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09)
January 2017
response and application of PCI strongly correlated with prolonged TTP and OS. Keywords: limited disease small cell lung cancer, Chemoradiotherapy, lung cancer, prophylactic cranial irradiation
PUB041 HGF, VEGFA and ANGPT2 Predict Clinical Benefit from Bevacizumab and Chemotherapy in Patients with Advanced NSCLC (SAKK19/09) Sacha Rothschild,1 Oliver Gautschi,2 Nathalie Schuster,3 Qiyu Li,4 Spasenija Savic,5 Martina Schneider,4 Christine Biaggi,4 Lukas Bubendorf,6 Martin Brutsche,7 Alfred Zippelius,1 Thilo Zander,2 Daniel Betticher,8 Martin Früh,9 Rolf Stahel,10 Richard Cathomas,11 Daniel Rauch,12 Miklos Pless,13 Adrian Ochsenbein,14 Rolf Jaggi3 1Medical Oncology, University Hospital Basel, Basel/Switzerland, 2Medical Oncology, Lucerne Cantonal Hospital, Luzern/Switzerland, 3Department Clinical Research, University of Berne, Bern/Switzerland, 4 Coordinating Center, Swiss Group for Clinical Cancer Research, Bern/Switzerland, 5Institute of Pathology, University Hospital Basel, Basel/Switzerland, 6Insitute of Pathology, University Hospital Basel, Basel/Switzerland, 7 Pneumology, Cantonal Hospital St. Gallen, St. Gallen/ Switzerland, 8Medical Oncology, Hfr Fribourg-Hôpital Cantonal, Fribourg/Switzerland, 9Medical Oncology, Cantonal Hospital St. Gallen, St. Gallen/Switzerland, 10 Clinic for Oncology, University Hospital Zurich, Zurich/ Switzerland, 11Medizinische Onkologie; Dpt. Innere Medizin, Cantonal Hospital Graubünden, Chur/ Switzerland, 12Medical Oncology, Regional Hospital Thun, Thun/Switzerland, 13Medizinische Onkologie, Cantonal Hospital Winterthur, Winterthur/Switzerland, 14Medical Oncology, University Hospital Bern, Bern/Switzerland Background: Bevacizumab (Bev) is a monoclonal antibody against the vascular endothelial growth factor. No predictive biomarkers for the use of Bev have been established so far. We aim to find out the candidates of predictive genes for progression-free survival (PFS) and overall survival (OS) using baseline tumor samples of patients treated in the trial SAKK19/ 09 (NCT01116219). Methods: SAKK19/09 was a non-randomized phase II trial with two sequential cohorts including patients with non-squamous NSCLC and EGFR wild-type. In
Abstracts
S1471
Cohort 1, 77 patients were treated with 4 cycles of cisplatin (C) 75mg/m2, pemetrexed (Pem) 500mg/m2 and Bev 7.5mg/kg, followed by Bev+Pem maintenance. Cohort 2 included 52 patients treated with C+Pem followed by Pem maintenance. RNA was isolated from tumor tissue sections and processed for gene expression analysis by Nanostring. Expression values were normalized using 4 control genes. For each gene, treatment and the interaction of these two, a Cox regression was performed with normalized gene expression divided by its interquartile range for PFS and OS. No adjustment for multiple testing was done. Results:
HR (95% CI) Gene
Cohort 1
Cohort 2
interaction p-value
Numb RPA3 CDC25A PRF1 TNFSF14 CDC34 VEGFA ERCC8 HGF TRAF2 CDC6 GZMB ERCC6 AURKB ANGPT1
0.98 1.97 2.54 0.99 0.98 1.02 1.03 1.00 1.21 1.04 1.29 1.07 0.92 1.29 1.31
0.07 0.98 0.99 0.40 1.32 0.36 0.55 0.42 0.51 0.36 0.91 0.65 0.36 0.66 0.85
0.002 0.005 0.006 0.016 0.023 0.026 0.027 0.028 0.032 0.034 0.041 0.043 0.047 0.047 0.048
(0.81-1.18) (1.29-3.00) (1.29-4.97) (0.87-1.13) (0.95-1.03) (0.79-1.33) (0.94-1.12) (0.83-1.22) (1.01-1.47) (0.88-1.24) (1.11-1.51) (0.90-1.27) (0.66-1.30) (1.01-1.63) (1.13-1.51)
(0.01-0.40) (0.86-1.11) (0.95-1.04) (0.18-0.89) (0.99-1.75) (0.15-0.90) (0.31-0.96) (0.18-0.96) (0.23-1.14) (0.13-0.99) (0.68-1.23) (0.39-1.07) (0.13-0.99) (0.34-1.28) (0.57-1.27)
We analyzed 109 patient samples (63 in Cohort 1; 46 in Cohort 2) with 201 genes assessed at baseline. We found 6 genes potentially predicting PFS (BTLA, CDC25A, FLT1, MSH4, RPA3, TCF7). Regarding to OS we found a significant effect of interaction for 3 angiogenesis-related genes (ANGPT2, HGF, VEGFA) and 12 other genes (Table 1). Several of these 12 genes (AURKB, CDC25A, CDC34, CDC6, ERCC6/8, RPA3) have previously been shown to play an important role in DNA repair and cell cycle regulation supporting the hypothesis that Bev improves chemotherapy activity. Additionally, ANGPT2, HGF and VEGFA directly involved in angiogenesis are also predictive. Conclusion: We identified several potentially predictive genes for Bev activity in combination with chemotherapy. Further work is ongoing to explore changes in gene expression using tumor rebiopsies at progression. Keywords: VEGFA, HGF, Gene Expression, bevacizumab
response and application of PCI strongly correlated with prolonged TTP and OS. Keywords: limited disease small cell lung cancer, Chemoradiotherapy, lung cancer, prophylactic cranial irradiation
PUB041 HGF, VEGFA and ANGPT2 Predict Clinical Benefit from Bevacizumab and Chemotherapy in Patients with Advanced NSCLC (SAKK19/09) Sacha Rothschild,1 Oliver Gautschi,2 Nathalie Schuster,3 Qiyu Li,4 Spasenija Savic,5 Martina Schneider,4 Christine Biaggi,4 Lukas Bubendorf,6 Martin Brutsche,7 Alfred Zippelius,1 Thilo Zander,2 Daniel Betticher,8 Martin Früh,9 Rolf Stahel,10 Richard Cathomas,11 Daniel Rauch,12 Miklos Pless,13 Adrian Ochsenbein,14 Rolf Jaggi3 1Medical Oncology, University Hospital Basel, Basel/Switzerland, 2Medical Oncology, Lucerne Cantonal Hospital, Luzern/Switzerland, 3Department Clinical Research, University of Berne, Bern/Switzerland, 4 Coordinating Center, Swiss Group for Clinical Cancer Research, Bern/Switzerland, 5Institute of Pathology, University Hospital Basel, Basel/Switzerland, 6Insitute of Pathology, University Hospital Basel, Basel/Switzerland, 7 Pneumology, Cantonal Hospital St. Gallen, St. Gallen/ Switzerland, 8Medical Oncology, Hfr Fribourg-Hôpital Cantonal, Fribourg/Switzerland, 9Medical Oncology, Cantonal Hospital St. Gallen, St. Gallen/Switzerland, 10 Clinic for Oncology, University Hospital Zurich, Zurich/ Switzerland, 11Medizinische Onkologie; Dpt. Innere Medizin, Cantonal Hospital Graubünden, Chur/ Switzerland, 12Medical Oncology, Regional Hospital Thun, Thun/Switzerland, 13Medizinische Onkologie, Cantonal Hospital Winterthur, Winterthur/Switzerland, 14Medical Oncology, University Hospital Bern, Bern/Switzerland Background: Bevacizumab (Bev) is a monoclonal antibody against the vascular endothelial growth factor. No predictive biomarkers for the use of Bev have been established so far. We aim to find out the candidates of predictive genes for progression-free survival (PFS) and overall survival (OS) using baseline tumor samples of patients treated in the trial SAKK19/ 09 (NCT01116219). Methods: SAKK19/09 was a non-randomized phase II trial with two sequential cohorts including patients with non-squamous NSCLC and EGFR wild-type. In
Abstracts
S1471
Cohort 1, 77 patients were treated with 4 cycles of cisplatin (C) 75mg/m2, pemetrexed (Pem) 500mg/m2 and Bev 7.5mg/kg, followed by Bev+Pem maintenance. Cohort 2 included 52 patients treated with C+Pem followed by Pem maintenance. RNA was isolated from tumor tissue sections and processed for gene expression analysis by Nanostring. Expression values were normalized using 4 control genes. For each gene, treatment and the interaction of these two, a Cox regression was performed with normalized gene expression divided by its interquartile range for PFS and OS. No adjustment for multiple testing was done. Results:
HR (95% CI) Gene
Cohort 1
Cohort 2
interaction p-value
Numb RPA3 CDC25A PRF1 TNFSF14 CDC34 VEGFA ERCC8 HGF TRAF2 CDC6 GZMB ERCC6 AURKB ANGPT1
0.98 1.97 2.54 0.99 0.98 1.02 1.03 1.00 1.21 1.04 1.29 1.07 0.92 1.29 1.31
0.07 0.98 0.99 0.40 1.32 0.36 0.55 0.42 0.51 0.36 0.91 0.65 0.36 0.66 0.85
0.002 0.005 0.006 0.016 0.023 0.026 0.027 0.028 0.032 0.034 0.041 0.043 0.047 0.047 0.048
(0.81-1.18) (1.29-3.00) (1.29-4.97) (0.87-1.13) (0.95-1.03) (0.79-1.33) (0.94-1.12) (0.83-1.22) (1.01-1.47) (0.88-1.24) (1.11-1.51) (0.90-1.27) (0.66-1.30) (1.01-1.63) (1.13-1.51)
(0.01-0.40) (0.86-1.11) (0.95-1.04) (0.18-0.89) (0.99-1.75) (0.15-0.90) (0.31-0.96) (0.18-0.96) (0.23-1.14) (0.13-0.99) (0.68-1.23) (0.39-1.07) (0.13-0.99) (0.34-1.28) (0.57-1.27)
We analyzed 109 patient samples (63 in Cohort 1; 46 in Cohort 2) with 201 genes assessed at baseline. We found 6 genes potentially predicting PFS (BTLA, CDC25A, FLT1, MSH4, RPA3, TCF7). Regarding to OS we found a significant effect of interaction for 3 angiogenesis-related genes (ANGPT2, HGF, VEGFA) and 12 other genes (Table 1). Several of these 12 genes (AURKB, CDC25A, CDC34, CDC6, ERCC6/8, RPA3) have previously been shown to play an important role in DNA repair and cell cycle regulation supporting the hypothesis that Bev improves chemotherapy activity. Additionally, ANGPT2, HGF and VEGFA directly involved in angiogenesis are also predictive. Conclusion: We identified several potentially predictive genes for Bev activity in combination with chemotherapy. Further work is ongoing to explore changes in gene expression using tumor rebiopsies at progression. Keywords: VEGFA, HGF, Gene Expression, bevacizumab