Publications (6)52.14 Total impact
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Article: Validity of bone marker measurements for monitoring response to bisphosphonate therapy with zoledronic acid in metastatic breast cancer.
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ABSTRACT: Bone is the most common site of metastasis in breast cancer. Detection relies on imaging technology which is costly and can only be performed to a certain degree. Bone markers are non-invasive, inexpensive and may potentially serve as predictive and prognostic surrogate endpoints in detecting bone metastases and response to bisphosphonates. This study analyzed the value of the serum bone turnover markers PINP and ICTP for bone metastases in metastatic breast cancer patients receiving zoledronic acid. The results were compared with the serum levels of CEA and CA 15-3, and analyzed with respect to the number of bone metastases as well as clinical response. Forty patients with confirmed bone metastases who received chemotherapy and/or hormonal therapy and zoledronic acid i.v. q4 weeks participated in the present study. blood (5 ml) was collected at the start of the study and q3 months for a period of one year for the analysis of PINP, ICTP, CEA and CA 15-3 using radioimmunoassays and ELISA, respectively. Imaging of bone metastases was performed at the same time points. In 29 out of 40 patients, more than 3 bone metastases were confirmed by imaging and 11 out of 40 patients presented with 3 or less. At the start of the study, the median value for ICTP was 6 µg/l and for PINP 58.7 µg/l. At the end of the study the median values were 4.5 µg/l for ICTP and 21 µg/l for PINP. When patients were stratified into responders and non-responders, a decrease in both PINP (P<0.0001) and ICTP (P=0.048) was observed for the responders, while the level of ICTP (P=0.02) increased for the non-responders. Serum PINP and ICTP concentrations were significantly different when patients were stratified into groups of those having more than 3 bone metastases and 3 or less, respectively (P<0.05). CEA and CA 15-3 levels did not differ with respect to the number of bone metastases, while the tumor marker levels determined at the end of the study significantly distinguished responders from non-responders (P=0.002 and P=0.004). In conclusion, in contrast to serum tumor markers, the determination of PINP and ICTP allows inferences to the number of bone metastases and appears to be a useful tool for prediction and monitoring metastatic breast cancer patients undergoing bisphosphonate therapy with zoledronic acid for the treatment of bone metastases.Oncology Reports 04/2013; · 1.84 Impact Factor -
Article: Comparison of estrogen and progesterone receptor status of circulating tumor cells and the primary tumor in metastatic breast cancer patients.
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ABSTRACT: The expression of predictive markers including the estrogen (ER) and progesterone receptor (PR) expression can change during the course of the disease. Therefore, reassessment of these markers at the time of disease progression might help to optimize treatment decisions. Metastatic tissue may be difficult to obtain for repeated analysis. In this context, characterization of circulating tumor cells (CTCs) could be of relevance. It was the purpose of the present study (1) to reevaluate the ER/PR expression by CTCs and (2) to compare the hormone receptor status expression profile of CTCs with the primary tumor. We evaluated 193 blood samples from metastatic breast cancer patients at the time of first diagnosis of metastatic disease or disease progression. All samples underwent immunomagnetic enrichment using the AdnaTest BreastCancerSelect (AdnaGen AG, Germany) within 4h after blood withdrawal followed by RNA isolation and subsequent gene expression analysis by reverse transcription and Multiplex-PCR in separated tumor cells using the AdnaTest BreastCancerDetect. CTCs were analyzed for the three breast cancer-associated markers: EpCAM, Muc-1, Her-2 and actin as an internal PCR control. Expression of the ER and PR was assessed in an additional RT-PCR. The analysis of PCR products was performed by capillary electrophoresis on the Agilent Bioanalyzer 2100. The overall detection rate for CTCs was 45% (87/193 patients) with the expression rates of 71% for EpCAM (62/87 patients), 73% for MUC1 (64/87 patients), 48% for HER2 (42/87 patients), 19% for ER (17/87 patients) and 10% for PR (9/87 patients), respectively. Comparisons with the primary tumor were only performed in CTC+ patients (n=87). In 48/62 (77%) patients with ER+ tumors, CTCs were ER- and 46/53 (87%) patients with PR+ tumors did not express PR on CTCs. Primary tumors and CTCs displayed a concordant ER and PR status in only 41% (p=0.260) and 45% (p=0.274) of cases, respectively. Most of the CTCs were ER/PR-negative despite the presence of an ER/PR- positive primary tumor. The predictive value of hormone receptor status expression profile of CTCs for palliative endocrine therapy has to be prospectively evaluated. STATEMENT: We recently demonstrated in more than 400 primary breast cancer patients that the expression profile between CTCs and the primary tumor with regard to ER/PR/HER2 positivity differs. The concordance rate between ER, PR and HER2 status of CTCs and the primary tumor was 29%, 25% and 53%, respectively (Fehm T et al., Breast Cancer Res Aug 10 2009, 11(4) pR59). Based on these results we studied blood samples of 193 metastatic breast cancer patients participating in the German DETECT study (1) to reevaluate the ER/PR expression by CTCs and (2) to compare the hormone receptor status expression profile of CTCs with the primary. As already shown for primary breast cancer, most of the CTCs were ER/PR-negative despite the presence of an ER/PR- positive primary tumor. In the metastatic setting the phenotype of CTC reflects the phenotype of metastatic disease. Therefore palliative treatment selected based on the expression profile may not be effective since the phenotype has changed during disease progression. To our knowledge, this study is one of the biggest to compare hormonal receptor expression on CTC and the primary tumor. We hope that our manuscript is suitable for publication in Gynecologic Oncology.Gynecologic Oncology 05/2011; 122(2):356-60. · 3.89 Impact Factor -
Article: Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients.
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ABSTRACT: The persistence of circulating tumor cells (CTC) in breast cancer patients might be associated with stem cell like tumor cells which have been suggested to be the active source of metastatic spread in primary tumors. Furthermore, these cells also may undergo phenotypic changes, known as epithelial-mesenchymal transition (EMT), which allows them to travel to the site of metastasis formation without getting affected by conventional treatment. Here we evaluated 226 blood samples of 39 metastatic breast cancer patients during a follow-up of palliative chemo-, antibody - or hormonal therapy for the expression of the stem cell marker ALDH1 and markers for EMT and correlated these findings with the presence of CTC and response to therapy. 2 x 5 ml blood was analyzed for CTC with the AdnaTest BreastCancer (AdnaGen AG) for the detection of EpCAM, MUC-1 and HER2 transcripts. The recovered c-DNA was additionally multiplex tested for three EMT markers [Twist1, Akt2, PI3Kalpha] and separately for the tumor stem-cell markers ALDH1. The identification of EMT markers was considered positive if at least one marker was detected in the sample. 97% of 30 healthy donor samples investigated were negative for EMT and 95% for ALDH1 transcripts. CTC were detected in 69/226 (31%) cancer samples. In the CTC (+) group, 62% were positive for at least one of the EMT markers and 69% for ALDH1, respectively. In the CTC (-) group the percentages were 7% and 14%, respectively. In non-responders, EMT and ALDH1 expression was found in 62% and 44% of patients, in responders the rates were 10% and 5%, respectively. Our data indicate that a major proportion of CTC of metastatic breast cancer patients shows EMT and tumor stem cell characteristics. Further studies are needed to prove whether these markers might serve as an indicator for therapy resistant tumor cell populations and, therefore, an inferior prognosis.Breast cancer research: BCR 08/2009; 11(4):R46. · 5.24 Impact Factor -
Article: Molecular profiling and predictive value of circulating tumor cells in patients with metastatic breast cancer: an option for monitoring response to breast cancer related therapies.
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ABSTRACT: We analyzed circulating tumor cells (CTC) in blood of metastatic breast cancer patients (n = 42) and determined the ability of this method to predict therapy response. CTC from blood were analyzed before and during therapy for EpCAM, MUC1 and HER2 transcripts with the AdnaTest BreastCancer. The estrogen (ER) and progesterone (PR) receptor expression was assessed by RT-PCR. The overall detection rate for CTC was 52% (thereof 86% EpCAM; 86% MUC1; 32% HER2; 35% ER; 12% PR). CTC were ER, PR and HER2 negative in 45% (ER), 78% (PR) and 60% (HER-2) of patients with steroid receptor-positive tumors. 29% of patients with HER2-negative tumors had HER2-positive CTC. The test predicted therapy response in 78% of all cases. Persistence of CTC significantly correlated with shorter overall survival (P = 0.005). Molecular profiling of CTC may offer superior prognostic information with regard to risk assessment for recurrence and predictive judgement of therapeutical regimens.Breast Cancer Research and Treatment 09/2008; 115(3):581-90. · 4.43 Impact Factor -
Article: Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors.
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ABSTRACT: BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor inhibitor that inhibits tumor cell proliferation and angiogenesis. This study established the safety and pharmacokinetics of BAY 43-9006 in 69 patients with advanced refractory solid tumors. BAY 43-9006 (50 to 800 mg) was administered once or twice daily on a varying weekly schedule. Pharmacokinetic sampling was performed in all patients; preliminary tumor response was also assessed. The effect of BAY 43-9006 on phorbol myristate acetate-stimulated ERK phosphorylation in peripheral blood lymphocytes was studied using flow cytometry. Mild to moderate diarrhea was the most common (55%) treatment-related adverse event. The maximum-tolerated dose was 400 mg bid continuous. Dose-limiting toxicities were grade 3 diarrhea and fatigue at 800 mg bid, and grade 3 skin toxicity at 600 mg bid. BAY 43-9006 pharmacokinetics were highly variable for single and multiple dosing, and toxicity did not appear to be dose dependent. Significant decreases of phorbol myristate acetate-stimulated ERK phosphorylation (P < .01) were identified at doses >/= 200 mg bid continuous. Forty-five patients were assessable for efficacy; one patient had a partial response (hepatocellular carcinoma at 400 mg bid continuous), 25 patients had stable disease, with eight lasting > 6 months and five for >12 months. Eighteen patients had progressive disease, and tumor response could not be evaluated in one patient. Oral BAY 43-9006 was well tolerated and appeared to provide some clinical benefits. Based on the results of this study, BAY 43-9006 at 400 mg bid continuous is recommended for ongoing and future studies.Journal of Clinical Oncology 03/2005; 23(5):965-72. · 18.37 Impact Factor -
Article: Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor.
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ABSTRACT: To investigate the safety and tolerability and to explore the pharmacokinetic and pharmacodynamic profile of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with solid tumors that express epidermal growth factor receptor (EGFR). This was a phase I dose-escalation trial of EMD72000 in patients with advanced, EGFR-positive, solid malignancies that were not amenable to any established chemotherapy or radiotherapy treatment. EMD72000 was administered weekly without routine premedication until disease progression or unacceptable toxicity. Twenty-two patients were treated with EMD72000 at five different dose levels (400 to 2,000 mg/wk). National Cancer Institute common toxicity criteria grade 3 headache and fever occurring after the first infusion were dose limiting at 2,000 mg/wk; thus, the maximum-tolerated dose was 1,600 mg/wk. No other severe side effects, especially no allergic reactions or diarrhea, were observed. Acneiform skin reaction was the most common toxicity, but it was mild, with grade 1 in 11 patients (50%) and grade 2 in three patients (14%). Pharmacokinetic analyses demonstrated a predictable pharmacokinetic profile for EMD72000. Pharmacodynamic studies on serial skin biopsies revealed that EMD72000 effectively abrogated EGFR-mediated cell signaling (eg, reduced phosphorylation of EGFR and mitogen-activated protein kinase), with no alteration in total EGFR protein. Objective responses (23%; 95% CI, 8% to 45%) and disease stabilization (27%; 95% CI, 11% to 50%) were achieved at all dose levels, and responding patients received treatment for up to 18 months without cumulative toxicity. Treatment with EMD72000 was well tolerated and showed evidence of activity in heavily pretreated patients with EGFR-expressing tumors. EMD72000 at the investigated doses significantly inhibited downstream EGFR-dependent processes.Journal of Clinical Oncology 02/2004; 22(1):175-84. · 18.37 Impact Factor
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2008–2013
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Universität Duisburg-Essen
Essen, North Rhine-Westphalia, Germany
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