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Germline Polymorphisms may Act as Predictors of Response to Preoperative Chemoradiation in Locally Advanced T3 Rectal Tumors

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Diseases of the Colon & Rectum

Purpose

Patients with locally advanced T3 rectal tumors who present with complete pathologic response to preoperative chemoradiation have a low rate of local recurrence and an excellent prognosis. Predictive markers for complete pathologic response are needed with the perspective of improving individualized treatment of these patients. This study was designed to investigate the predictive value of a new combination of three gene polymorphisms: thymidylate synthase, epidermal growth factor receptor Sp1-216, and epidermal growth factor A61G.

Methods

Pretreatment blood samples from 60 patients with locally advanced T3 rectal tumors were analyzed for thymidylate synthase, epidermal growth factor receptor Sp1-216, and epidermal growth factor A61G gene polymorphisms by polymerase chain reaction. Treatment consisted of preoperative radiotherapy (total dose 65 Gy) and concomitant chemotherapy (Uftoral) followed by total mesorectal excision eight weeks after treatment. Pathologic response was evaluated according to the tumor regression grade system.

Results

Thirty percent (18/60) of patients presented with complete pathologic response. Patients with thymidylate synthase genotype 2/2 had a significantly higher rate of complete pathologic response with 53 percent (8/15) compared with 22 percent in the 2/3 or 3/3 group. When combining thymidylate synthase and epidermal growth factor A61G genotype analysis, a small subgroup with a complete pathologic response rate of 100 percent was identified. Only a minor proportion of the complete responders were identified by this combination. Adding the epidermal growth factor receptor Sp1-216 genotype analysis, a complete pathologic response rate of 64 percent in the combination group was found compared with 21 percent and an 87 percent risk of being a noncomplete responder in the noncombination group.

Conclusions

A promising new combination of predictive markers for complete pathologic response was presented and warrants further investigation in prospective clinical trials.

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References

  1. RJ Heald BJ Moran RD Ryall R Sexton JK MacFarlane (1998) ArticleTitleRectal cancer: the Basingstoke experience of total mesorectal excision, 1978–1997 Arch Surg 133 894–899 Occurrence Handle9711965 Occurrence Handle10.1001/archsurg.133.8.894 Occurrence Handle1:STN:280:DyaK1cznsFOrsQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  2. E Kapiteijn CA Marijnen ID Nagtegaal et al. (2001) ArticleTitlePreoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer N Engl J Med 345 638–646 Occurrence Handle11547717 Occurrence Handle10.1056/NEJMoa010580 Occurrence Handle1:STN:280:DC%2BD3Mvps1ektw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  3. CA Marijnen ID Nagtegaal E Kapiteijn et al. (2003) ArticleTitleRadiotherapy does not compensate for positive resection margins in rectal cancer patients: report of a multicenter randomized trial Int J Radiat Oncol Biol Phys 55 1311–1320 Occurrence Handle12654443 Occurrence Handle10.1016/S0360-3016(02)04291-8 Occurrence Handle1:STN:280:DC%2BD3s7jvFyjtg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  4. JP Gerard O Chapet C Nemoz et al. (2004) ArticleTitleImproved sphincter preservation in low rectal cancer with high-dose preoperative radiotherapy: the Lyon R96-02 randomized trial J Clin Oncol 22 2404–2409 Occurrence Handle15197202 Occurrence Handle10.1200/JCO.2004.08.170

    Article  PubMed  Google Scholar 

  5. A Jakobsen JP Mortensen C Bisgaard J Lindebjerg JW Hansen SR Rafaelsen (2006) ArticleTitlePreoperative chemoradiation of locally advanced T3 rectal cancer combined with an endorectal boost Int J Radiat Oncol Biol Phys 64 461–465 Occurrence Handle16226396 Occurrence Handle10.1016/j.ijrobp.2005.07.969

    Article  PubMed  Google Scholar 

  6. CH Crane JM Skibber BW Feig et al. (2003) ArticleTitleResponse to preoperative chemoradiation increases the use of sphincter-preserving surgery in patients with locally advanced low rectal carcinoma Cancer 97 517–524 Occurrence Handle12518377 Occurrence Handle10.1002/cncr.11075

    Article  PubMed  Google Scholar 

  7. JF Bosset G Calais L Mineur et al. (2005) ArticleTitleEnhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results-EORTC 22921 J Clin Oncol 23 5620–5627 Occurrence Handle16009958 Occurrence Handle10.1200/JCO.2005.02.113 Occurrence Handle1:CAS:528:DC%2BD2MXhtVersr%2FF

    Article  PubMed  CAS  Google Scholar 

  8. K Bujko MP Nowacki A Nasierowska-Guttmejer et al. (2004) ArticleTitleSphincter preservation following preoperative radiotherapy for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy Radiother Oncol 72 15–24 Occurrence Handle15236870 Occurrence Handle10.1016/j.radonc.2003.12.006 Occurrence Handle1:STN:280:DC%2BD2czpsVSmsQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  9. G Theodoropoulos WE Wise A Padmanabhan et al. (2002) ArticleTitleT-level downstaging and complete pathologic response after preoperative chemoradiation for advanced rectal cancer result in decreased recurrence and improved disease-free survival Dis Colon Rectum 45 895–903 Occurrence Handle12130878 Occurrence Handle10.1007/s10350-004-6325-7

    Article  PubMed  Google Scholar 

  10. FM Vecchio V Valentini BD Minsky et al. (2005) ArticleTitleThe relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer Int J Radiat Oncol Biol Phys 62 752–760 Occurrence Handle15936556 Occurrence Handle10.1016/j.ijrobp.2004.11.017

    Article  PubMed  Google Scholar 

  11. F Bozzetti S Andreola D Baratti et al. (2002) ArticleTitlePreoperative chemoradiation in patients with resectable rectal cancer: results on tumor response Ann Surg Oncol 9 444–449 Occurrence Handle12052754 Occurrence Handle10.1007/BF02557266

    Article  PubMed  Google Scholar 

  12. H Bouzourene FT Bosman W Seelentag M Matter P Coucke (2002) ArticleTitleImportance of tumor regression assessment in predicting the outcome in patients with locally advanced rectal carcinoma who are treated with preoperative radiotherapy Cancer 94 1121–1130 Occurrence Handle11920483 Occurrence Handle10.1002/cncr.10327

    Article  PubMed  Google Scholar 

  13. P Luna-Perez S Rodriguez-Ramirez J Vega E Sandoval S Labastida (2001) ArticleTitleMorbidity and mortality following abdominoperineal resection for low rectal adenocarcinoma Rev Invest Clin 53 388–395 Occurrence Handle11795103 Occurrence Handle1:STN:280:DC%2BD38%2FmvFShsg%3D%3D

    PubMed  CAS  Google Scholar 

  14. A Habr-Gama RO Perez W Nadalin et al. (2004) ArticleTitleOperative vs. nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results Ann Surg 240 711–717 Occurrence Handle15383798

    PubMed  Google Scholar 

  15. S Popat A Matakidou RS Houlston (2004) ArticleTitleThymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis J Clin Oncol 22 529–536 Occurrence Handle14752076 Occurrence Handle10.1200/JCO.2004.05.064 Occurrence Handle1:CAS:528:DC%2BD2cXptlCrs74%3D

    Article  PubMed  CAS  Google Scholar 

  16. K Kawakami D Salonga JM Park et al. (2001) ArticleTitleDifferent lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression Clin Cancer Res 7 4096–4101 Occurrence Handle11751507 Occurrence Handle1:CAS:528:DC%2BD38XltFShsg%3D%3D

    PubMed  CAS  Google Scholar 

  17. ST Pullarkat J Stoehlmacher V Ghaderi et al. (2001) ArticleTitleThymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy Pharmacogenomics J 1 65–70 Occurrence Handle11913730 Occurrence Handle1:CAS:528:DC%2BD3MXltVSqsrc%3D

    PubMed  CAS  Google Scholar 

  18. A Jakobsen JN Nielsen N Gyldenkerne J Lindeberg (2005) ArticleTitleThymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity J Clin Oncol 23 1365–1369 Occurrence Handle15735113 Occurrence Handle10.1200/JCO.2005.06.219 Occurrence Handle1:CAS:528:DC%2BD2MXis1Gnu7g%3D

    Article  PubMed  CAS  Google Scholar 

  19. E Villafranca Y Okruzhnov MA Dominguez et al. (2001) ArticleTitlePolymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer J Clin Oncol 19 1779–1786 Occurrence Handle11251009 Occurrence Handle1:CAS:528:DC%2BD3MXisFygs7c%3D

    PubMed  CAS  Google Scholar 

  20. M Shahbazi V Pravica N Nasreen et al. (2002) ArticleTitleAssociation between functional polymorphism in EGF gene and malignant melanoma Lancet 359 397–401 Occurrence Handle11844511 Occurrence Handle10.1016/S0140-6736(02)07600-6 Occurrence Handle1:CAS:528:DC%2BD38XhtFyrs7g%3D

    Article  PubMed  CAS  Google Scholar 

  21. L Milas Z Fan NH Andratschke KK Ang (2004) ArticleTitleEpidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies Int J Radiat Oncol Biol Phys 58 966–971 Occurrence Handle14967457 Occurrence Handle10.1016/j.ijrobp.2003.08.035 Occurrence Handle1:CAS:528:DC%2BD2cXhtVyhu7k%3D

    Article  PubMed  CAS  Google Scholar 

  22. J Giralt HM de las L Cerezo et al. (2005) ArticleTitleThe expression of epidermal growth factor receptor results in a worse prognosis for patients with rectal cancer treated with preoperative radiotherapy: a multicenter, retrospective analysis Radiother Oncol 74 101–108 Occurrence Handle15816107 Occurrence Handle10.1016/j.radonc.2004.12.021 Occurrence Handle1:CAS:528:DC%2BD2MXhslWnsrc%3D

    Article  PubMed  CAS  Google Scholar 

  23. D Azria F Bibeau N Barbier et al. (2005) ArticleTitlePrognostic impact of epidermal growth factor receptor (EGFR) expression on loco-regional recurrence after preoperative radiotherapy in rectal cancer BMC Cancer 5 62 Occurrence Handle15967033 Occurrence Handle10.1186/1471-2407-5-62 Occurrence Handle1:CAS:528:DC%2BD2MXpsFGrurY%3D

    Article  PubMed  CAS  Google Scholar 

  24. W Liu F Innocenti MH Wu et al. (2005) ArticleTitleA functional common polymorphism in a Sp1 recognition site of the epidermal growth factor receptor gene promoter Cancer Res 65 46–53 Occurrence Handle15665278 Occurrence Handle1:CAS:528:DC%2BD2MXhvFahug%3D%3D

    PubMed  CAS  Google Scholar 

  25. KL Spindler JN Nielsen J Lindebjerg I Brandslund A Jakobsen (2006) ArticleTitlePrediction of response to chemoradiation in rectal cancer by a gene polymorphism in the epidermal growth factor receptor promoter region Int J Radiat Oncol Biol Phys 66 500–504 Occurrence Handle16757132

    PubMed  Google Scholar 

  26. W Zhang M Gordon OA Press et al. (2006) ArticleTitleCyclin D1 and epidermal growth factor polymorphisms associated with survival in patients with advanced colorectal cancer treated with Cetuximab Pharmacogenet Genomics 16 475–483 Occurrence Handle16788380 Occurrence Handle10.1097/01.fpc.0000204995.99429.0f Occurrence Handle1:CAS:528:DC%2BD28XkslKrt78%3D

    Article  PubMed  CAS  Google Scholar 

  27. JW Hansen A Jakobsen (2006) ArticleTitleThe importance of applicator design for intraluminal brachytherapy of rectal cancer Med Phys 33 3220–3224 Occurrence Handle17022215 Occurrence Handle10.1118/1.2207143

    Article  PubMed  Google Scholar 

  28. B Iacopetta F Grieu D Joseph H Elsaleh (2001) ArticleTitleA polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil Br J Cancer 85 827–830 Occurrence Handle11556832 Occurrence Handle10.1054/bjoc.2001.2007 Occurrence Handle1:CAS:528:DC%2BD3MXpt1KisLY%3D

    Article  PubMed  CAS  Google Scholar 

  29. SP Hiotis SM Weber AM Cohen et al. (2002) ArticleTitleAssessing the predictive value of clinical complete response to neoadjuvant therapy for rectal cancer: an analysis of 488 patients J Am Coll Surg 194 131–135 Occurrence Handle11848629 Occurrence Handle10.1016/S1072-7515(01)01159-0

    Article  PubMed  Google Scholar 

  30. C Chung-Kang M Ohno K Nishimura Y Kuroda (2006) ArticleTitleIntratumoral heterogeneous expression of thymidylate synthase in gastric cancer Hepatogastroenterology 53 458–462 Occurrence Handle16795992 Occurrence Handle1:CAS:528:DC%2BD28XmslCltL0%3D

    PubMed  CAS  Google Scholar 

  31. J Giralt A Eraso M Armengol et al. (2002) ArticleTitleEpidermal growth factor receptor is a predictor of tumor response in locally advanced rectal cancer patients treated with preoperative radiotherapy Int J Radiat Oncol Biol Phys 54 1460–1465 Occurrence Handle12459370 Occurrence Handle10.1016/S0360-3016(02)03752-5 Occurrence Handle1:CAS:528:DC%2BD38XovFKjsLo%3D

    Article  PubMed  CAS  Google Scholar 

  32. FM Smith JV Reynolds N Miller RB Stephens MJ Kennedy (2006) ArticleTitlePathologic and molecular predictors of the response of rectal cancer to neoadjuvant radiochemotherapy Eur J Surg Oncol 32 55–64 Occurrence Handle16324817 Occurrence Handle10.1016/j.ejso.2005.09.010 Occurrence Handle1:STN:280:DC%2BD28%2FjvFKjuw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  33. MA Gordon J Gil B Lu et al. (2006) ArticleTitleGenomic profiling associated with recurrence in patients with rectal cancer treated with chemoradiation Pharmacogenomics 7 67–88 Occurrence Handle16354126 Occurrence Handle10.2217/14622416.7.1.67 Occurrence Handle1:CAS:528:DC%2BD28XlsFGjtrk%3D

    Article  PubMed  CAS  Google Scholar 

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Aknowledgment

The authors thank Lone Frischknecht for technical assistance.

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Authors and Affiliations

  1. Department of Oncology, Vejle Hospital, Vejle, 7100, Denmark

    Karen-Lise G. Spindler M.D. & Anders Jakobsen D.M.Sc.

  2. Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark

    Jens N. Nielsen Ph.D.

  3. Department of Pathology, Vejle Hospital, Vejle, Denmark

    Jan Lindebjerg M.D.

Authors
  1. Karen-Lise G. Spindler M.D.
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  2. Jens N. Nielsen Ph.D.
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  3. Jan Lindebjerg M.D.
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  4. Anders Jakobsen D.M.Sc.
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Corresponding author

Correspondence to Karen-Lise G. Spindler M.D..

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Spindler, KL.G., Nielsen, J.N., Lindebjerg, J. et al. Germline Polymorphisms may Act as Predictors of Response to Preoperative Chemoradiation in Locally Advanced T3 Rectal Tumors. Dis Colon Rectum 50, 1363–1369 (2007). https://doi.org/10.1007/s10350-007-0264-z

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  • DOI: https://doi.org/10.1007/s10350-007-0264-z

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