this study was to investigate whether growth arrest of tumors treated with anti-EGFR MAb (EMD 55900) was dependent on EGF-R expression and distinct histopathologic criteria of those neoplasms. Nine different adenocarcinomas, squamous cell carcinomas and two neoplastic epithelial cell lines (A431 and Detroit 562), which were characterized by high EGF-R expression, were xenotransplanted onto NMRI-nu/nu mice and treated with an anti-EGF-R antibody (EMD 55900). Results revealed that EGF-R expression and distinct histopathologic growth patterns play an important role for the therapeutic effect of the EGF-R antibody treatment. Tumors with high epithelial cellularity and little connective tissue responded to EMD 55900 treatment to a greater degree of growth reduction than tumors with lower cellularity. These results will be helpful for evaluation of patients who would benefit from tumor therapy with anti-EGF-R antibody.
Die Frankfurter Universitätsklinik hat mit der Eröffnung des interdisziplinären Brustkrebszentrums 1997 im Rhein-Main-Gebiet neue Maßstäbe bei der Behandlung von Brustkrebs gesetzt. Ziel ist es, die diagnostischen und therapeutischen Abläufe in der Brustkrebsbehandlung zu optimieren sowie die ökonomischen und fachlichen Ressourcen besser zu nutzen. Doch eine gute Therapie ist nur ein Werkzeug bei der Bekämpfung der seit Jahren zunehmenden Brustkrebserkrankungen. Nach Kaufmanns Ansicht ist es wichtig, "zweigleisig zu fahren: Früherkennungsmaßnahmen tragen dazu bei, Tumoren früh zu erkennen. Darüber hinaus gilt es, durch mehr Information mehr Körper- und Gesundheitsbewusstsein zu entwickeln. Denn wer gut informiert ist, hat die besseren Chancen."
Meeting Abstract : 27. Deutscher Krebskongress. Berlin, 22.-26.03.2006.
Docetaxel, Adriamycin, Cyclophosphamide (TAC) is considered today as one treatment option for patients with node-positive primary breast cancer. However, treatment is associated with anaemia grade 1-4 (2-4) in up to 95% (36%) of patients. We prospectively investigated the use of a primary prophylaxis with Darbepoetin alfa once every 3 weeks in 35 patients receiving six to eight cycles of TAC as neoadjuvant treatment for breast cancer. Darbepoetin treatment started on day 1 of a TAC cycle if haemoglobin (Hb) was ≤ 14.0 g/dl. Dosage was adapted to 9 µg/kg if Hb was ≤ 13.0 g/dl on day 21 of the previous cycle, to 4.5 µg/kg if Hb was between 13.0 and 14.0 g/dl and was discontinued if Hb increased to ≥ 14 g/dl. The primary aim was to prevent Hb levels ≤ 12 g/dl before surgery. During 112 (50.2%) and 93 (41.7%) of 223 cycles, 4.5 µg/kg and 9 µg/kg Darbepoetin were given, respectively. Dosage was decreased from 9 to 4.5 µg/kg in 21 (60%) patients and 28 (12.4%) cycles. Treatment was discontinued due to Hb > 14.0 g/dl in 12 (34.3%) patients and 13 (5.4%) cycles. Hb level on day 21 of the last cycle was ≤ 12.0 g/dl in 4 (11.4%) patients. Eighteen (51.4%) patients during 36 (16.1%) cycles showed Hb levels ≤ 12 g/dl throughout treatment. No NCI-CTC grade 2 to 4 anaemia was observed. Symptoms of fatigue (FACT-AN) decreased slightly throughout treatment. Anaemia during TAC chemotherapy can be avoided by a single injection of Darbepoetin alfa every 3 weeks.
Introduction To investigate the predictive value of clinical and biological markers for a pathological complete remission after a preoperative dose-dense regimen of doxorubicin and docetaxel, with or without tamoxifen, in primary operable breast cancer. Methods Patients with a histologically confirmed diagnosis of previously untreated, operable, and measurable primary breast cancer (tumour (T), nodes (N) and metastases (M) score: T2-3(>= 3 cm) N0-2 M0) were treated in a prospectively randomised trial with four cycles of dose-dense (bi-weekly) doxorubicin and docetaxel (ddAT) chemotherapy, with or without tamoxifen, prior to surgery. Clinical and pathological parameters (menopausal status, clinical tumour size and nodal status, grade, and clinical response after two cycles) and a panel of biomarkers (oestrogen and progesterone receptors, Ki-67, human epidermal growth factor receptor 2 (HER2), p53, bcl-2, all detected by immunohistochemistry) were correlated with the detection of a pathological complete response (pCR). Results A pCR was observed in 9.7% in 248 patients randomised in the study and in 8.6% in the subset of 196 patients with available tumour tissue. Clinically negative axillary lymph nodes, poor tumour differentiation, negative oestrogen receptor status, negative progesterone receptor status, and loss of bcl-2 were significantly predictive for a pCR in a univariate logistic regression model, whereas in a multivariate analysis only the clinical nodal status and hormonal receptor status provided significantly independent information. Backward stepwise logistic regression revealed a response after two cycles, with hormone receptor status and lymph-node status as significant predictors. Patients with a low percentage of cells stained positive for Ki-67 showed a better response when treated with tamoxifen, whereas patients with a high percentage of Ki-67 positive cells did not have an additional benefit when treated with tamoxifen. Tumours overexpressing HER2 showed a similar response to that in HER2-negative patients when treated without tamoxifen, but when HER2-positive tumours were treated with tamoxifen, no pCR was observed. Conclusion Reliable prediction of a pathological complete response after preoperative chemotherapy is not possible with clinical and biological factors routinely determined before start of treatment. The response after two cycles of chemotherapy is a strong but dependent predictor. The only independent factor in this subset of patients was bcl-2. Trial registration number NCT00543829
Background: In this study, we examined patients who had non-progressive disease for at least 2 years after diagnosis of inoperable locoregional recurrent or metastatic breast cancer under continuous trastuzumab treatment. Our primary goal was to assess the long-term outcome of patients with durable response to trastuzumab.
Methods: 268 patients with HER2-positive inoperable locally recurrent or metastatic breast cancer and non-progressive disease for at least 2 years under trastuzumab treatment were documented retrospectively or prospectively in the HER-OS registry, an online documentation tool, between December 2006 and September 2010 by 71 German oncology centers. The study end point was time to tumor progression.
Results: Overall, 47.1% of patients (95% confidence interval (CI): 39.9–54.1%) remained in remission for more than 5 years, while the median time to progression was 4.5 years (95% CI: 4.0–6.6 years). Lower age (<50 years) and good performance status (ECOG 0) at time of trastuzumab treatment initiation as well as complete remission after initial trastuzumab treatment were associated with longer time to progression. Interruption of trastuzumab therapy correlated with shorter time to progression.
Conclusions: HER2-positive patients, who initially respond to palliative treatment with trastuzumab, can achieve a long-term tumor remission of several years.
In eukaryotes, double-stranded (ds) RNA induces sequence-specific inhibition of gene expression referred to as RNA interference (RNAi). We exploited RNAi to define the role of HER2/neu in the neoplastic proliferation of human breast cancer cells. We transfected SK-BR-3, BT-474, MCF-7, and MDA-MB-468 breast cancer cells with short interfering RNA (siRNA) targeted against human HER2/neu and analyzed the specific inhibition of HER2/neu expression by Northern and Western blots. Transfection with HER2/neu-specific siRNA resulted in a sequence-specific decrease in HER2/neu mRNA and protein levels. Moreover, transfection with HER2/neu siRNA caused cell cycle arrest at G0/G1 in the breast cancer cell lines SKBR-3 and BT-474, consistent with a powerful RNA silencing effect. siRNA treatment resulted in an antiproliferative and apoptotic response in cells overexpressing HER2/neu, but had no influence in cells with almost no expression of HER2/neu proteins like MDA-MB-468 cells. These data indicate that HER2/neu function is essential for the proliferation of HER2/neuoverexpressing breast cancer cells. Our observations suggest that siRNA targeted against human HER2/neu may be valuable tools as anti proliferative agents that display activity against neoplastic cells at very low doses.
RNA interference (RNAi) has emerged as a powerful tool to induce loss-of-function phenotypes by post-transcriptional silencing of gene expression. In this study we wondered whether inducible RNAi-cassettes integrated into cellular DNA possess the power to trigger neoplastic growth. For this purpose inducible RNAi vectors containing tetracycline (Tet)-responsive derivatives of the H1 promoter for the conditional expression of short hairpin RNA (shRNA) were used to target human polo-like kinase 1 (Plk1), which is overexpressed in a broad spectrum of human tumors. In the absence of doxycycline (Dox) HeLa clones expressing TetR, that carry the RNAi-cassette stably integrated, exhibited no significant alteration in Plk1 expression levels. In contrast, exposure to Dox led to marked downregulation of Plk1 mRNA to 3% and Plk1 protein to 14% in cell culture compared to mismatch shRNA/Plk1-expressing cells. As a result of Plk1 depletion cell proliferation decreased to 17%. Furthermore, for harnessing RNAi for silencing disease-related genes in vivo we transplanted inducible RNAi-HeLa cells onto nude mice. After administration of Dox knockdown of Plk1 expression was observed correlating to a significant inhibition of tumor growth. Taken together, our data revealed that genomically integrated RNAi-elements are suitable to hamper tumor growth by conditional expression of shRNA.