Clinical Cancer Research Targets Metabolism
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Warnecke-Eberz, U.
Right arrow Articles by Schneider, P. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Warnecke-Eberz, U.
Right arrow Articles by Schneider, P. M.
Clinical Cancer Research Vol. 10, 3794-3799, June 1, 2004
© 2004 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

High Specificity of Quantitative Excision Repair Cross-Complementing 1 Messenger RNA Expression for Prediction of Minor Histopathological Response to Neoadjuvant Radiochemotherapy in Esophageal Cancer

Ute Warnecke-Eberz1, Ralf Metzger1, Futoshi Miyazono1,5, Stephan E. Baldus3, Susanne Neiss1, Jan Brabender1, Hartmut Schaefer1, Walter Doerfler4, Elfriede Bollschweiler1, Hans P. Dienes3, Rolf P. Mueller2, Peter V. Danenberg6, Arnulf H. Hoelscher1 and Paul M. Schneider1

Departments of 1 Visceral and Vascular Surgery and 2 Radiation-Oncology and Institutes of 3 Pathology and 4 Genetics, University of Cologne, Cologne, Germany; 5 First Department of Surgery, Kagoshima University School of Medicine, Kagoshima, Japan; and 6 Department of Biochemistry and Molecular Biology, University of Southern California School of Medicine and Norris Comprehensive Cancer Center, Los Angeles, California


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: The excision repair cross-complementing 1 (ERCC1) gene is coding for a nucleotide excision repair protein involved in the repair of radiation- and chemotherapy-induced DNA damage. We examined the potential of quantitative ERCC1 mRNA expression to predict minor or major histopathological response to neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil, and 36 Gy of radiation) followed by transthoracic en bloc esophagectomy in patients with locally advanced esophageal cancer (cT2–4, Nx, M0).

Experimental Design: Tissue samples were collected by endoscopic biopsy before treatment. RNA was isolated from biopsies, and quantitative real-time reverse transcriptase PCR assays were performed to determine ERCC1 mRNA expression. Relative mRNA levels (tumor/normal ratios) were calculated as (ERCC1/ß-actin in tumor)/(ERCC1/ß-actin in paired normal tissue). ERCC1 expression levels were correlated with the objective histopathological response in resected specimens. Histomorphological regression was defined as major response when resected specimens contained <10% of residual vital tumor cells or in case a pathologically complete response was achieved.

Results: Twelve of 36 tumors showed a major histopathological response, and 24 of 36 showed a minor histopathological response. Relative expression levels of ERCC1 of >1.09 were not associated with a major histopathological response (sensitivity, 62.5%; specificity, 100%) and 15 of 24 patients with minor histopathological response to the delivered neoadjuvant radiochemotherapy could be unequivocally identified. This association of dichotomized relative ERCC1 mRNA expression and histopathological response was statistically significant (P < 0.001).

Conclusions: Relative expression levels of ERCC1 mRNA determined by quantitative real-time reverse transcriptase-PCR appear highly specific to predict minor response to our neoadjuvant radiochemotherapy protocol in patients with locally advanced esophageal cancer and could be applied to prevent expensive, noneffective, and potentially harmful therapies in a substantial number (42%) of patients.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Patients with locally advanced esophageal cancer have a dismal prognosis when treated exclusively by surgery. This fact prompted many investigators to apply neoadjuvant treatment strategies in an effort to improve survival (1) . Results from Phase III randomized trials are encouraging; however, they revealed that only patients with major histopathological response will finally benefit from treatment (2, 3, 4) . In addition, these therapies are expensive and potentially harmful with increased therapy-associated complication rates (5) . Therefore, predictive molecular markers indicating response or nonresponse to neoadjuvant treatment would be extremely helpful in selecting patients for future treatment protocols.

The nucleotide excision repair pathway is one of the most important pathways that guards the integrity of the genome, removing a wide variety of DNA lesions including interstrand cross-links caused by cisplatin (CDDP) or radiation (6 , 7) . Removal of these adducts from genomic DNA is mediated by a complex interaction of various proteins (8 , 9) . A critical step in this process is the interaction of the product of the excision repair cross-complementing 1 (ERCC1) gene with XPA and XPF (10) .

Metzger et al. (11) have reported increased ERCC1 mRNA expression as an indicator for nonresponse to neoadjuvant CDDP-based chemotherapy (CDDP, leucovorin, and 5-fluorouracil) for gastric cancer. A correlation of increased ERCC1 expression with nonresponse and/or survival has also been reported recently for colon cancer (12) and non-small cell lung cancer (13) .

The purpose of this prospective study was to investigate the potential of quantitative ERCC1 mRNA expression to predict a minor or major histopathological response to neoadjuvant therapy with CDDP, 5-fluorouracil, and simultaneous radiation (36 Gy) in locally advanced, resectable esophageal cancers.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Population, Demographic Data, and Neoadjuvant Therapy.
All patients were recruited from an ongoing clinical trial on neoadjuvant radiochemotherapy for esophageal cancer during the period between August 2001 and August 2003. None of the patients had prior radio- and/or chemotherapy.

Thirty-nine consecutive patients (median age, 60 years; age range, 29–72 years; gender, 30 men and 9 women) with locally advanced, resectable esophageal cancers (cT2–4, Nx, M0) in good general health with an Eastern Cooperative Oncology Group performance status of 0–1 and normal to moderate risk factors for esophageal surgery (14) were offered standardized neoadjuvant radiochemotherapy. Clinical staging was based on a barium swallow, endoscopic ultrasound, and computed tomography of chest and abdomen. Diagnostic laparoscopy was performed in all patients with adenocarcinomas to exclude peritoneal carcinomatosis. CDDP (20 mg/m2/day) was administered as a short-term infusion on days 1–5, and 5-fluorouracil (1000 mg/m2/day) was administered as a continuous infusion over 24 h on days 1–5. Radiation therapy was administered by linear accelerators with 10–15-MV photons. Radiation therapy was simulated to encompass the tumor volume with 5-cm cephalo-caudal-margins and 2-cm radial margins, and treatment ports were designed to include enlarged regional nodes based on computed tomography evaluation and endoscopic ultrasound. Radiation was delivered in daily fractions of 1.8 Gy (days 1–5, 8–12, 15–19, and 22–26) to a total dose of 36 Gy using a multiple field technique. Surgical resection was performed 4–5 weeks after completion of chemoradiation after clinical restaging using the same procedures as for staging, except for laparoscopy. Standardized transthoracic en bloc esophagectomy with two-field lymphadenectomy and reconstruction by gastric tube interposition with either left cervical or high intrathoracic anastomosis was performed in all patients (15) .

Three patients had to be excluded due to systemic progression during neoadjuvant therapy; these patients therefore did not proceed to surgical resection.

Therefore, 36 patients were included in the final analysis, and clinical data are summarized in Table 1Citation . Informed consent was obtained from each patient, and the scientific protocol was approved by the local ethics committee.


View this table:
[in this window]
[in a new window]

  		Table 1 Clinical and histopathological parameters for 36 patients with tumor resection

 
Histomorphological Grading of Tumor Regression.
Because clinical response evaluation after neoadjuvant therapy for esophageal cancer was known to be highly inaccurate (16) , objective histopathological response analysis was applied using morphological criteria described by Junker et al. (17) .

The resected specimens were fixed in 10% formaldehyde, en bloc embedded in paraffin, and sectioned into 5-µm slices that were stained with H&E. These sections were used for both histopathological staging according to the tumor-node-metastasis (TNM) classification system (18) and histomorphological evaluation of the effect of radiochemotherapy. The degree of histomorphological regression was classified into four categories: (a) grade I, >50% vital residual tumor cells; (b) grade II, 10–50% vital residual tumor cells; (c) grade III, nearly complete response with <10% vital residual tumor cells; and (d) grade IV, complete response (pCR, ypT0). This analysis was performed by two independent staff pathologists who were blinded for all other clinical data (S. E. B. and H. P. D.). Regression grades III and IV were considered as major histomorphological response compared with grades I and II constituting minor histopathological response.

Tissue Acquisition and RNA Isolation.
Tissue samples from esophageal cancers and corresponding normal tissues were collected by endoscopic biopsy before starting neoadjuvant treatment. Samples were snap-frozen in liquid nitrogen and stored at –80°C until further processing. Samples were carefully chosen after control staining with H&E of individual biopsies.

Total cellular RNA was isolated using Trizol reagent (Life Technologies, Inc./GIBCO, Grand Island, NY) and quantitated at A260/280 nm (Smart Spec; Bio-Rad, Hercules, CA).

Quantitative Reverse Transcription-PCR.
Total cellular RNA (0.5 µg) was reverse transcribed using an oligo(dT)18 primer and Moloney murine leukemia virus reverse transcriptase (Clontech, Palo Alto, CA) according to the manufacturer’s recommendations. Placenta RNA from this kit was used to prepare standard curves. Twenty-five ng of cDNA were taken for real-time PCR using the Light Cycler System (Roche, Mannheim, Germany). Amplification was monitored by SYBR Green intercalation. For hot start, LC-DNA Master SYBR Green was preincubated with TaqStart antibody (Clontech) as suggested by the manufacturer. Briefly, the 10-µl reaction volume contained 2 mM MgCl2 and 1 µM of each primer. Primers used for PCR amplification were chosen to encompass the intron between exon sequences. A 494-bp amplification product was obtained for ERCC1 mRNA, and a 276-bp product was obtained for ß-actin mRNA. Primer sequences were as follows: ß-actin, 5'-CAA-GAG-ATG-GCC-ACG-GCT (sense primer) and 5'-TCC-TTC-TGC-ATC-CTG-TCG-GCA [antisense primer (19) ]; and ERCC1, 5'-GTG-CAG-TCG-GCC-AGG-ATA-CAC (sense primer) and 5'-GTC-CTC-CTG-GAG-TGG-CCA-AG [antisense primer (20) ]. PCR conditions were 30 s at 95°C for initial denaturation, followed by 40 cycles of 0 s at 95°C, 20 s at 63°C, and 20 s at 72°C.

Product purity was controlled by melting point analysis, and PCR products were further analyzed electrophoretically on 2% agarose gels in a Horizon 58 electrophoresis chamber (GIBCO/BRL, Eggenstein, Germany) and visualized by ethidium bromide staining.

Absolute expression levels were calculated as ERCC1/ß-actin ratio in tumor and normal tissues, respectively. Relative mRNA expression levels (tumor/normal ratio) were calculated as (ERCC1/ß-actin in tumor)/(ERCC1/ß-actin in paired normal tissue).

Statistical Analysis.
Gene expression levels were described using the median as a point estimator and the range of values. Cutoff values for discrimination of mRNA expression levels and histopathological response were derived from receiver operating curve data (area under the curve and the 95% confidence interval) according to Metz et al. (21) .

Associations between gene expression levels and clinicopathological parameters were evaluated using {chi}2, Kendall analysis, or Wilcoxon rank test and t test applying Fisher’s exact testing for significance (Software Package SPSS for Windows, Version 11.0; SPSS, Chicago, IL). The level of significance was set to P < 0.05. Unless otherwise specified, P values are given for two-sided testing.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Distribution of ERCC1 mRNA Expression Levels.
ERCC1 mRNA expression was detected in all tumor (n = 36) and corresponding normal epithelium (n = 36) specimens. Median absolute ERCC1 mRNA expression levels standardized for ß-actin were 1.02 (range, 0.35–13.82) in tumors and 1.17 (range, 0.25–3.85) in normal tissues, respectively. The median relative expression level (tumor/normal ratio) was 1.01 (range, 0.15–6.34). ERCC1 mRNA expression levels did not show a statistically significant difference (P = 0.61) in three different measurements from tumor biopsies by Kendall’s analysis, and results are shown Fig. 1Citation . There were also no significant differences of absolute mRNA expression levels in tumor or paired normal tissue (paired t test, P = 0.34; Wilcoxon rank test, P = 0.65).



View larger version (14K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Error bar diagram showing mean (± 95% confidence intervals) ERCC1 mRNA and ß-actin expression levels in three tumor measurements (ERCC1 1–3 and ß-actin 1–3) from 36 patients. There were no significant differences in ERCC1 (P = 0.61) and ß-actin gene expression levels (P = 0.58).

 
Histomorphological Response to Radiochemotherapy and ERCC1 mRNA Levels.
The response frequencies for the 36 resected tumors were as follows: one-third (12 of 36) of the tumors demonstrated major (grades III and IV) histopathological response, and two-thirds (24 of 36) of the tumors demonstrated minor histopathological response (grades I and II) to our neoadjuvant treatment regimen (Table 1)Citation .

In Fig. 2Citation , individual relative ERCC1 expression levels were blotted against the respective regression grades, and in Table 2Citation , absolute and relative ERCC1 mRNA expression levels are shown with the respective response grades for each individual patient. Cutoff values (21) for ERCC1 expression and histopathological response were calculated for an expression level of 1.09 (area under the curve, 0.74; 95% confidence interval, 0.58–0.89) to identify minor histopathological response to neoadjuvant therapy.



View larger version (13K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. Scattergram showing relative ERCC1 mRNA expression levels (T/N, ratio of tumor to normal tissue) in relation to minor and major histopathological response in resected specimens. ERCC1 expression levels of >1.09 are exclusively present in the group of minor histopathological response (sensitivity, 62.5%; specificity, 100%).

 

View this table:
[in this window]
[in a new window]

  		Table 2 ERCC1 mRNA expression levels and response

 
There were no significant associations between dichotomized maximum cutoff values for ERCC1 expression (<=1.09 or >1.09) and pT categories (P = 0.9), pN categories (P = 0.9), or grading of the primary tumor (P = 0.4). In addition, when absolute ERCC1 mRNA expression levels in tumors were analyzed, no cutoff values could be identified to discriminate between minor and major histomorphological response.

Whereas 9 of 20 squamous cell cancers showed expression levels of >1.09, only 3 of 13 adenocarcinomas exhibited this class of expression levels. This association was only marginally significant by one-sided Fisher’s exact test (P = 0.05).

Table 3Citation shows the association between major and minor histopathological response groups and dichotomized relative ERCC1 expression levels for the whole study group (n = 36), and Table 4Citation shows the association between major and minor histopathological response groups and dichotomized relative ERCC1 expression levels for patients with squamous cell histology (n = 23). The sensitivity for detection of a minor histopathological response was 62.5% with a specificity of 100% and was even higher for squamous cell cancers, with a sensitivity of 85.7% and a specificity of 100% (area under the curve, 0.89; 95% confidence interval, 0.76–1). This association of dichotomized ERCC1 mRNA levels and histopathological response was highly significant for the whole group of tumors (P < 0.001) and the subgroup of squamous cell cancers (P < 0.001), as shown in Tables 2Citation and 3Citation . Subgroup analysis was not meaningful for adenocarcinomas due to the small sample size.


View this table:
[in this window]
[in a new window]

  		Table 3 ERCC1 mRNA expression and regression: sensitivity and specificity of response prediction

Prediction of minor histopathological response (ERCC1 > 1.09): sensitivity, 62.5%; specificity, 100%; {chi}2-analysis (Fisher’s exact test), P < 0.001.

 

View this table:
[in this window]
[in a new window]

  		Table 4 ERCC1 mRNA expression and regression in squamous cell carcinoma: sensitivity and specificity of response prediction

Prediction of minor histopathological response (ERCC1 > 1.09): sensitivity, 85.7%; specificity, 100%; {chi}2-analysis (Fisher’s exact test), P < 0.001.

 
In summary, quantitative ERCC1 mRNA expression testing unequivocally identified 15 of 36 (42%) patients whose tumors will not exhibit a major histopathological response to the applied neoadjuvant radiochemotherapy with a specificity of 100%.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Because DNA is the primary cellular target for both chemotherapy- and radiation-induced damage, DNA repair efficiency could be a limiting factor for therapeutic response, preventing tumor cells from undergoing the process of apoptosis. In this study we have shown a significant association between ERCC1 mRNA expression levels in esophageal cancers and minor histopathological response to CDDP-based neoadjuvant radiochemotherapy.

In fact, quantitative ERCC1 mRNA expression testing by real-time reverse transcription-PCR unequivocally identified 15 of 36 patients whose tumors did not exhibit (specificity, 100%) a major histopathological response to the applied neoadjuvant radiochemotherapy. Experimental studies have demonstrated that increased ERCC1 levels are associated with removal of CDDP-induced strand adducts and relative CDDP resistance (22) . In addition, ERCC1 defective knockout mice are highly sensitive to DNA cross-linking agents (23) .

ERCC1 is also associated with radiation-induced DNA damage, although this mechanism is still poorly understood and is probably not associated with defects in the nucleotide excision repair pathway but rather mediated by radiation-induced DNA-protein cross-links and influenced by hypoxic conditions (7 , 24) .

Association of ERCC1 expression with treatment response to CDDP-based chemotherapy has been shown in various tumor cell lines (25 , 26) as well as solid tumors (6 , 27) . Associations with clinical response as well as prognosis and altered ERCC1 mRNA expression have been demonstrated for neoadjuvant chemotherapy in locally advanced gastric cancers (11) . However, in advanced stages (IIB and IV) of non-small cell lung cancer, no association between ERCC1 levels and clinical response to CDDP-based chemotherapy could be demonstrated. A significant association was found with median survival time (13) . In contrast, osteosarcomas did not show evidence for an association between clinical response and expression levels of ERCC1 (28) .

Expression levels of genes involved in the metabolism of 5-fluorouracil might also contribute to improve prediction sensitivity of response in our treatment setting, as shown for thymidylate synthase in gastric cancer (11 , 29) and thymidine phosphorylase in colon cancer (30) .

Clinical response evaluation after neoadjuvant therapy in solid tumors is highly inaccurate, as shown for esophageal cancer (16) , gastric cancer (31) , and non-small cell lung cancer (32) . However, histopathological evaluation results in an objective analysis of remission with prognostic importance as convincingly demonstrated for non-small cell lung cancer (17 , 33) . We applied histopathological criteria instead of inaccurate clinical restaging modalities for objective response evaluation in neoadjuvant-treated esophageal cancers and identified a significant association with minor histopathological response and dichotomized relative ERCC1 mRNA expression levels (P < 0.001).

The sensitivity is 62.5% for the whole group of esophageal cancers and 85.7% for squamous cell cancer group. More important, however, is the specificity of 100%, which would allow the unequivocal identification of a subset of patients with minor responses before treatment. We can expect, however, that the measured cutoff value in this pilot study might change with increasing numbers of patients analyzed in large prospective trials. Although median follow-up is too short to allow a meaningful evaluation between the association of ERCC1 expression levels and survival in our protocol, it has been demonstrated in the past that only patients with major histopathological responses benefit from this type of treatment independent of the applied protocol (3, 4, 5) .

The present, still early results of this ongoing study are promising, and it appears that we might expect to unequivocally identify approximately one-third of patients who fulfill the criteria for neoadjuvant treatment for locally advanced esophageal cancer but will not benefit from our treatment protocol. This might prevent our patients from expensive, noneffective, and potentially harmful therapies and lead to a more individualized type of multimodal treatment in the near future.


   FOOTNOTES
 
Grant support: Grants from the Marga and Walter Boll-Stiftung and the Deutsche Krebshilfe/Dr. Mildred Scheel Stiftung (70-2300-MeI).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Paul M. Schneider, Department of Visceral and Vascular Surgery, University of Cologne, Joseph-Stelzmann-Strasse 9, 50931 Cologne, Germany. E-mail: Paul.Schneider{at}Medizin.Uni-Koeln.de

Received 8/22/03; revised 2/ 4/04; accepted 2/10/04.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Sherman CA, Turrisi AT, Wallace MB, Reed CE. Locally advanced esophageal cancer. Curr Treat Options Oncol, 3: 475-85, 2002.[Medline]
  2. MRC Esophageal Study Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet, 359: 1727-33, 2002.[CrossRef][Medline]
  3. Urba SG, Orringer MB, Turrisi A, et al Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol, 19: 305-13, 2001.[Abstract/Free Full Text]
  4. Walsh TN, Noonan N, Hollywood D, et al A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med, 335: 462-7, 1996.[Abstract/Free Full Text]
  5. Kelsen DP. Multimodality therapy of esophageal cancer: an update. Cancer J, 6(Suppl 2): S177-81, 2000.
  6. Dabholkar M, Vionnet J, Bostick-Bruton F, Yu JJ, Reed E. Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. J Clin Investig, 94: 703-8, 1994.
  7. Murray D, Rosenberg E. The importance of the ERCC1/ERCC4[XPF] complex for hypoxic-cell radioresistance does not appear to derive from its participation in the nucleotide excision repair pathway. Mutat Res, 364: 217-26, 1996.[Medline]
  8. Wood RD, Mitchell M, Sgouros J, Lindahl T. Human DNA repair genes. Science (Wash DC), 291: 1284-9, 2001.[Abstract/Free Full Text]
  9. You JS, Wang M, Lee SH. Biochemical analysis of damage recognition process in nucleotide excision repair. J Biol Chem, 278: 7476-85, 2003.[Abstract/Free Full Text]
  10. Houtsmuller AB, Rademakers S, Nigg AL, et al Action of DNA repair endonuclease ERCC1/XPF in living cells. Science (Wash DC), 284: 958-61, 1999.[Abstract/Free Full Text]
  11. Metzger R, Leichman CG, Danenberg KD, et al ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. J Clin Oncol, 16: 309-16, 1998.[Abstract/Free Full Text]
  12. Shirota Y, Stoehlmacher J, Brabender J, et al ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol, 19: 4298-304, 2001.[Abstract/Free Full Text]
  13. Lord RV, Brabender J, Gandara D, et al Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res, 8: 2286-91, 2002.[Abstract/Free Full Text]
  14. Bollschweiler E, Schroeder W, Hoelscher AH, Siewert JR. Preoperative risk analysis in patients with adenocarcinoma or squamous cell carcinoma of the oesophagus. Br J Surg, 87: 1106-10, 2000.[CrossRef][Medline]
  15. Schroeder W, Moenig SP, Baldus SE, et al Frequency of nodal metastases to the upper mediastinum in Barrett’s cancer. Ann Surg Oncol, 9: 807-11, 2002.[Abstract/Free Full Text]
  16. Adelstein DJ, Rice TW, Becker M, et al Use of concurrent chemotherapy, accelerated fractionation radiation, and surgery for patients with esophageal carcinoma. Cancer (Phila), 80: 1011-20, 1997.
  17. Junker K, Thomas M, Schulmann K, et al Tumour regression in non-small-cell lung cancer following neoadjuvant therapy. Histological assessment. J Cancer Res Clin Oncol, 123: 469-77, 1997.[Medline]
  18. Union Internationale contre le Cancer. Sobin LH Wittekind C eds. . TNM classification of malignant tumours, 5th ed. Wiley New York 1997.
  19. Tokuchi Y, Hashimoto T, Kobayashi Y, et al The expression of p73 is increased in lung cancer, independent of p53 gene alteration. Br J Cancer, 80: 1623-9, 1999.[CrossRef][Medline]
  20. Dabholkar MD, Berger MS, Vionnet JA, et al Malignant and nonmalignant brain tissues differ in their messenger RNA expression patterns for ERCC1 and ERCC2. Cancer Res, 55: 1261-6, 1995.[Abstract/Free Full Text]
  21. Metz CE, Goodenough DJ, Rossmann K. Evaluation of receiver operating characteristic curve data in terms of information theory, with applications in radiography. Radiology, 109: 297-303, 1973.[Medline]
  22. Reed E. Platinum-DNA adduct, nucleotide excision repair and platinum based anti-cancer chemotherapy. Cancer Treat Rev, 24: 331-44, 1998.[CrossRef][Medline]
  23. Melton DW, Ketchen AM, Nunez F, et al Cells from ERCC1-deficient mice show increased genome instability and a reduced frequency of S-phase-dependent illegitimate chromosome exchange but a normal frequency of homologous recombination. J Cell Sci, 111: 395-404, 1998.[Abstract]
  24. Murray D, Vallee-Lucic L, Rosenberg E, Andersson B. Sensitivity of nucleotide excision repair-deficient human cells to ionizing radiation and cyclophosphamide. Anticancer Res, 22: 21-6, 2002.[Medline]
  25. Britten RA, Liu D, Tessier A, Hutchison MJ, Murray D. ERCC1 expression as a molecular marker of cisplatin resistance in human cervical tumor cells. Int J Cancer, 89: 453-7, 2000.[CrossRef][Medline]
  26. Selvakumaran M, Pisarcik DA, Bao R, et al Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines. Cancer Res, 63: 1311-6, 2003.[Abstract/Free Full Text]
  27. Dabholkar M, Bostick-Bruton F, Weber C, et al ERCC1 and ERCC2 expression in malignant tissues from ovarian cancer patients. J Natl Cancer Inst (Bethesda), 84: 1512-7, 1992.[Abstract/Free Full Text]
  28. Nathrath M, Kremer M, Letzel H, et al Expression of genes of potential importance in the response to chemotherapy in osteosarcoma patients. Klin Paediatrie, 214: 230-5, 2002.[CrossRef]
  29. Lenz HJ, Leichman CG, Danenberg KD, et al Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival. J Clin Oncol, 14: 176-82, 1996.[Abstract]
  30. Metzger R, Danenberg K, Leichman CG, et al High basal level gene expression of thymidine phosphorylase (platelet-derived endothelial cell growth factor) in colorectal tumors is associated with nonresponse to 5-fluorouracil. Clin Cancer Res, 4: 2371-6, 1998.[Abstract/Free Full Text]
  31. Fink U, Schuhmacher C, Stein HJ, et al Preoperative chemotherapy for stage III-IV gastric carcinoma: feasibility, response and outcome after complete resection. Br J Surg, 82: 1248-52, 1995.[Medline]
  32. Langner K, Thomas M, Klinke F, et al Neoadjuvant therapy in non-small cell lung cancer. Prognostic impact of "mediastinal downstaging". Chirurg, 74: 42-9, 2003.[CrossRef][Medline]
  33. Thomas M, Rube C, Semik M, et al Impact of preoperative bimodality induction including twice-daily radiation on tumor regression and survival in stage III non-small-cell lung cancer. J Clin Oncol, 17: 1185 1999.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 GutHome page
K R Fareed, P Kaye, I N Soomro, M Ilyas, S Martin, S L Parsons, and S Madhusudan
Biomarkers of response to therapy in oesophago-gastric cancer
Gut, January 1, 2009; 58(1): 127 - 143.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
R. Langer, K. Ott, K. Specht, K. Becker, F. Lordick, M. Burian, K. Herrmann, A. Schrattenholz, M. A. Cahill, M. Schwaiger, et al.
Protein Expression Profiling in Esophageal Adenocarcinoma Patients Indicates Association of Heat-Shock Protein 27 Expression and Chemotherapy Response
Clin. Cancer Res., December 15, 2008; 14(24): 8279 - 8287.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
A. Woelfelschneider, O. Popanda, C. Lilla, J. Linseisen, C. Mayer, O. Celebi, J. Debus, H. Bartsch, J. Chang-Claude, and P. Schmezer
A distinct ERCC1 haplotype is associated with mRNA expression levels in prostate cancer patients
Carcinogenesis, September 1, 2008; 29(9): 1758 - 1764.
[Abstract] [Full Text] [PDF]

Home page
 Eur. J. Cardiothorac. Surg.Home page
D. Breen and F. Barlesi
The place of excision repair cross complementation 1 (ERCC1) in surgically treated non-small cell lung cancer
Eur. J. Cardiothorac. Surg., May 1, 2008; 33(5): 805 - 811.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
A. Handra-Luca, J. Hernandez, G. Mountzios, E. Taranchon, J. Lacau-St-Guily, J.-C. Soria, and P. Fouret
Excision Repair Cross Complementation Group 1 Immunohistochemical Expression Predicts Objective Response and Cancer-Specific Survival in Patients Treated by Cisplatin-Based Induction Chemotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma
Clin. Cancer Res., July 1, 2007; 13(13): 3855 - 3859.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
K. Ott, W. A. Weber, F. Lordick, K. Becker, R. Busch, K. Herrmann, H. Wieder, U. Fink, M. Schwaiger, and J.-R. Siewert
Metabolic Imaging Predicts Response, Survival, and Recurrence in Adenocarcinomas of the Esophagogastric Junction
J. Clin. Oncol., October 10, 2006; 24(29): 4692 - 4698.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
K. A. Olaussen, A. Dunant, P. Fouret, E. Brambilla, F. Andre, V. Haddad, E. Taranchon, M. Filipits, R. Pirker, H. H. Popper, et al.
DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy.
N. Engl. J. Med., September 7, 2006; 355(10): 983 - 991.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
R. Langer, K. Specht, K. Becker, P. Ewald, M. Bekesch, M. Sarbia, R. Busch, M. Feith, H. J. Stein, J.-R. Siewert, et al.
Association of Pretherapeutic Expression of Chemotherapy-Related Genes with Response to Neoadjuvant Chemotherapy in Barrett Carcinoma
Clin. Cancer Res., October 15, 2005; 11(20): 7462 - 7469.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Warnecke-Eberz, U.
Right arrow Articles by Schneider, P. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Warnecke-Eberz, U.
Right arrow Articles by Schneider, P. M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online