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Predictive genetic markers in neoadjuvant chemoradiotherapy for locally advanced esophageal cancer: a long way to go. Review of the literature

The Pharmacogenomics Journal volume 18, pages 14–22 (2018)Cite this article

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Abstract

The role of genetic molecular markers in neoadjuvant treatment for locally advanced esophageal cancer has been reviewed, focusing strictly on concurrent chemoradiation protocols followed by surgery. Eleven studies evaluated the role of mRNA expression profile; the end point was overall survival (OS) in two studies and different definitions of histological response in nine. Genes reported as significant were involved in cell cycle control (30), apoptosis (7), structural molecules (9), cell metabolism (6) and DNA repair (1). Seven studies reported about 15 microRNA (miRNA) molecules associated with OS (2) or histological response (13), however, defined with different classifications. Their target genes were prevalently involved in cell cycle control (4), apoptosis (1), cell adhesion (1), migration (1) and angiogenesis (1). Gene polymorphisms (single-nucleotide polymorphisms (SNPs)) have been evaluated in 8 studies reporting 10 variants associated with survival or pathological response. OS was the end point in six of these studies. SNPs reported as significant were involved in DNA repair system (4), detoxification (2), folate metabolism (6), drug efflux (2) and others (2). In a study, a panel including histology, pathological response and five SNPs discriminated two subsets of patients with 5-year survival rates of 79.3% and 26.3% (hazard ratio 6.25, P<0.0001). In another study, combination of stage, grade and 4 miRNAs improved prediction of pathological response (P=10−30). At present, given the great inconsistency of the data and the variability of the end points, definite conclusions are extremely difficult, if not impossible. More consistent data can derive only from analyses obtained from patients included in prospective randomized trials while panels combining genetic and clinical factors may improve prediction.

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References

  1. Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, Barbour A et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for respectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol 2011; 12: 681–692.

    Article  Google Scholar 

  2. Pasini F, de Manzoni G, Zanoni A, Grandinetti A, Capirci C, Pavarana M et al. Neoadjuvant therapy with weekly docetaxel and cisplatin, 5-fluorouracil continuous infusion, and concurrent radiotherapy in patients with locally advanced esophageal cancer produced a high percentage of long-lasting pathological complete response: a phase 2 study. Cancer 2013; 119: 939–945.

    Article  CAS  Google Scholar 

  3. Luthra R, Wu T, Luthra MG, Izzo J, Lopez-Alvarez E, Zhang L et al. Gene expression profiling of localized esophageal carcinomas: association with pathologic response to preoperative chemoradiation. J Clin Oncol 2006; 24: 259–267.

    Article  CAS  Google Scholar 

  4. Luthra MG, Ajani JA, Izzo J, Ensor J, Wu TT, Rashid A et al. Decreased expression of gene cluster at chromosome 1q21 defines molecular subgroups of chemoradiotherapy response in esophageal cancers. Clin Cancer Res 2007; 13: 912–919.

    Article  CAS  Google Scholar 

  5. Duong C, Greenawalt DM, Kowalczyk A, Ciavarella ML, Raskutti G, Murray WK et al. Pretreatment gene expression profiles can be used to predict response to neoadjuvant chemoradiotherapy in esophageal cancer. Ann Surg Oncol 2007; 14: 3602–3609.

    Article  Google Scholar 

  6. Maher SG, Gillham CM, Duggan SP, Smyth PC, Miller N, Muldoon C et al. Gene expression analysis of diagnostic biopsies predicts pathological response to neoadjuvant chemoradiotherapy of esophageal cancer. Ann Surg 2009; 250: 729–737.

    Article  Google Scholar 

  7. Tanaka K, Mohri Y, Ohi M, Yokoe T, Koike Y, Morimoto Y et al. Excision-repair cross-complementing 1 predicts response to cisplatin-based neoadjuvant chemoradiotherapy in patients with esophageal squamous cell carcinoma. Mol Med Rep 2009; 2: 903–909.

    Article  CAS  Google Scholar 

  8. Warnecke-Eberz U, Metzger R, Bollschweiler E, Baldus SE, Mueller RP, Dienes HP et al. TaqMan low-density arrays and analysis by artificial neuronal networks predict response to neoadjuvant chemoradiation in esophageal cancer. Pharmacogenomics 2010; 11: 55–64.

    Article  CAS  Google Scholar 

  9. Bollschweiler E, Metzger R, Drebber U, Baldus S, Vallböhmer D, Kocher M et al. Histological type of esophageal cancer might affect response to neo-adjuvant radiochemotherapy and subsequent prognosis. Ann Oncol 2009; 20: 231–238.

    Article  CAS  Google Scholar 

  10. Warnecke-Eberz U, Metzger R, Miyazono F, Baldus SE, Neiss S, Brabender J et al. High specificity of quantitative excision repair cross-complementing 1 messenger RNA expression for prediction of minor histopathological response to neoadjuvant radiochemotherapy in esophageal cancer. Clin Cancer Res 2004; 10: 3794–3799.

    Article  CAS  Google Scholar 

  11. Miyazono F, Metzger R, Warnecke-Eberz U, Baldus SE, Brabender J, Bollschweiler E et al. Quantitative c-erbB-2 but not c-erbB-1 mRNA expression is a promising marker to predict minor histopathologic response to neoadjuvant radiochemotherapy in oesophageal cancer. Br J Cancer 2004; 91: 666–672.

    Article  CAS  Google Scholar 

  12. Metzger R, Heukamp L, Drebber U, Bollschweiler E, Zander T, Hoelscher AH et al. CUL2 and STK11 as novel response-predictive genes for neoadjuvant radiochemotherapy in esophageal cancer. Pharmacogenomics 2010; 11: 1105–1113.

    Article  CAS  Google Scholar 

  13. Kim SM, Park YY, Park ES, Cho JY, Izzo JG, Zhang D et al. Prognostic biomarkers for esophageal adenocarcinoma identified by analysis of tumor transcriptome. PLoS ONE 2010; 5: e15074.

    Article  CAS  Google Scholar 

  14. Brabender J, Metzger R, Vallböhmer D, Ling F, Neiss S, Bollschweiler E et al. Roles of thymidylate synthase and dihydropyrimidine dehydrogenase expression in blood as predictors of response to multimodal therapy in esophageal cancer. Surgery 2012; 151: 306–312.

    Article  Google Scholar 

  15. Wen J, Yang H, Liu MZ, Luo KJ, Liu H, Hu Y et al. Gene expression analysis of pretreatment biopsies predicts the pathological response of esophageal squamous cell carcinomas to neo-chemoradiotherapy. Ann Oncol 2014; 25: 1769–1774.

    Article  CAS  Google Scholar 

  16. Piro G, Giacopuzzi S, Bencivenga M, Carbone C, Verlato G, Frizziero M et al. TAK1-regulated expression of BIRC3 predicts resistance to preoperative chemoradiotherapy in oesophageal adenocarcinoma patients. Br J Cancer 2015; 113: 878–885.

    Article  CAS  Google Scholar 

  17. Mathé EA, Nguyen GH, Bowman ED, Zhao Y, Budhu A, Schetter AJ et al. MicroRNA expression in squamous cell carcinoma and adenocarcinoma of the esophagus: associations with survival. Clin Cancer Res 2009; 15: 6192–6200.

    Article  Google Scholar 

  18. Ko MA, Zehong G, Virtanen C, Guindi M, Waddell TK, Keshavjee S et al. MicroRNA expression profiling of esophageal cancer before and after induction chemoradiotherapy. Ann Thorac Surg 2012; 94: 1094–1102.

    Article  Google Scholar 

  19. Lynam-Lennon N, Reynolds JV, Marignol L, Sheils OM, Pidgeon GP, Maher SG . MicroRNA-31 modulates tumour sensitivity to radiation in oesophageal adenocarcinoma. J Mol Med (Berl) 2012; 90: 1449–1458.

    Article  CAS  Google Scholar 

  20. Lynam-Lennon N, Bibby BA, Mongan AM, Marignol L, Paxton CN, Geiersbach K et al. Low miR-187 expression promotes resistance to chemoradiation therapy in vitro and correlates with treatment failure in patients with esophageal adenocarcinoma. Mol Med 2016; 22: 388–397.

    Article  CAS  Google Scholar 

  21. Odenthal M, Bollschweiler E, Grimminger PP, Schröder W, Brabender J, Drebber U et al. MicroRNA profiling in locally advanced esophageal cancer indicates a high potential of miR-192 in prediction of multimodality therapy response. Int J Cancer 2013; 133: 2454–2463.

    Article  CAS  Google Scholar 

  22. Skinner HD, Lee JH, Bhutani MS, Weston B, Hofstetter W, Komaki R et al. A validated miRNA profile predicts response to therapy in esophageal adenocarcinoma. Cancer 2014; 120: 3635–3641.

    Article  CAS  Google Scholar 

  23. Wen J, Luo K, Liu H, Liu S, Lin G, Hu Y et al. MiRNA expression analysis of pretreatment biopsies predicts the pathological response of esophageal squamous cell carcinomas to neoadjuvant chemoradiotherapy. Ann Surg 2016; 263: 942–948.

    Article  Google Scholar 

  24. Warnecke-Eberz U, Vallböhmer D, Alakus H, Kütting F, Lurje G, Bollschweiler E et al. ERCC1 and XRCC1 gene polymorphisms predict response to neoadjuvant radiochemotherapy in esophageal cancer. J Gastrointest Surg 2009; 13: 1411–1421.

    Article  Google Scholar 

  25. Wu X, Gu J, Wu TT, Swisher SG, Liao Z, Correa AM et al. Genetic variations in radiation and chemotherapy drug action pathways predict clinical outcomes in esophageal cancer. J Clin Oncol 2006; 24: 3789–3798.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  27. Yu JJ, Lee KB, Mu C, Li Q, Abernathy TV, Bostick-Bruton F et al. 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.

    CAS  PubMed  Google Scholar 

  28. Metzger R, Warnecke-Eberz U, Alakus H, Kütting F, Brabender J, Vallböhmer D et al. Neoadjuvant radiochemotherapy in adenocarcinoma of the esophagus: ERCC1 gene polymorphisms for prediction of response and prognosis. J Gastrointest Surg 2012; 16: 26–34.

    Article  Google Scholar 

  29. Butkiewicz D, Rusin M, Harris CC, Chorazy M . Identification of four single nucleotide polymorphisms in DNA repair genes: XPA and XPB (ERCC3) in Polish population. Hum Mutat 2000; 15: 577–578.

    Article  CAS  Google Scholar 

  30. Akiri G, Nahari D, Finkelstein Y, Le SY, Elroy-Stein O, Levi BZ . Regulation of vascular endothelial growth factor (VEGF) expression is mediated by internal initiation of translation and alternative initiation of transcription. Oncogene 1998; 17: 227–236.

    Article  CAS  Google Scholar 

  31. Miller KL, Karagas MR, Kraft P, Hunter DJ, Catalano PJ, Byler SH et al. XPA, haplotypes, and risk of basal and squamous cell carcinoma. Carcinogenesis 2006; 27: 1670–1675.

    Article  CAS  Google Scholar 

  32. Zhang D, Chen C, Fu X, Gu S, Mao Y, Xie Y et al. A meta-analysis of DNA repair gene XPC polymorphisms and cancer risk. J Hum Genet 2008; 53: 18–33.

    Article  CAS  Google Scholar 

  33. Ryk C, Kumar R, Sanyal S, de Verdier PJ, Hemminki K, Larsson P et al. Influence of polymorphism in DNA repair and defence genes on p53 mutations in bladder tumours. Cancer Lett 2006; 241: 142–149.

    Article  CAS  Google Scholar 

  34. Yang PW, Hsieh CY, Kuo FT, Huang PM, Hsu HH, Kuo SW et al. The survival impact of XPA and XPC genetic polymorphisms on patients with esophageal squamous cell carcinoma. Ann Surg Oncol 2013; 20: 562–571.

    Article  Google Scholar 

  35. Narumiya K, Metzger R, Bollschweiler E, Alakus H, Brabender J, Drebber U et al. Impact of ABCB1 C3435T polymorphism on lymph node regression in multimodality treatment of locally advanced esophageal cancer. Pharmacogenomics 2011; 12: 205–214.

    Article  CAS  Google Scholar 

  36. Ali-Osman F, Akande O, Antoun G, Mao JX, Buolamwini J . Molecular cloning, characterization, and expression in Escherichia coli of full-length cDNAs of three human glutathione S-transferase Pi gene variants. Evidence for differential catalytic activity of the encoded proteins. J Biol Chem 1997; 11: 10004–10012.

    Article  Google Scholar 

  37. Goekkurt E, Hoehn S, Wolschke C, Wittmer C, Stueber C, Hossfeld DK et al. Polymorphisms of glutathione S-transferases (GST) and thymidylate synthase (TS)novel predictors for response and survival in gastric cancer patients. Br J Cancer 2006; 94: 281–286.

    Article  CAS  Google Scholar 

  38. Shiga H, Heath EI, Rasmussen AA, Trock B, Johnston PG, Forastiere AA et al. Prognostic value of p53, glutathione S-transferase pi, and thymidylate synthase for neoadjuvant cisplatin-based chemotherapy in head and neck cancer. Clin Cancer Res 1999; 5: 4097–4104.

    CAS  PubMed  Google Scholar 

  39. Okuno T, Tamura T, Yamamori M, Chayahara N, Yamada T, Miki I et al. Favorable genetic polymorphisms predictive of clinical outcome of chemoradiotherapy for stage II/III esophageal squamous cell carcinoma in Japanese. Am J Clin Oncol 2007; 30: 252–257.

    Article  CAS  Google Scholar 

  40. Horie N, Aiba H, Oguro K, Hojo H, Takeishi K . Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5'-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 1995; 20: 191–197.

    Article  CAS  Google Scholar 

  41. Kawakami K, Watanabe G . Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of thymidylate synthase gene. Cancer Res 2003; 63: 6004–6007.

    CAS  PubMed  Google Scholar 

  42. Marcuello E, Altés A, Menoyo A, Rio ED, Baiget M . Methylenetetrahydrofolate reductase gene polymorphisms: genomic predictors of clinical response to fluoropyrimidine-based chemotherapy? Cancer Chemother Pharmacol 2006; 57: 835–840.

    Article  CAS  Google Scholar 

  43. Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE et al. Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci 2001; 22: 195–201.

    Article  CAS  Google Scholar 

  44. Frey UH, Eisenhardt A, Lümmen G, Rübben H, Jöckel KH, Schmid KW et al. The T393C polymorphism of the G alpha s gene (GNAS1) is a novel prognostic marker in bladder cancer. Cancer Epidemiol Biomarkers Prev 2005; 14: 871–877.

    Article  CAS  Google Scholar 

  45. Alakus H, Bollschweiler E, Hölscher AH, Warnecke-Eberz U, Frazer KA, Harismendy O et al. Homozygous GNAS 393C-allele carriers with locally advanced esophageal cancer fail to benefit from platinum-based preoperative chemoradiotherapy. Ann Surg Oncol 2014; 21: 4375–4382.

    Article  Google Scholar 

  46. Gusella M, Giacopuzzi S, Bertolaso L, Zanoni A, Pezzolo E, Modena Y et al. Genetic prediction of long-term survival after neoadjuvant chemoradiation in locally advanced esophageal cancer. Pharmacogenomics J 2017; 17: 252–257.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by a partial grant from LILT-Lega Italiana per la Lotta contro i Tumori-sezione di Rovigo, Italy.

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Authors and Affiliations

  1. Department of Oncology, Laboratory of Pharmacology and Molecular Biology, San Luca Hospital, Rovigo, Italy

    M Gusella & E Pezzolo

  2. Department of Oncology, Medical Oncology Unit, S. Maria della Misericordia Hospital, Rovigo, Italy

    Y Modena, C Barile, D Menon, G Crepaldi & F La Russa

  3. Medical Oncology Unit, Pederzoli Hospital, Peschiera del Garda (Verona), Italy

    A P Fraccon & F Pasini

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Gusella, M., Pezzolo, E., Modena, Y. et al. Predictive genetic markers in neoadjuvant chemoradiotherapy for locally advanced esophageal cancer: a long way to go. Review of the literature. Pharmacogenomics J 18, 14–22 (2018). https://doi.org/10.1038/tpj.2017.25

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