Annals of Oncology Advance Access originally published online on December 18, 2008
Annals of Oncology 2009 20(3):469-474; doi:10.1093/annonc/mdn647
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gastrointestinal tumors |
Epidermal growth factor receptor gene copy number, K-ras mutation and pathological response to preoperative cetuximab, 5-FU and radiation therapy in locally advanced rectal cancer
1 Division of Medical Oncology, Department of Oncology and Hematology
2 Laboratory of Pathology and Cell Biology, University of Modena and Reggio Emilia, Modena
3 Division of Medical Oncology
4 Institute of Pathology, National Institute for Cancer Research, Genova, Italy
* Correspondence to: Dr C. Bengala, Division of Medical Oncology, Department of Oncology and Hematology, University Hospital, University of Modena and Reggio Emilia, Via del Pozzo, 71, 41100 Modena, Italy. Tel: +39-059-422-3035; Fax: +39-059-422-4429; E-mail: bengala.carmelo{at}unimore.it
Background: Cetuximab improves activity of chemotherapy in metastatic colorectal cancer (mCRC). Gene copy number (GCN) of epidermal growth factor receptor (EGFR) has been suggested to be a predictive factor of response to cetuximab in patients (pts) with mCRC; on the contrary, K-ras mutation has been associated with cetuximab resistance.
Patients and methods: We have conducted a phase II study with cetuximab administered weekly for 3 weeks as single agent and then with 5-fluorouracil and radiation therapy as neo-adjuvant treatment for locally advanced rectal cancer (LARC). EGFR immunohistochemistry expression, EGFR GCN and K-ras mutation were evaluated on diagnostic tumor biopsy. Dworak's tumor regression grade (TRG) was evaluated on surgical specimens.
Results: Forty pts have been treated; 39 pts are assessable. TRG 3 and 4 were achieved in nine (23.1%) and three pts (7.7%) respectively; TRG 3–4 rate was 55% and 5.3% in case of high and low GCN, respectively (P 0.0016). Pts with K-ras mutated tumors had lower rate of high TRG: 11% versus 36.7% (P 0.12). In pts with wild-type K-ras, TRG 3–4 rate was 58.8% versus 7.7% in case of high or low GCN, respectively (P 0.0012).
Conclusions: In pts with LARC, EGFR GCN is predictive of high TRG to cetuximab plus 5-FU radiotherapy. Moreover, our data suggest that a wild-type K-ras associated with a high EGFR GCN can predict sensitivity to cetuximab-based treatment.
Key words: cetuximab, EGFR, KRAS, neoadjuvant chemo-radiotherapy, rectal cancer
Received for publication June 30, 2008. Revision received August 26, 2008. Accepted for publication August 28, 2008.