Artikel
EGF +61 A>G polymorphism predicts complete pathologic response independent of KRAS status in locally advanced rectal cancer patients undergoing neoadjuvant cetuximab-based chemoradiation
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Autoren
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Daniel Vallböhmer
- Universität zu Köln, Klinik und Poliklinik für Allgemein-, Viszeral- und Tumorchirurgie, Köln
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Siwen Hu-Lieskovan
- University of Southern California, Department of Medical Oncology, Los Angeles
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Peter Grimminger
- Universität zu Köln, Klinik und Poliklinik für Allgemein-, Viszeral- und Tumorchirurgie, Köln
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Jan Brabender
- Universität zu Köln, Klinik und Poliklinik für Allgemein-, Viszeral- und Tumorchirurgie, Köln
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Arnulf H. Hölscher
- Universität zu Köln, Klinik und Poliklinik für Allgemein-, Viszeral- und Tumorchirurgie, Köln
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Robert Semrau
- Universität zu Köln, Klinik für Strahlentherapie, Köln
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Dirk Arnold
- Martin-Luther-Universität Halle-Wittenberg, Klinik für Hämatologie und Onkologie, Halle
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Jean-Pascal Machiels
- Universität zu Köln, Klinik und Poliklinik für Allgemein-, Viszeral- und Tumorchirurgie, Köln
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Claus Rödel
- Universität Frankfurt am Main, Klinik für Strahlentherapie, Frankfurt am Main
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Vaneja Velenik
- Institute of Oncology, Department of Radiotherapy, Ljubljana
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Heinz-Josef Lenz
- University of Southern California, Department of Medical Oncology, Los Angeles
| Veröffentlicht: | 20. Mai 2011 |
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Gliederung
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Introduction: Cetuximab has demonstrated significant clinical activity in metastatic colon cancer. However, cetuximab-containing neoadjuvant chemoradiation has not been shown to improve local control or survival in locally advanced rectal cancer patients in recent phase I/II trials. In order to identify a subgroup of patients who may benefit from the cetuximab protocol, we evaluated functional germline polymorphisms of genes involved in EGFR pathway (COX-2, EGF, EGFR, Kras, CyclinD1), angiogenesis (VEGF, IL-8), ADCC (FCGR2A/3A), DNA repair (XRCC3, Rad51), and drug metabolism (TS, MTHFR), as well as KRAS mutation status for their potential role as molecular predictors for clinical outcome in locally advanced rectal cancer patients treated with preoperative cetuximab-based chemoradiation followed by surgery.
Materials and methods: One hundred and thirty patients with locally advanced rectal cancer who were enrolled in phase I/II clinical trials treated with cetuximab-based chemoradiation in European cancer centers were included. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor samples and genotyping was performed using PCR-RFLP assays. KRAS analysis (7 mutations on codon 12/13) was done by a real-time PCR-based mutation assay. Fisher’s exact test was used to examine associations between polymorphisms/KRAS mutation status and complete pathologic response (pCR) that was determined by the Dworak classification system.
Results: Patients with the EGF 61 G/G genotype had a pCR rate of 45% (5/11), compared with 21% (11/53) in patients heterozygous, and 2% (1/54) in patients homozygous for the A/A allele (p<0.001). KRAS mutations were found in 42% of the patients and KRAS wild-type was significantly associated with pCR(p=0.025). In addition, the association between EGF 61 G allele and pCR remained significant (p=0.019) in the 56 patients with KRAS wild-type.
Conclusion: This study suggests EGF A+61G polymorphism to be a predictive marker for complete pathologic response, independent of KRAS mutation status, to cetuximab-based neoadjuvant chemoradiation of patients with locally advanced rectal cancer.
