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Association of ERCC1 gene expression with outcome in stage II-III esophageal adenocarcinoma patients treated with preoperative platinum-based chemoradiation.

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Presentation on theme: "Association of ERCC1 gene expression with outcome in stage II-III esophageal adenocarcinoma patients treated with preoperative platinum-based chemoradiation."— Presentation transcript:

1 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. Bohanes 1, B. H. Goldman 2, J. K. Benedetti 2, C. Blanke 3, L. P. Leichman 4, S. Iqbal 1, C. R. Thomas 5, C. L. Corless 5, K. G. Billingsley 5, K. D. Danenberg 6, P. J. Gold 7, and H.J. Lenz 1 1 University of Southern California, Los Angeles, CA; 2 SWOG Statistical Center, Seattle WA; 3 University of British Columbia Vancouver, BC, Canada; 4 Desert Regional Medical Center, Palm Springs, CA; 5 Oregon Health and Science University, Portland, OR; 6 Response Genetics, Inc, Los Angeles, CA; 7 Swedish Cancer Institute, Seattle, WA

2 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

3 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.

4 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)

5 Cell viability (%) ERCC1 down-regulation sensitizes cells to all platinum compounds Youn et al. Cancer Res 2004

6 Tumor ERCC1 mRNA Levels Type of CancerNSCLCColorectalEsophageal Median Value Range % with low expression 57%78%42% References Cobo et al. JCO.2007 Lenz et al. ASCO Current study

7 AuthorTumorSettingPatientsCutoffResults Shirota et al. J Clin Oncol 2001 ColorectalFOLFOX50> 1.7 x  OS Lenz et al. ASCO 2008 ColorectalFOLFOX191> 1.7 x  RR,  OS Uchida et al. BMC Cancer 2006 Colorectal Oxaliplatin + capecitabine 91> 3.4 x  TTR Metzger et al. J Clin Oncol 1998 GastricCisplatin + 5-FU38> 1.46 x  OS Wei et al. Br J Cancer 2008 GastricFOLFOX76> 2.2 x  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  RR Joshi et al. Clin Cancer Res 2005 Esophageal Cisplatin + 5-FU + EBRT 99> 3.0 x  OS ERCC1 in Gastrointestinal Malignancies

8 AuthorTumorSettingPatientsCutoffResults Shirota et al. J Clin Oncol 2001 ColorectalFOLFOX50> 1.7 x  OS Lenz et al. ASCO 2008 ColorectalFOLFOX191> 1.7 x  RR,  OS Uchida et al. BMC Cancer 2006 Colorectal Oxaliplatin + capecitabine 91> 3.4 x  TTR Metzger et al. J Clin Oncol 1998 GastricCisplatin + 5-FU38> 1.46 x  OS Wei et al. Br J Cancer 2008 GastricFOLFOX76> 2.2 x  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  RR Joshi et al. Clin Cancer Res 2005 Esophageal Cisplatin + 5-FU + EBRT 99> 3.0 x  OS ERCC1 in Gastrointestinal Malignancies

9 AuthorTumorSettingPatientsCutoffResults Shirota et al. J Clin Oncol 2001 ColorectalFOLFOX50> 1.7 x  OS Lenz et al. ASCO 2008 ColorectalFOLFOX191> 1.7 x  RR,  OS Uchida et al. BMC Cancer 2006 Colorectal Oxaliplatin + capecitabine 91> 3.4 x  TTR Metzger et al. J Clin Oncol 1998 GastricCisplatin + 5-FU38> 1.46 x  OS Wei et al. Br J Cancer 2008 GastricFOLFOX76> 2.2 x  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  RR Joshi et al. Clin Cancer Res 2005 Esophageal Cisplatin + 5-FU + EBRT 99> 3.0 x  OS ERCC1 in Gastrointestinal Malignancies

10 AuthorTumorSettingPatientsCutoffResults Shirota et al. J Clin Oncol 2001 ColorectalFOLFOX50> 1.7 x  OS Lenz et al. ASCO 2008 ColorectalFOLFOX191> 1.7 x  RR,  OS Uchida et al. BMC Cancer 2006 Colorectal Oxaliplatin + capecitabine 91> 3.4 x  TTR Metzger et al. J Clin Oncol 1998 GastricCisplatin + 5-FU38> 1.46 x  OS Wei et al. Br J Cancer 2008 GastricFOLFOX76> 2.2 x  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  RR Joshi et al. Clin Cancer Res 2005 Esophageal Cisplatin + 5-FU + EBRT 99> 3.0 x  OS ERCC1 in Gastrointestinal Malignancies

11 AuthorTumorSettingPatientsCutoffResults Shirota et al. J Clin Oncol 2001 ColorectalFOLFOX50> 1.7 x  OS Lenz et al. ASCO 2008 ColorectalFOLFOX191> 1.7 x  RR,  OS Uchida et al. BMC Cancer 2006 Colorectal Oxaliplatin + capecitabine 91> 3.4 x  TTR Metzger et al. J Clin Oncol 1998 GastricCisplatin + 5-FU38> 1.46 x  OS Wei et al. Br J Cancer 2008 GastricFOLFOX76> 2.2 x  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  RR Joshi et al. Clin Cancer Res 2005 Esophageal Cisplatin + 5-FU + EBRT 99> 3.0 x  OS ERCC1 in Gastrointestinal Malignancies

12 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.

13 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) Secondary Objectives

14 SWOG S0356 Treatment Design Tumor biopsy Surgery CTX + EBRT CTX D1 D8D15D22D29D36D43 D1 D8D15D22D29D36D43 OHP 85 mg/m 2 PI 5FU 180 mg/m 2 /day

15 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

16 Patient Characteristics N=92 Median Age (range)62.0 ( ) 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 54 (60%) 36 (40%) 2 February 2005 to August patients registered 92 eligible for clinical outcome evaluation and this study 6 ineligible patients* *2 squamous tumors, 2 met disease, 2 with biopsy/scans performed >28 days from protocol entry

17 Pathologic Response 26 (28.2%) patients = pCR (centrally confirmed) 10 patients had either T in situ N0M0 or T1N0M0 Leichman et al. Annual Meeting of the ASTRO, San Diego, 2010

18 2-year PFS 45.6% 2-year OS 55.4% Median follow-up of 36.8 months Leichman et al. Annual Meeting of the ASTRO, San Diego, 2010

19 Gene Expression RNA Extracted Reverse Transcription PCR with TaqMan ® Data Analysis RNA cDNA Laser Capture Micro-dissection

20 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

21 Genes Analyzed for mRNA Levels GenesNumber of patientsMedian expression level (Range) GSTP ( ) ERCC ( ) TP ( ) TS ( ) DPD (0-2.22) RRM ( ) XPD ( ) 92 patients -> 90 pre-treatment samples -> 55 with sufficient tumor tissue

22 Overall (N=92) Gene Expression Dataset (N=55) Median age (range)62.0 ( ) 63.9 ( ) 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 Performance status 0/1 Missing 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 pCR26 (28%)14 (25%)

23 PFS by ERCC1 mRNA Levels 0% 20% 40% 60% 80% 100% Years After Registration >1.7 ≤1.7 N Median 14.8 mos NR 2-year PFS 17% 67% HR (95% CI) 2.97 ( ) 1.0 (ref) p* Median follow-up of 36.8 months

24 OS by ERCC1 mRNA Levels > 1.7 ≤ 1.7 N Median 22.4 mos NR 2-year OS 37% 72% HR (95% CI) 2.32 ( ) 1.0 (ref) p* Median follow-up of 36.8 months

25 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

26 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 ERCC1 8092C>A GSTP1 Ile105Val RAD51 135G>C XPD 156A>C XPD Lys751Gln XRCC1 Arg391Gln XRCC3 Thr241Met MTHFR 677C>T MTHFR 1298A>C TS 3’UTR 6bp+/6bp- TS 5’UTR VNTR TS 5’UTR G/C SNP None are significant after adjusting for multiple comparisons

27 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.

28 Study Limitations Small sample size. Lack of sufficient tumor tissue collection. No differentiation between clinical stage II and clinical stage III patients

29 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.

30 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-CA Pierre Bohanes was partially funded by Cancer & Solidarité Fondation


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