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93 oral Predicting local recurrence in breast conserving therapy by gene expression profiling
S43
Monday, October 25, 2004
Proffered papers Molecular markers of outcome 93 oral
Predicting local recurrence in breast conserving therapy by gene expression profiling D.S.A. Nuyten ~, H.Y. Chang 2, J.B. Sneddon 2, B. Kreike ~, A.A.M. Hart ~, L.J. Veer van 't~, J.L. Peterse 3, P.O. Brown2, M.J. Vijver van de 3, H. Bartelink 1
~Netherlands Cancer Institute, Department of Radiation Oncology, Amsterdam, The Netherlands 2Stanford University School of Medicine, Department of Biochemistry, Stanford, United States of America 4Netherlands Cancer Institute, Department of Diagnostic Oncology, Amsterdam, The Netherlands Introduction: Gene expression profiling (GEP) has been used to identify subgroups in breast cancer to predict clinical outcome (metastasis free interval and overall survival; MFI and OS). In radiation oncology local recurrence (LR) is an important end point, especially after breast conserving therapy (BCT). Recently, a Wound Signature (WS) like gene expression profile was defined (Chang et al PLOS 2004). It was shown that patients with an "activated Wound Signature" have a relatively poor outcome (Disease free survival and OS) in different types of carcinomas. Here we have tested the association between prognostic performance of the WS with respect to local recurrence in 161 tumors treated with BCT. Methods: In a previously described series of 295 stage I and II breast carcinomas treated at the Netherlands Cancer Institute, we have obtained gene expression data of 25,000 genes using microarray analysis. 161 patients were treated with BCT (17 LR's). We have used the genes from the WS to determine whether the tumors show an activated or quiescent WS (unsupervised hierarchical clustering). To further optimize the prognostic performance, we developed a supervised method on a randomly selected training set (n=81,9 LR) and tested this on the remaining validation set (n=80, 8 LR). For all patients we calculated the correlation to the average expression of WS-genes in patients with an LR in the test set. We determined a cut off value for this correlation that optimally predicted which patients developed a local recurrence. This threshold was subsequently used to study risk of local recurrence in the validation set. Results: The median follow up was 7.8 years; the LR-free rate at 10 years for the entire group is 85%. Using unsupervised classification, tumors from 65 patients showed an activated WS; and 96 were quiescent and LR-rates at 10 years are 87.1% (activated WS) vs. 81.3% (quiescent WS; p--0.037). Using the supervised approach, the rates at 10 years in the validation series are 95% vs. 69.5% (p=0.0005). Discussion: In this consecutively treated series of breast cancer patients, the Wound Signature classification is able to distinguish significantly in risk of LR after BCT. Although the number of patients with LR in this study is low, our results suggest that gene expression profiling may be of use in predicting the risk of local recurrence and thereby tailor local treatment for breast cancer.
94 oral Significance of plasma TGF-I~ levels in radiotherapy for NSCLC
C.E. REIbeI, M. Erren 2, C. Sebastian-Welsch ~, K. Eggeling ~, K. Dommes ~, J. Palm ~, K. Remberger3, C. R#be ~ ~Saarland University, Radiotherapy / Radiooncology, Homburg/Saar, Germany 2Muenster University, Clinical Chemistry, Muenster, Germany 3Saarland University, Pathology, Homburg/Saar, Germany Purpose: The purpose of this study was to investigate prospectively the time course of plasma TGF-I~ levels in patients irradiated for NSCLC in relation to the development of radiation pneumonitis. In addition, the TGF-6 expression in the turnout biopsies of all patients were correlated with the plasma TGF-~ levels and their significance to predict tumour progression was evaluated. Methods and Materials: Blood samples were obtained in 36 patients irradiated for medically inoperable or locally advanced NSCLC before, weekly during radiotherapy (RT), 1 month after RT and subsequently in 3 months intervals after completion of RT. Plasma TGF-I~ levels were determined by ELISA. Tumour biopsies were immunohistochemically stained for TGF-6 and the immunoreactivity was quantified by image-analysis-system. All patients underwent clinical evaluation, chest radiography, chest computed tomography (CT) and high-resolution CT, pulmonary function tests (including CO diffusing capacity) prior to RT, at 1 month after RT and, subsequently, in 3 months intervals after completion of RT. Results: The pre-RT TGF-I~ levels were increased in 17 patients with NSCLC compared with healthy individuals; the tumour biopsies of these patients were highly positive for TGFI~. On average, these TGF-rS levels decreased below the pretreatment value during the RT treatment reflecting tumour response. At the time of tumour progression (recurrence or metastasis) TGF-6 levels were significantly elevated in patients with TGF-I~ positive tumours. 7 patients developed radiation pneumonitis (RTOG Ill°: 3 pat.; I1°: 1 pat.; I°: 3 pat.). Most, but not all of these patients revealed a variable increase of the plasma TGF-I~ levels in the middle or at the end of radiotherapy; at the time of radiation pneumonitis TGF-I~ levels were significantly increased. Conclusion: Our results confirm the hypothesis that changes in the plasma TGF-I~ levels can be caused by at least two, partly counteractive, mechanisms: on one hand, TGF-I~ levels may decrease or increase due to the TGF-I& producing tumour mass. On the other hand, radiation may increase the TGF-6 pool due to elevated production in the injured normal lung tissue. But while plasma TGF-6 levels may reflect these mechanisms, the predictive value for radiation pneumonitis or for tumour progression is rather low. 95 oral Whatever happened to Tpot? G.D. Wilson ~, N. Paschoud, P.A. Coucke 1Karmanos Cancer Institute, Radiation Oncology, Detroit, U.S.A. 22 pl Benjamin - Constant, Lausanne, Switzerland 3Central Hospitalier Universitaire Vaudois, Radiotherapy, Lausanne, Switzerland The development of flow cytometric techniques to measure the potential doubling time (Tpot) from a single biopsy caused a resurgence in the interest of applying cell kinetic measurements
Monday, October 25, 2004
Proffered papers Molecular markers of outcome 93 oral
Predicting local recurrence in breast conserving therapy by gene expression profiling D.S.A. Nuyten ~, H.Y. Chang 2, J.B. Sneddon 2, B. Kreike ~, A.A.M. Hart ~, L.J. Veer van 't~, J.L. Peterse 3, P.O. Brown2, M.J. Vijver van de 3, H. Bartelink 1
~Netherlands Cancer Institute, Department of Radiation Oncology, Amsterdam, The Netherlands 2Stanford University School of Medicine, Department of Biochemistry, Stanford, United States of America 4Netherlands Cancer Institute, Department of Diagnostic Oncology, Amsterdam, The Netherlands Introduction: Gene expression profiling (GEP) has been used to identify subgroups in breast cancer to predict clinical outcome (metastasis free interval and overall survival; MFI and OS). In radiation oncology local recurrence (LR) is an important end point, especially after breast conserving therapy (BCT). Recently, a Wound Signature (WS) like gene expression profile was defined (Chang et al PLOS 2004). It was shown that patients with an "activated Wound Signature" have a relatively poor outcome (Disease free survival and OS) in different types of carcinomas. Here we have tested the association between prognostic performance of the WS with respect to local recurrence in 161 tumors treated with BCT. Methods: In a previously described series of 295 stage I and II breast carcinomas treated at the Netherlands Cancer Institute, we have obtained gene expression data of 25,000 genes using microarray analysis. 161 patients were treated with BCT (17 LR's). We have used the genes from the WS to determine whether the tumors show an activated or quiescent WS (unsupervised hierarchical clustering). To further optimize the prognostic performance, we developed a supervised method on a randomly selected training set (n=81,9 LR) and tested this on the remaining validation set (n=80, 8 LR). For all patients we calculated the correlation to the average expression of WS-genes in patients with an LR in the test set. We determined a cut off value for this correlation that optimally predicted which patients developed a local recurrence. This threshold was subsequently used to study risk of local recurrence in the validation set. Results: The median follow up was 7.8 years; the LR-free rate at 10 years for the entire group is 85%. Using unsupervised classification, tumors from 65 patients showed an activated WS; and 96 were quiescent and LR-rates at 10 years are 87.1% (activated WS) vs. 81.3% (quiescent WS; p--0.037). Using the supervised approach, the rates at 10 years in the validation series are 95% vs. 69.5% (p=0.0005). Discussion: In this consecutively treated series of breast cancer patients, the Wound Signature classification is able to distinguish significantly in risk of LR after BCT. Although the number of patients with LR in this study is low, our results suggest that gene expression profiling may be of use in predicting the risk of local recurrence and thereby tailor local treatment for breast cancer.
94 oral Significance of plasma TGF-I~ levels in radiotherapy for NSCLC
C.E. REIbeI, M. Erren 2, C. Sebastian-Welsch ~, K. Eggeling ~, K. Dommes ~, J. Palm ~, K. Remberger3, C. R#be ~ ~Saarland University, Radiotherapy / Radiooncology, Homburg/Saar, Germany 2Muenster University, Clinical Chemistry, Muenster, Germany 3Saarland University, Pathology, Homburg/Saar, Germany Purpose: The purpose of this study was to investigate prospectively the time course of plasma TGF-I~ levels in patients irradiated for NSCLC in relation to the development of radiation pneumonitis. In addition, the TGF-6 expression in the turnout biopsies of all patients were correlated with the plasma TGF-~ levels and their significance to predict tumour progression was evaluated. Methods and Materials: Blood samples were obtained in 36 patients irradiated for medically inoperable or locally advanced NSCLC before, weekly during radiotherapy (RT), 1 month after RT and subsequently in 3 months intervals after completion of RT. Plasma TGF-I~ levels were determined by ELISA. Tumour biopsies were immunohistochemically stained for TGF-6 and the immunoreactivity was quantified by image-analysis-system. All patients underwent clinical evaluation, chest radiography, chest computed tomography (CT) and high-resolution CT, pulmonary function tests (including CO diffusing capacity) prior to RT, at 1 month after RT and, subsequently, in 3 months intervals after completion of RT. Results: The pre-RT TGF-I~ levels were increased in 17 patients with NSCLC compared with healthy individuals; the tumour biopsies of these patients were highly positive for TGFI~. On average, these TGF-rS levels decreased below the pretreatment value during the RT treatment reflecting tumour response. At the time of tumour progression (recurrence or metastasis) TGF-6 levels were significantly elevated in patients with TGF-I~ positive tumours. 7 patients developed radiation pneumonitis (RTOG Ill°: 3 pat.; I1°: 1 pat.; I°: 3 pat.). Most, but not all of these patients revealed a variable increase of the plasma TGF-I~ levels in the middle or at the end of radiotherapy; at the time of radiation pneumonitis TGF-I~ levels were significantly increased. Conclusion: Our results confirm the hypothesis that changes in the plasma TGF-I~ levels can be caused by at least two, partly counteractive, mechanisms: on one hand, TGF-I~ levels may decrease or increase due to the TGF-I& producing tumour mass. On the other hand, radiation may increase the TGF-6 pool due to elevated production in the injured normal lung tissue. But while plasma TGF-6 levels may reflect these mechanisms, the predictive value for radiation pneumonitis or for tumour progression is rather low. 95 oral Whatever happened to Tpot? G.D. Wilson ~, N. Paschoud, P.A. Coucke 1Karmanos Cancer Institute, Radiation Oncology, Detroit, U.S.A. 22 pl Benjamin - Constant, Lausanne, Switzerland 3Central Hospitalier Universitaire Vaudois, Radiotherapy, Lausanne, Switzerland The development of flow cytometric techniques to measure the potential doubling time (Tpot) from a single biopsy caused a resurgence in the interest of applying cell kinetic measurements