Publikationen
A New Molecular Predictor of Distant Recurrence in ER-Positive, HER2-Negative Breast Cancer Adds Independent Information to Conventional Clinical Risk Factors
Martin Filipits, Margaretha Rudas, Raimund Jakesz, Peter Dubsky, Florian Fitzal, Christian F. Singer, Otto Dietze, Richard Greil, Andrea Jelen, Paul Sevelda, Christa Freibauer, Volkmar M€uller, Fritz J€anicke, Marcus Schmidt, Heinz K€olbl, Achim Rody, Manfred Kaufmann, Werner Schroth, Hiltrud Brauch, Matthias Schwab, Peter Fritz, Karsten E. Weber, Inke S. Feder, Guido Hennig, Ralf Kronenwett, Mathias Gehrmann, and Michael Gnant, for the EP Investigators
Abstract
Purpose: According to current guidelines molecular tests predicting outcome of breast cancer patients can be used to assist in making treatment decisions after consideration of conventional markers. We developed and validated a gene-expression signature predicting the likelihood of distant recurrence in patients with ER-positive, HER2-negative breast cancer treated with adjuvant endocrine therapy.
Experimental Design: RNA levels assessed by RT-qPCR in formalin-fixed paraffin-embedded (FFPE) tumor tissue were used to calculate a risk score (Endopredict, EP) consisting of 8 cancer-related and 3 reference genes. EP was combined with nodal status and tumor size into a comprehensive risk score EPclin. Both pre-specified risk scores including cutoff values to determine a risk group for each patient (low, high) were validated independently in patients from two large randomized phase III trials (ABCSG-6: n=378, ABCSG-8: n=1324).
Results: In both validation cohorts, continuous EP was an independent predictor of distant recurrence in multivariate analysis (ABCSG-6: P=0.010; ABCSG-8: P<0.001). Combining Adjuvant!Online, quantitative ER, Ki67, and treatment with EP yielded a prognostic power significantly superior to the clinicopathological factors alone (c-indices: 0.764 vs. 0.750, P=0.024 [ABCSG-6]; 0.726 vs. 0.701, P=0.003 [ABCSG-8]). EPclin had c-indices of 0.788 and 0.732 and resulted in 10-year distant recurrence rates of 4% and 4% in EPclin-low-risk and 28% and 22% in EPclin-high-risk patients in ABCSG-6 (P<0.001) and ABCSG-8 (P<0.001), respectively.
Conclusions: The multigene EP risk score provided additional prognostic information to the risk of distant recurrence of breast cancer patients, independent from clinicopathological parameters. The EPclin score outperformed all conventional clinicopathological risk factors.
Clin Cancer Res Published OnlineFirst August 1, 2011
Low p27 Expression Predicts Early Relapse and Death in Postmenopausal Hormone Receptor-Positive Breast Cancer Patients Receiving Adjuvant Tamoxifen Therapy
By Martin Filipits, Margaretha Rudas, Harald Heinzl, Raimund Jakesz, Ernst Kubista, Sigurd Lax, Walter Schippinger, Otto Dietze, Richard Greil, Wolfgang Stiglbauer, Werner Kwasny, Alexander Nader, Michael Stierer, and Michael F.X. Gnant for the Austrian Breast and Colorectal Cancer Study Group
Abstract
Purpose: Previously, we have shown that p27 may be a potential predictive biomarker for the selection of premenopausal women with early-stage hormone-responsive breast cancer for adjuvant endocrine therapy. The purpose of the present study was to assess the clinical relevance of p27 expression in postmenopausal hormone receptor–positive breast cancer patients who were treated with adjuvant tamoxifen therapy.
Experimental Design: We determined the expression of p27 by immunohistochemistry in the surgical specimens of breast carcinoma patients who had been enrolled in Austrian Breast and Colorectal Cancer Study Group Trial 06 and received tamoxifen for 5 years. Early relapse and death within the first 5 years of follow-up were analyzed using Cox models adjusted for clinical and pathologic factors.
Results: p27 expression was high (>70% p27-positive tumor cells) in 252 of 483 (52%) tumor specimens and was associated with favorable outcome of the patients. Women with high p27 expression had a significantly longer disease-free survival (adjusted hazard ratio for relapse, 0.22; 95% confidence interval, 0.11-0.42; P < 0.001) and overall survival (adjusted hazard ratio for death, 0.39; 95% confidence interval, 0.21-0.72; P = 0.002) as compared with women with low p27 expression.
Conclusion: Low p27 expression independently predicts early relapse and death in postmenopausal women with early-stage, hormone receptor–positive breast cancer who received adjuvant tamoxifen for 5 years. (Clin Cancer Res 2009;15(18):5888–94)
Clin Cancer Res 15(18): 5888- 5894, 2009
Clinical Role of Multidrug Resistance Protein 1 Expression in Chemotherapy Resistance in Early-Stage Breast Cancer: The Austrian Breast and Colorectal Cancer Study Group
By Martin Filipits, Gudrun Pohl, Margaretha Rudas, Otto Dietze, Sigurd Lax, Renate Grill, Robert Pirker, Christoph C. Zielinski, Hubert Hausmaninger, Ernst Kubista, Hellmut Samonigg, and Raimund Jakesz for the Austrian Breast and Colorectal Cancer Study Group
Abstract
PURPOSE: The multidrug resistance protein 1 (MRP1) is expressed in human breast cancer cells and may contribute to the clinical drug resistance of breast cancer patients. Therefore, we determined the impact of MRP1 expression on the clinical outcome of adjuvant therapy in patients with early-stage breast cancer.
PATIENTS AND METHODS: Immunostaining for MRP1 was performed on tissue sections from 516 premenopausal, hormone receptor-positive breast cancer patients with stage I and II disease. Statistical analyses were performed to assess the effect of MRP1 expression on survival and to test for interaction between MRP1 expression and treatment.
RESULTS: MRP1 expression independently predicted shorter relapse-free survival (RFS) and overall survival (OS) in patients treated with cyclophosphamide, methotrexate, and fluorouracil (CMF; RFS: hazard ratio [HR] = 1.48; 95% CI, 1.16 to 1.88; P = .002; OS: HR = 1.82; 95% CI, 1.10 to 3.01; P = .02), but it did not predict shorter RFS and OS in patients who received tamoxifen plus goserelin (RFS: HR = 0.99; 95% CI, 0.74 to 1.31; P = .9; OS: HR = 0.68; 95% CI, 0.40 to 1.15; P = .1). Tests for interaction between MRP1 expression and treatment were statistically significant for both RFS (P = .04) and OS (P = .006).
CONCLUSION: Our data suggest that MRP1 expression plays an important role in the clinical resistance to adjuvant CMF chemotherapy but does not seem to affect response to adjuvant endocrine treatment with tamoxifen plus goserelin. Thus, MRP1 may be a useful marker for the selection of patients with early-stage breast cancer for the appropriate adjuvant therapy after prospective confirmatory evaluation.
J Clin Oncol 23: 1161-1168, 2005
High p27Kip1 Expression Predicts Superior Relapse-Free and Overall Survival for Premenopausal Women With Early-Stage Breast Cancer Receiving Adjuvant Treatment With Tamoxifen Plus Goserelin
By Gudrun Pohl, Margaretha Rudas, Otto Dietze, Sigurd Lax, Eva Markis, Robert Pirker, Christoph C. Zielinski, Hubert Hausmaninger, Ernst Kubista, Hellmut Samonigg, Raimund Jakesz, and Martin Filipits for the Austrian Breast and Colorectal Cancer Study Group
Abstract
Purpose: To determine the predictive value of p27Kip1 in premenopausal women with early-stage hormone receptor–positive breast cancer.
Patients and Methods: We retrospectively examined tumor specimens from 512 patients with breast cancer who were enrolled onto Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 5. In this trial, premenopausal, hormone receptor–positive breast cancer patients with stage I and II disease were randomly assigned to receive either 5 years of tamoxifen plus 3 years of goserelin or six cycles of cyclophosphamide, methotrexate, and fluorouracil. p27Kip1 expression was assessed by immunohistochemistry, and its association with clinical outcome was determined. Statistical analyses were performed to test for interaction between p27Kip1 status and treatment.
Results: High p27Kip1 expression (nuclear p27Kip1 staining in ≥ 50% of tumor cells) independently predicted superior relapse-free survival (RFS) and overall survival (OS) in both the total study population (RFS: relative risk [RR], 0.53; 95% CI, 0.34 to 0.82; P = .004; OS: RR, 0.29; 95% CI, 0.15 to 0.58; P < .001) and patients treated with combination endocrine therapy (RFS: RR, 0.32; 95% CI, 0.16 to 0.63; P = .001; OS: RR, 0.16; 95% CI, 0.05 to 0.53; P = .003). The interaction between p27Kip1 expression and treatment was statistically significant for RFS (P = .04) but not for OS (P = .27).
Conclusion: High p27Kip1 expression was an independent predictor of responsiveness to hormonal therapy and thus may be useful for the selection of premenopausal women with early-stage hormone receptor–positive breast cancer for adjuvant combination endocrine therapy.
J Clin Oncol 21: 3594-3600, 2003
Cyclin D1 Expression in Breast Cancer Patients Receiving Adjuvant Tamoxifen-Based Therapy
Margaretha Rudas, Martina Lehnert, Anh Huynh, Raimund Jakesz, Christian Singer,Sigurd Lax, Walter Schippinger, Otto Dietze, Richard Greil, Wolfgang Stiglbauer, Werner Kwasny, Renate Grill, Michael Stierer, Michael F. X. Gnant and Martin Filipits for the Austrian Breast and Colorectal Cancer Study Group
Abstract
PURPOSE: The objective of our study was to determine the clinical relevance of cyclin D1 expression in hormone receptor-positive breast cancer patients who were treated with tamoxifen-based therapy.
EXPERIMENTAL DESIGN: We assessed expression of cyclin D1 in surgical specimens of breast carcinoma by means of immunohistochemistry. Patients had been enrolled in either Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 05 or ABCSG Trial 06 and received tamoxifen as part of their adjuvant treatment. Overall survival and relapse-free survival were analyzed with Cox models adjusted for clinical and pathologic factors.
RESULTS: Cyclin D1 was expressed in 140 of 253 (55%) tumors of ABCSG Trial 05 and in 569 of 948 (60%) tumors of ABCSG Trial 06. Expression of cyclin D1 was associated with poor outcome in both cohorts. Overall survival was significantly shorter in patients with cyclin D1-positive tumors compared with patients with cyclin D1-negative tumors [adjusted hazard ratio (HR) for death (ABCSG Trial 05), 2.47; 95% confidence interval (95% CI), 1.08-5.63; P = 0.03; adjusted HR for death (ABCSG Trial 06), 1.78; 95% CI, 1.36-2.34; P < 0.0001]. Relapse-free survival was also shorter in patients with cyclin D1-positive tumors than in patients with cyclin D1-negative tumors [adjusted HR for relapse (ABCSG Trial 05), 2.73; 95% CI, 1.50-4.96; P = 0.001; adjusted HR for relapse (ABCSG Trial 06), 1.52; 95% CI, 1.14-2.04; P = 0.005].
CONCLUSION: Cyclin D1 expression is an independent poor prognostic factor in women with early-stage, hormone receptor-positive breast cancer who received adjuvant tamoxifen-based therapy.
Clin Cancer Res 2008;14(6) March 15, 2008