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Association of ERCC1 gene expression with outcome in stage II-III esophageal adenocarcinoma patients treated with preoperative platinum-based chemoradiation in a phase II cooperative group study (SWOG S0356). P. Bohanes1, B. H. Goldman2, J. K. Benedetti2, C. Blanke3, L. P. Leichman4, S. Iqbal1, C. R. Thomas5, C. L. Corless5, K. G. Billingsley5, K. D. Danenberg6, P. J. Gold7, and H.J. Lenz1 1University of Southern California, Los Angeles, CA; 2SWOG Statistical Center, Seattle WA; 3University of British Columbia Vancouver, BC, Canada; 4Desert Regional Medical Center, Palm Springs, CA; 5Oregon Health and Science University, Portland, OR; 6Response Genetics, Inc, Los Angeles, CA; 7Swedish Cancer Institute, Seattle, WA Author’s Disclosures P. Bohanes: None B.H. Goldman: None L. Leichman: None C. Blanke: Sanofi-Aventis S. Iqbal: Sanofi-Aventis C.R. Thomas: None C.L. Corless: None J.K. Benedetti: None K.G. Billingsley: None K.D. Danenberg: Response Genetics P. Gold: None H.J. Lenz: Sanofi-Aventis, Response Genetics Background There is no worldwide accepted standard treatment for locally advanced esophageal adenocarcinoma. ◦ Neoadjuvant chemo-radiation prior to surgery is one of the accepted treatment strategies ◦ Platinum agents are often used as the chemotherapy backbone for patients treated with trimodality therapy In contrast to the growing number of predictive biomarkers for anti-cancer agents, there are no established biomarkers to select patients who will benefit most from chemo-radiation. Utilization of predictive biomarkers to select therapy should lead to higher cure rates. Background – ERCC1 ERCC1 has been shown to be a critical gene in DNA repair ◦ NER pathway - recognizes and removes platinum-induced DNA adducts ◦ DSBR pathway- repairs radiation-induced damage (Bohanes et al. Clin Colorectal Cancer. In Press; Ahmad et al. Moll Cell Biol 2008) A prospective clinical trial demonstrated in advanced NSCLC that customized therapy based on ERCC1 mRNA levels increased the response rate to cisplatin-based chemotherapy administered to patients with low ERCC1 mRNA levels (Cobo et al. J Clin Oncol 2007) ERCC1 down-regulation sensitizes cells to all platinum compounds 90 80 Cell viability (%) 70 60 50 control 40 siRNA 30 20 10 0 Cisplatin (4 uM) Oxaliplatin (2 uM) Carboplatin (20 uM) Youn et al. Cancer Res 2004 Tumor ERCC1 mRNA Levels Type of Cancer NSCLC Colorectal Esophageal Median Value 1.65 1.15 1.92 Range 0.14-13.4 0.34-4.66 0.33-5.29 % with low expression 57% 78% 42% References Cobo et al. JCO.2007 Lenz et al. ASCO. 2008 Current study ERCC1 in Gastrointestinal Malignancies Author Tumor Setting Patients Cutoff Results Shirota et al. J Clin Oncol 2001 Colorectal FOLFOX 50 > 1.7 x 10-3 OS Lenz et al. ASCO 2008 Colorectal FOLFOX 191 > 1.7 x 10-3 RR, OS Uchida et al. BMC Cancer 2006 Colorectal Oxaliplatin + capecitabine 91 > 3.4 x 10-3 TTR Metzger et al. J Clin Oncol 1998 Gastric Cisplatin + 5-FU 38 > 1.46 x 10-3 OS Wei et al. Br J Cancer 2008 Gastric FOLFOX 76 > 2.2 x 10-3 OS Langer et al. Clin Cancer Res 2008 Esophageal Cisplatin + 5-FU ± Paclitaxel 38 -- NS for RR Warnecke-Eberz et al. Clin Cancer Res 2004 Esophageal Oxaliplatin + 5FU + EBRT 36 > 1.1 x 10-3 RR Joshi et al. Clin Cancer Res 2005 Esophageal Cisplatin + 5-FU + EBRT 99 > 3.0 x 10-3 OS ERCC1 in Gastrointestinal Malignancies Author Tumor Setting Patients Cutoff Results Shirota et al. J Clin Oncol 2001 Colorectal FOLFOX 50 > 1.7 x 10-3 OS Lenz et al. ASCO 2008 Colorectal FOLFOX 191 > 1.7 x 10-3 RR, OS Uchida et al. BMC Cancer 2006 Colorectal Oxaliplatin + capecitabine 91 > 3.4 x 10-3 TTR Metzger et al. J Clin Oncol 1998 Gastric Cisplatin + 5-FU 38 > 1.46 x 10-3 OS Wei et al. Br J Cancer 2008 Gastric FOLFOX 76 > 2.2 x 10-3 OS Langer et al. Clin Cancer Res 2008 Esophageal Cisplatin + 5-FU ± Paclitaxel 38 -- NS for RR Warnecke-Eberz et al. Clin Cancer Res 2004 Esophageal Oxaliplatin + 5FU + EBRT 36 > 1.1 x 10-3 RR Joshi et al. Clin Cancer Res 2005 Esophageal Cisplatin + 5-FU + EBRT 99 > 3.0 x 10-3 OS ERCC1 in Gastrointestinal Malignancies Author Tumor Setting Patients Cutoff Results Shirota et al. J Clin Oncol 2001 Colorectal FOLFOX 50 > 1.7 x 10-3 OS Lenz et al. ASCO 2008 Colorectal FOLFOX 191 > 1.7 x 10-3 RR, OS Uchida et al. BMC Cancer 2006 Colorectal Oxaliplatin + capecitabine 91 > 3.4 x 10-3 TTR Metzger et al. J Clin Oncol 1998 Gastric Cisplatin + 5-FU 38 > 1.46 x 10-3 OS Wei et al. Br J Cancer 2008 Gastric FOLFOX 76 > 2.2 x 10-3 OS Langer et al. Clin Cancer Res 2008 Esophageal Cisplatin + 5-FU ± Paclitaxel 38 -- NS for RR Warnecke-Eberz et al. Clin Cancer Res 2004 Esophageal Oxaliplatin + 5FU + EBRT 36 > 1.1 x 10-3 RR Joshi et al. Clin Cancer Res 2005 Esophageal Cisplatin + 5-FU + EBRT 99 > 3.0 x 10-3 OS ERCC1 in Gastrointestinal Malignancies Author Tumor Setting Patients Cutoff Results Shirota et al. J Clin Oncol 2001 Colorectal FOLFOX 50 > 1.7 x 10-3 OS Lenz et al. ASCO 2008 Colorectal FOLFOX 191 > 1.7 x 10-3 RR, OS Uchida et al. BMC Cancer 2006 Colorectal Oxaliplatin + capecitabine 91 > 3.4 x 10-3 TTR Metzger et al. J Clin Oncol 1998 Gastric Cisplatin + 5-FU 38 > 1.46 x 10-3 OS Wei et al. Br J Cancer 2008 Gastric FOLFOX 76 > 2.2 x 10-3 OS Langer et al. Clin Cancer Res 2008 Esophageal Cisplatin + 5-FU ± Paclitaxel 38 -- NS for RR Warnecke-Eberz et al. Clin Cancer Res 2004 Esophageal Oxaliplatin + 5FU + EBRT 36 > 1.1 x 10-3 RR Joshi et al. Clin Cancer Res 2005 Esophageal Cisplatin + 5-FU + EBRT 99 > 3.0 x 10-3 OS ERCC1 in Gastrointestinal Malignancies Author Tumor Setting Patients Cutoff Results Shirota et al. J Clin Oncol 2001 Colorectal FOLFOX 50 > 1.7 x 10-3 OS Lenz et al. ASCO 2008 Colorectal FOLFOX 191 > 1.7 x 10-3 RR, OS Uchida et al. BMC Cancer 2006 Colorectal Oxaliplatin + capecitabine 91 > 3.4 x 10-3 TTR Metzger et al. J Clin Oncol 1998 Gastric Cisplatin + 5-FU 38 > 1.46 x 10-3 OS Wei et al. Br J Cancer 2008 Gastric FOLFOX 76 > 2.2 x 10-3 OS Langer et al. Clin Cancer Res 2008 Esophageal Cisplatin + 5-FU ± Paclitaxel 38 -- NS for RR Warnecke-Eberz et al. Clin Cancer Res 2004 Esophageal Oxaliplatin + 5FU + EBRT 36 > 1.1 x 10-3 RR Joshi et al. Clin Cancer Res 2005 Esophageal Cisplatin + 5-FU + EBRT 99 > 3.0 x 10-3 OS Main Objective To validate prospectively ERCC1 gene expression (predefined cutoff of 1.7) as a biomarker predicting outcome in patients treated with oxaliplatin-based chemotherapy in combination with radiation in the SWOG S0356 trial. Secondary Objectives To explore the association between outcome and : ◦ Other baseline mRNA levels of genes involved in DNA repair (XPD, RRM1) and 5-FU metabolism (TS, TP, DPD and GSTP1) ◦ Functional polymorphisms in genes involved in DNA repair (ERCC1, XPD, RAD51, XRCC1, XRCC3) and 5-FU metabolism (TS, MTHFR, GSTP1) SWOG S0356 Treatment Design Tumor biopsy D1 D8 D15 D22 D29 D36 D43 D22 D29 D36 D43 CTX + EBRT Surgery CTX D1 D8 OHP 85 mg/m2 D15 PI 5FU 180 mg/m2/day Inclusion Criteria Esophageal or gastroesophageal junction adenocarcinoma ◦ Patients > 18 years ◦ Clinical stage II or III; Zubrod PS ≤ 2 ◦ Endoscopic ultrasound only for tumors that do not form a clear mass on CT scan ◦ Pre-tx PET scans mandatory ◦ Thoracic esophagus or gastroesophageal junction ◦ Tumors < 2 cm into the gastric cardia (Siewert I-II) ◦ Standard hematologic/non-hematologic parameters Patient Characteristics N=92 February 2005 to August 2008 98 patients registered 6 ineligible patients* 92 eligible for clinical outcome evaluation and this study Median Age (range) 62.0 (41.6-83.1) Gender Male Female 86 (93%) 6 (7%) Race White Other Missing 85 (96%) 4 (4%) 3 Performance Status 0/1 Missing 54/37 (59%/41%) 1 Primary Site Esophagus GE Junction Missing *2 squamous tumors, 2 met disease, 2 with biopsy/scans performed >28 days from protocol entry 54 (60%) 36 (40%) 2 Pathologic Response 26 (28.2%) patients = pCR (centrally confirmed) 10 patients had either Tin situ N0M0 or T1N0M0 Leichman et al. Annual Meeting of the ASTRO, San Diego, 2010 Progression-Free Survival (PFS) 100% 80% N 60% 92 Events 55 Median in Months 20.8 2-year PFS 40% 45.6% 20% 0% 0 2 4 Years After Registration 6 Overall Survival (OS) 100% N 92 80% 60% Events 47 Median in Months 33.7 2-year OS 40% 55.4% 20% 0% 0 2 4 Years After Registration 6 Median follow-up of 36.8 months Leichman et al. Annual Meeting of the ASTRO, San Diego, 2010 Gene Expression RNA Extracted RNA Laser Capture Micro-dissection Reverse Transcription cDNA PCR with TaqMan® Data Analysis Statistical Considerations Cox regression used for univariate analyses of biomarker association with outcome ◦ Adjustment for baseline factors did not affect any results Recursive partitioning used to look for optimal cut points for continuous markers ◦ Also used for building “regression trees” ◦ P values adjusted for the multiple comparisons implied by this technique Genes Analyzed for mRNA Levels 92 patients -> 90 pre-treatment samples -> 55 with sufficient tumor tissue Genes Number of patients Median expression level (Range) GSTP1 55 1.61 (0.52-8.73) ERCC1 53 1.92 (0.33-5.29) TP 52 8.93 (1.36-38.45) TS 50 3.32 (0.92-8.62) DPD 39 0.57 (0-2.22) RRM1 26 1.75 (0.35-5.81) XPD 19 1.88 (0.76-3.60) Overall (N=92) Gene Expression Dataset (N=55) 62.0 (41.6-83.1) 63.9 (43.6-83.1) Gender Male Female 86 (93%) 6 (7%) 51 (93%) 4 (7%) Race White Other Missing 85 (96%) 4 (4%) 3 51 (94%) 3 (6%) 1 54/37 (59%/41%) 1 34/21 (62%/38%) 0 Primary Site Esophagus GE Junction Missing 54 (60%) 36 (40%) 2 34 (62%) 21 (38%) 0 pCR 26 (28%) 14 (25%) Median age (range) Performance status 0/1 Missing PFS by ERCC1 mRNA Levels 100% ≤1.7 >1.7 80% N 22 31 Median 2-year PFS HR (95% CI) NR 67% 1.0 (ref) 14.8 mos 17% 2.97 (1.37-6.45) p* 0.0058 60% 40% Median follow-up of 36.8 months 20% 0% 0 1 2 3 Years After Registration 4 5 OS by ERCC1 mRNA Levels 100% ≤ 1.7 > 1.7 N Median 22 31 NR 22.4 mos 2-year OS 72% 37% p* HR (95% CI) 1.0 (ref) 2.32 (1.01-5.31) 0.047 80% 60% 40% Median follow-up of 36.8 months 20% 0% 0 1 2 3 Years After Registration 4 5 Other Results An analysis of PFS using a recursive partitioning model found the optimal split for ERCC1 gene expression to be 1.66 (adjusted p=0.04). ERCC1 mRNA levels were not associated with pCR None of the other accessed mRNA levels were associated with outcome (either univariate or in recursive partitioning) ◦ DNA-repair: XPD, RRM1 ◦ Platinum detoxification: GSTP1 ◦ 5-FU metabolism: TS, TP, DPD Genotyping DNA was extracted from blood (Qiagen, CA, USA). Genotyping was performed by using PCR-RFLP technique. Performed in 91 patients (out of 92 eligible) ERCC1 118C>T MTHFR 677C>T ERCC1 8092C>A MTHFR 1298A>C GSTP1 Ile105Val TS 3’UTR 6bp+/6bp- RAD51 135G>C TS 5’UTR VNTR XPD 156A>C TS 5’UTR G/C SNP XPD Lys751Gln XRCC1 Arg391Gln XRCC3 Thr241Met None are significant after adjusting for multiple comparisons Summary In this trial, using oxaliplatin and protracted-infusion 5FU with radiation, low intratumoral ERCC1 from the primary esophageal cancer predicted for PFS and OS. Pre-established ERCC1 mRNA cutoff of 1.7 was confirmed in this trial. This pre-specified cutoff was further validated by using recursive partitioning (optimal cutoff of 1.66). Genomic polymorphisms analyzed were not associated with outcome in this study. Study Limitations Small sample size. Lack of sufficient tumor tissue collection. No differentiation between clinical stage II and clinical stage III patients Conclusions ERCC1 mRNA level is a very promising pre-treatment biomarker in patients with localized esophageal and gastroesophageal adenocarcinoma treated with trimodality treatment. Biomarker studies are feasible within cooperative groups. Based on these and published data, the SWOG is planning a prospective biomarker-driven clinical trial. Acknowledgments The patients and their families and Investigators who participated in SWOG S0356 Response Genetics: Kathleen D. Danenberg. SWOG Statistical Center: Bryan Goldman. Funded by SWOG award 5-U10-CA058882-18 Pierre Bohanes was partially funded by Cancer & Solidarité Fondation