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Neoadjuvant Radiochemotherapy in Adenocarcinoma of the Esophagus: ERCC1 Gene Polymorphisms for Prediction of Response and Prognosis

  • 2011 SSAT Plenary Presentation
  • Published:
Journal of Gastrointestinal Surgery Aims and scope

Abstract

Introduction

Neoadjuvant radiochemotherapy (RT/CTx) regimens were primarily designed for treatment of squamous cell carcinoma of the esophagus. Own preliminary results demonstrate that also patients with locally advanced adenocarcinoma of the esophagus may achieve a major response in 30% with a 3-year survival rate of 80%. To identify these patients, ERCC1 (rs11615) gene polymorphisms were analyzed. ERCC1 is a key enzyme of the nucleotide excision and repair (NER) complex to prevent DNA inter- and intra-strand crosslinks.

Patients and Methods

Genomic DNA from 217 patients with cT3/4 adenocarcinoma of the esophagus was extracted from paraffin-embedded tissues. Of these patients, 153 underwent neoadjuvant RT/CTx (CDDP, 5-FU, 36 Gy). For analysis of ERCC1 single nucleotide polymorphisms (SNPs), allelic discrimination was performed by quantitative real-time PCR. Two allele-specific TaqMan probes in competition were used for amplification of ERCC1 (rs11615). Allelic genotyping was correlated with histomorphologic tumor regression after neoadjuvant RT/CTx and survival. Major response (MaHR) was defined as <10% vital residual tumor cells (VRTC).

Results

Analysis of tumor regression revealed a MaHR in 56/153 (36.6%) patients with a 5-year survival rate (5-YSR) of 74% (p < 0.001). ERCC1 gene polymorphisms for all patients showed the following expression pattern: ERCC1 polymorphism (rs11615) CC: n = 27 (12.4%), TT: n = 98 (45.2%), C/T: n = 92 (42.4%). ERCC1 polymorphism CT was identified as a predictor for response to the neoadjuvant RT/CTx (p < 0.001). The 5-YSR for patients with C/T genotype was 51%. Contrary to this, the 5-YSR for the group of patients with a CC/TT polymorphism decreased to 34%.

Conclusion

Analysis of ERCC1 (rs11615) gene polymorphisms reveals a significant correlation with response and survival in patients with adenocarcinoma of the esophagus treated with a neoadjuvant radiochemotherapy. Single nucleotide polymorphisms of ERCC1 (rs11615) could therefore be applied to further individualize therapy in esophageal cancer.

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References

  1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer Statistics 2007. CA Cancer J Clin 2007;57:43–66.

    Article  PubMed  Google Scholar 

  2. Bollschweiler E, Wolfgarten E, Gutschow C, Hölscher AH Demographic variations in the rising incidence of esophageal adenocarcinoma in white males. Cancer 2001; 92: 549–555

    Article  PubMed  CAS  Google Scholar 

  3. Rouvelas I, Zeng W, Lindblad M, Viklund P, Ye W, Lagergren J. Survival after surgery for oesophageal cancer: a population-based study. Lancet Oncol 2005;6:864–870.

    Article  PubMed  Google Scholar 

  4. Sherman, CA, Turrisi, AT, Wallace MB, Reed CE. Locally advanced esophageal cancer. Curr Treat Options Oncol 2002;3:475–485.

    Article  PubMed  Google Scholar 

  5. Leichman CG, Benedetti JK, Zalupski MM, Hochster H, Shields AF, Lenz HJ, Wade Iii IL, Bearden Iii JD, Macdonald JS. Assessment of infusional 5-fluorouracil schedule and dose intensity: a Southwest Oncology Group and Eastern Cooperative Oncology Group study. Clin Colorectal Cancer 2004;5:119–123.

    Article  Google Scholar 

  6. Kaklamanos I, Walker G, Ferry K, Franceschi D, Livingstone AS. Neoadjuvant treatment for respectable cancer of the esophagus and the gastroesophageal junction: a meta-analysis of randomized clinical trials. Ann Surg Oncol 2003;10:754–761.

    Article  PubMed  Google Scholar 

  7. Urschel J, Vasan H. A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for respectable esophageal cancer. Am J Surg 2003;185:538–543.

    Article  PubMed  Google Scholar 

  8. Fiorica F, Di BD, Schepis F, Licata A, Shahied L, Venturi A, Falchi AM, Cramma C. Preoperative chemoradiotherapy for oesophageal cancer: a systematic review and meta-analysis. Gut 2004;53:925–930.

    Article  PubMed  CAS  Google Scholar 

  9. Gebski V, Burmeister B, Smithers BM, Foo K, Zalcberg J, Simes J. Australasian Gastro-Intestinal Trials Group. Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol 2007;8:226–234.

    Article  PubMed  CAS  Google Scholar 

  10. Bollschweiler E, Metzger R, Drebber U, Baldus S, Vallböhmer D, Kocher M, Hölscher A. Histological type of esophageal cancer might affect response to neoadjuvant radiochemotherapy and subsequent prognosis. Ann Oncol 2009; 20: 231–238

    Article  PubMed  CAS  Google Scholar 

  11. Schneider PM, Baldus SE, Metzger R, Kocher M, Bongartz R, Bollschweiler E, Schaefer H, Thiele J, Dienes HP, Mueller RP, Hoelscher AH. Histomorphologic tumor regression and lymph node metastases determine prognosis following neoadjuvant radiochemotherapy for esophageal cancer: implications for response classification. Ann Surg 2005;242:684–692.

    Article  PubMed  Google Scholar 

  12. Selvakumaran M, Pisarcik DA, Bao R, Yeung AT, Hamilton TC: Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines. Cancer Res. 63, 1311–6 (2003)

    PubMed  CAS  Google Scholar 

  13. 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)

    Article  PubMed  CAS  Google Scholar 

  14. Dabholkar M, Bostick-Bruton F, Weber C, Bohr VA, Egwuagu C, Reed E: ERCC1 and ERCC2 expression in malignant tissues from ovarian cancer patients. J Natl Cancer Inst. 84, 1512–7 (1992)

    Article  PubMed  CAS  Google Scholar 

  15. Metzger R, Bollschweiler E, Hölscher AH, Warnecke-Eberz U. ERCC1: impact in multimodality treatment of upper gastrointestinal cancer. Future Oncol 2010; 6(11):1735–1749

    Article  PubMed  CAS  Google Scholar 

  16. Hoeijmakers JHJ: Molecular origins of cancer: DNA damage, aging, and cancer. N Engl J Med. 2009; 361: 1475–1485

    Article  PubMed  CAS  Google Scholar 

  17. Wu X, Gu J, Wu TT, Swisher SG, Liao Y, Correa AM, Liu J, Etyel CJ, Amos CI, Huang M, Chiang SS, Milas L, Hittelman WN, Ajani JA. Genetic variations in radiation and chemotherapy drug action pathways predict clinical outcomes in esophageal cancer. J Clin Oncol 2006;14:3789–3798.

    Article  Google Scholar 

  18. Brookes AJ: The essence of SNPs. Gene. 1999; 234: 177–186

    Article  PubMed  CAS  Google Scholar 

  19. Junker K, Thomas M, Schulmann K, Klinke F, Bosse U, Müller KM. Tumour regression in non-small-cell lung cancer following neoadjuvant therapy. Histological assessment. J Cancer Res Clin Oncol 1997;123:469–477.

    Article  PubMed  CAS  Google Scholar 

  20. Baldus Se, Mönig SP, Schröder W, et al: Regression of oesophageal carcinoms after neoadjuvant radiochemotherapy: criteria of the histopathological evaluation. Pathologe 2004;25:4780–4788.

    Google Scholar 

  21. Bollschweiler E. Benefits and limitations of Kaplan-Meier calculations of survival chance in cancer surgery. Langenbeck’s Arch Surg 2003;388:239–244.

    Article  Google Scholar 

  22. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Amer Statist Asoc 1958;53:457–481.

    Article  Google Scholar 

  23. Pocock SJ, Clayton TC, Altman DG. Survival plots of time-to-event outcomes in clinical trials: good practice and pitfalls. Lancet 2002;359:1686–1689.

    Article  PubMed  Google Scholar 

  24. Geh J, Bond S, Bentzen S, Glynne-Jones R. Systemic overview of preoperative (neoadjuvant) chemoradiotherapy trials in oesophageal cancer: evidence of a radiation and chemotherapy dose response. Radiother Oncol 2006; 78:236–244

    Article  PubMed  CAS  Google Scholar 

  25. Bollschweiler E, Hölscher A, Metzger R. Histologic tumor type and the rate of complete response after neoadjuvant therapy for esophageal cancer. Future Oncol 2010; 6(1): 25–35

    Article  PubMed  CAS  Google Scholar 

  26. Samel S, Hofheinz R, Hundt A et al. Neoadjuvant radio-chemotherapy of adenocarcinoma of the oesophagogastric junction. Onkologie 2001; 24: 278–282

    Article  PubMed  CAS  Google Scholar 

  27. Cunningham D, Allum W, Stenning SP et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006; 355:11–20

    Article  PubMed  CAS  Google Scholar 

  28. Macdonald J, Samlley SR, Benedetti J et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001; 345:725–730

    Article  PubMed  CAS  Google Scholar 

  29. Hölscher, AH, Bollschweiler E, Schneider P, Siewert JR. Early adenocarcinoma in Barrett's oesophagus Br J Surg 1997; 84: 1470–1473

    Article  PubMed  Google Scholar 

  30. Peyre C, DeMeester SR, Rizetto C et al. Vagal-sparing esophagectomy: the ideal operation for intramucosal adenocarcinoma and Barrett with high-grade dysplasia. Ann Surg 2007; 246: 665–674

    Article  PubMed  Google Scholar 

  31. Houtsmuller AB, Rademakers S, Nigg AL, Hoogstraten D, Hoeijmakers JHJ, Vermeulen W: Action of RNA repair endonuclease ERCC1/XPF in living cells. Science 1995; 284: 958–961

    Article  Google Scholar 

  32. Gillet LC, Scharer OD: Molecular mechanisms of mammalian global genome nucleotide excision repair. Chem. Rev. 2006; 106: 253–276

    Article  PubMed  CAS  Google Scholar 

  33. Goode EL, Ulrich MC, Potter JD. Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiology, Biomarkers & Prevention 2002;11:1513–1530.

    CAS  Google Scholar 

  34. Wood RD, Mitchell M Sgouros J, Lindahl T. Human DNA repair genes. Science (Walsh DC) 2001;291:1284–1289.

    Article  CAS  Google Scholar 

  35. Reed E. Platinum-DNA adduct, nucleotide excision repair and platinum based anti-cancer chemotherapy. Cancer Treat Rev 1998;24:331–344.

    Article  PubMed  CAS  Google Scholar 

  36. Shen MR, Jones IM, Mohrenweiser H: Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans. Cancer Res. 1998; 58: 604–608

    PubMed  CAS  Google Scholar 

  37. Warnecke-Eberz U, Vallböhmer D, Alakus H, Kütting F, Lurje G, Bollschweiler E, Wienand-Dorweiler A, Drebber U, Hölscher AH, Metzger R: ERCC1 and XRCC1 gene polymorphisms predict response to neoadjuvant radiochemotherapy in esophageal cancer. J Gastrointest Surg. 2009; 13: 1411–1421

    Article  PubMed  Google Scholar 

  38. Yu JJ, Lee KB, Mu C, Li Q, Abernathy TV, Bostick-Bruton F, Reed E: Comparison of two human ovarian carcinoma cell lines (A2780/CP70 and MCAS) that are equally resistant to platinum, but differ at codon 118 of the ERCC1 gene. Int J Oncol. 2000; 16: 555–560

    PubMed  CAS  Google Scholar 

  39. Su D, Ma S, Liu P, Jiang Z, Lv W, Zhang Y, Deng Q, Smith S, Yu H. Genetic polymorphisms and treatment response in advanced non-small cell lung cancer. Lung Cancer 2007;56:281–288.

    Article  PubMed  Google Scholar 

  40. Metzger R, Leichman CG, Danenberg KD, Danenerg PV, Lenz HJ, Hayashi K, Groshen S, Salonga D, Cohen H, Laine L, Crookes P, Silberman H, Baranda J, Konda B, Leichman L. ERCC1 mRNA levels complement thymdylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. J Clin Oncol1998;16:309–316.

    PubMed  CAS  Google Scholar 

  41. Chen P, Wiencke J, Aldape K, Kesler-Diaz A, Miike R, Kelsey K, Lee M, Liu J, Wrensch M: Association of an ERCC1 polymorphism with adult-onset glioma. Cancer Epidemiol Biomarkers Prev. 2000; 9(8):843–847.

    PubMed  CAS  Google Scholar 

  42. Bradbury PA, Kulke MH, Heist RS, Zhou W, Ma C, Xu W, Marshall AL, Zhai R, Hooshmand SM, Asomaning K, Su L, Shepherd FA, Lynch TJ, Wain JC, Christiani DC, Liu G: Cisplatin pharmacogenetics, DNA repair polymorphisms, and esophageal cancer outcomes. Pharmacogenet Genomics. 2009; 19: 613–625

    Article  PubMed  CAS  Google Scholar 

  43. Kim MK, Cho KJ, Kwon GY, Park SI, Kim YH, Kim JH, Song HY, Shin JH, Jung HY, Lee GH, Choi KD, Kim SB: Patients with ERCC1-negative locally advanced esophageal cancers may benefit from preoperative chemoradiotherapy. Clin Cancer Res. 2008; 14: 4225–4231

    Article  PubMed  CAS  Google Scholar 

  44. Schneider S, Uchida K, Brabender J, Baldus SE, Yochim J, Danenberg KD, Salonga D, Chen P, Tsao-Wei D, Groshen S, Hoelscher AH, Schneider PM, Danenberg PV: Downregulation of TS, DPD, ERCC1, GST-Pi, EGFR, and HER2 gene expression after neoadjuvant three-modality treatment in patients with esophageal cancer. J Am Coll Surg. 2005; 200: 336–344

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of General, Visceral and Cancer Surgery, Center for Integrated Oncology (CIO Cologne Bonn), University Hospital of Cologne, Cologne, Germany

    Ralf Metzger, Ute Warnecke-Eberz, Hakan Alakus, Fabian Kütting, Jan Brabender, Daniel Vallböhmer, Peter P. Grimminger, Stefan P. Mönig, Uta Drebber, Arnulf H. Hölscher & Elfriede Bollschweiler

  2. Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany

    Ralf Metzger

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Discussion

Dr. Jeffrey H. Peters (Rochester, NY): Response prediction is a necessary and evolving advance in the adjuvant treatment of solid tumors including esophageal adenocarcinoma. While on average, adjuvant therapy may provide a 10–15% survival advantage it is widely recognized that a substantial subset of patients fail to respond and thus do not benefit and may even be harmed by neoadjuvant treatment.

Somatic genetic polymorphisms, that is the underlying genetic variability from patient to patient in one or more gene loci are among the possible predictive biomarkers.

The authors study ERCC polymorphism in a large cohort of patients with esophageal adenocarcinoma treated with neoadjuvant chemoradiotherapy.

I have 3 questions:

1. The patients received neoadjuvant chemoradiotherapy although the locus selected may be most sensitive to chemotherapy response. Would you extrapolate this data to patients receiving chemotherapy alone?

Closing Discussant

Dr. Ralf Metzger: Based on the data known, it is right that the locus selected in the study—ERCC1 SNP C118T—is most sensitive to chemotherapy response. Although there is evidence that ERCC1 is involved in repair of radiation-induced DNA damage, the most important function is the repair of DNA inter- and intra-strand crosslinks caused by platinum agents. Therefore, we also would extrapolate the data to patients receiving platinum-based chemotherapy alone.

2. If I recall correctly, ERCC mRNA levels have also been associated with response to platinum-based chemotherapy regimens. This raises the question of the mechanism of difference among the polymorphic groups. Are expression levels different for the three genetic phenotypes?

Closing Discussant

Dr. Ralf Metzger: This question raised by the primary discussant addresses the next step of research regarding ERCC1 and response prediction: There is evidence that ERCC1 mRNA levels might be a predictor of response to platinum-based chemotherapy regimens in upper GI cancer. With the detection of different single nucleotide polymorphisms of ERCC1, the question arises whether the different genotypes might also result in varying gene expressions. Given that the different genotypes code for the same (silent mutations) or different (missense mutations) amino acids, it is possible that the three genetic phenotypes have varying effects on health depending on whether they alter the function of essential proteins. To address this issue, ERCC1 SNPs and mRNA expressions should be analyzed within the same patient.

Recognizing that the data will require prospective validation, and that for the study to be meaningful it must facilitate clinical management, are the findings compelling enough for you to alter neoadjuvant treatment in patients without the CT genotype.

Closing Discussant

Dr. Ralf Metzger: The data presented are preliminary to make treatment decisions based on the ERCC1 genotype. However, a prospective randomized study should be initiated to validate the potential of ERCC1 SNP for prediction of response in multimodality treatment of esophageal cancer.

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Metzger, R., Warnecke-Eberz, U., Alakus, H. et al. Neoadjuvant Radiochemotherapy in Adenocarcinoma of the Esophagus: ERCC1 Gene Polymorphisms for Prediction of Response and Prognosis. J Gastrointest Surg 16, 26–34 (2012). https://doi.org/10.1007/s11605-011-1700-x

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