author’s disclosures

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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. 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

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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). - PowerPoint PPT Presentation

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Page 1: Author’s Disclosures

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

Page 2: Author’s Disclosures

Author’s Disclosures

P. Bohanes: NoneB.H. Goldman: NoneL. Leichman: NoneC. Blanke: Sanofi-AventisS. Iqbal: Sanofi-AventisC.R. Thomas: NoneC.L. Corless: NoneJ.K. Benedetti: NoneK.G. Billingsley: NoneK.D. Danenberg: Response Genetics P. Gold: NoneH.J. Lenz: Sanofi-Aventis, Response Genetics

Page 3: Author’s Disclosures

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.

Page 4: Author’s Disclosures

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)

Page 5: Author’s Disclosures

Cisplatin (4 uM) Oxaliplatin (2 uM) Carboplatin (20 uM)

0102030405060708090

controlsiRNA

Cell

viab

ility

(%)

ERCC1 down-regulation sensitizes cells to all platinum compounds

Youn et al. Cancer Res 2004

Page 6: Author’s Disclosures

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

Page 7: Author’s Disclosures

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,

OSUchida et al.

BMC Cancer 2006Colorect

alOxaliplatin + 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

2008Esophag

ealCisplatin +

5-FU ± Paclitaxel

38 -- NS for RR

Warnecke-Eberz et al. Clin Cancer

Res 2004Esophag

ealOxaliplatin + 5FU + EBRT 36 > 1.1 x

10-3 RR

Joshi et al. Clin Cancer Res

2005Esophag

ealCisplatin +

5-FU+ EBRT

99 > 3.0 x 10-3 OS

ERCC1 in Gastrointestinal Malignancies

Page 8: Author’s Disclosures

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,

OSUchida et al.

BMC Cancer 2006Colorect

alOxaliplatin + 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

2008Esophag

ealCisplatin +

5-FU ± Paclitaxel

38 -- NS for RR

Warnecke-Eberz et al. Clin Cancer

Res 2004Esophag

ealOxaliplatin + 5FU + EBRT 36 > 1.1 x

10-3 RR

Joshi et al. Clin Cancer Res

2005Esophag

ealCisplatin +

5-FU+ EBRT

99 > 3.0 x 10-3 OS

ERCC1 in Gastrointestinal Malignancies

Page 9: Author’s Disclosures

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,

OSUchida et al.

BMC Cancer 2006Colorect

alOxaliplatin + 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

2008Esophag

ealCisplatin +

5-FU ± Paclitaxel

38 -- NS for RR

Warnecke-Eberz et al. Clin Cancer

Res 2004Esophag

ealOxaliplatin + 5FU + EBRT 36 > 1.1 x

10-3 RR

Joshi et al. Clin Cancer Res

2005Esophag

ealCisplatin +

5-FU+ EBRT

99 > 3.0 x 10-3 OS

ERCC1 in Gastrointestinal Malignancies

Page 10: Author’s Disclosures

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,

OSUchida et al.

BMC Cancer 2006Colorect

alOxaliplatin + 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

2008Esophag

ealCisplatin +

5-FU ± Paclitaxel

38 -- NS for RR

Warnecke-Eberz et al. Clin Cancer

Res 2004Esophag

ealOxaliplatin + 5FU + EBRT 36 > 1.1 x

10-3 RR

Joshi et al. Clin Cancer Res

2005Esophag

ealCisplatin +

5-FU+ EBRT

99 > 3.0 x 10-3 OS

ERCC1 in Gastrointestinal Malignancies

Page 11: Author’s Disclosures

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,

OSUchida et al.

BMC Cancer 2006Colorect

alOxaliplatin + 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

2008Esophag

ealCisplatin +

5-FU ± Paclitaxel

38 -- NS for RR

Warnecke-Eberz et al. Clin Cancer

Res 2004Esophag

ealOxaliplatin + 5FU + EBRT 36 > 1.1 x

10-3 RR

Joshi et al. Clin Cancer Res

2005Esophag

ealCisplatin +

5-FU+ EBRT

99 > 3.0 x 10-3 OS

ERCC1 in Gastrointestinal Malignancies

Page 12: Author’s Disclosures

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.

Page 13: Author’s Disclosures

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

Page 14: Author’s Disclosures

SWOG S0356 Treatment Design

Tumor biopsy

Surgery

CTX + EBRT

CTX

D1 D8 D15 D22 D29 D36 D43

D1 D8 D15 D22 D29 D36 D43

OHP 85 mg/m2PI 5FU 180 mg/m2/dayEBRT 180 cGy/day

Page 15: Author’s Disclosures

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

Page 16: Author’s Disclosures

Patient CharacteristicsN=92

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

 54 (60%)36 (40%)

2

February 2005 to August 2008

98 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

Page 17: Author’s Disclosures

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

Page 18: Author’s Disclosures

Overall Survival (OS)

0%

20%

40%

60%

80%

100%

0 2 4 6Years After Registration

N92

Events47

Median in Months33.7

Progression-Free Survival (PFS)

0%

20%

40%

60%

80%

100%

0 2 4 6Years After Registration

92N Events

55Median in Months

20.8

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

Page 19: Author’s Disclosures

Gene Expression

RNA Extracted

Reverse Transcription

PCR with TaqMan®

Data Analysis

RNA

cDNA

Laser Capture Micro-dissection

Page 20: Author’s Disclosures

Statistical ConsiderationsCox 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

Page 21: Author’s Disclosures

Genes Analyzed for mRNA Levels

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)

92 patients -> 90 pre-treatment samples -> 55 with sufficient tumor tissue

Page 22: Author’s Disclosures

Overall (N=92)

Gene Expression Dataset (N=55)

Median age (range)

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

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 pCR 26 (28%) 14 (25%)

Page 23: Author’s Disclosures

PFS by ERCC1 mRNA Levels

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5Years After Registration

>1.7≤1.7

N

3122

Median

14.8 mosNR

2-year PFS

17%67%

HR (95% CI)

2.97 (1.37-6.45)1.0 (ref)

p*

0.0058

Median follow-up of 36.8 months

Page 24: Author’s Disclosures

OS by ERCC1 mRNA Levels

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5Years After Registration

> 1.7≤ 1.7

N

3122

Median

22.4 mosNR

2-year OS

37%72%

HR (95% CI)

2.32 (1.01-5.31)1.0 (ref)

p*

0.047

Median follow-up of 36.8 months

Page 25: Author’s Disclosures

Other ResultsAn 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

Page 26: Author’s Disclosures

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

Page 27: Author’s Disclosures

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.

Page 28: Author’s Disclosures

Study Limitations

Small sample size.

Lack of sufficient tumor tissue collection.

No differentiation between clinical stage II and clinical stage III patients

Page 29: Author’s Disclosures

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.

Page 30: Author’s Disclosures

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-CA058882-18Pierre Bohanes was partially funded by Cancer & Solidarité Fondation