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Annals of Oncology Advance Access originally published online on October 31, 2007
Annals of Oncology 2008 19(4):717-723; doi:10.1093/annonc/mdm492
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© The Author 2007. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

gastrointestinal tumors

EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients

F. Cappuzzo1,*, G. Finocchiaro1,2, E. Rossi3, P.A. Jänne4, C. Carnaghi5, C. Calandri6, K. Bencardino7, C. Ligorio1, F. Ciardiello7, T. Pressiani1, A. Destro1,8, M. Roncalli1,8, L. Crino9, W. A. Franklin2, A. Santoro1 and M. Varella-Garcia1

1 Department of Medical Oncology, Istituto Clinico Humanitas IRCCS, Rozzano, Italy
2 Department of Medicine/Medical Oncology, University of Colorado Cancer Center, Aurora, CO, USA
3 CINECA-Interuniversity Consortium, Bologna, Italy
4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
5 Department of Medical Oncology, Bellaria-Maggiore Hospital, Bologna
6 Department of Medical Oncology, San Matteo Hospital, Pavia
7 Department of Medical Oncology, Seconda Universita’ di Napoli, Napoli
8 Pathology Unit, Milan University, Istituto Clinico Humanitas IRCCS, Rozzano
9 Department of Medical Oncology, Ospedale Silvestrini, Perugia, Italy

* Correspondence to: Dr F. Cappuzzo, Istituto Clinico Humanitas, via Manzoni 56, 20089-Rozzano, Italy. Tel: +39-02-82244097; Fax: +39-02-82244097; E-mail: federico.cappuzzo{at}humanitas.it

Background: Standardized conditions to distinguish subpopulations of colorectal cancer (CRC) patients more and less sensitive to cetuximab therapy remain undefined.

Materials and methods: We retrospectively analyzed epidermal growth factor receptor (EGFR) copy number by fluorescence in situ hybridization (FISH) in paraffin-embedded tumor blocks from 85 chemorefractory CRC patients treated with cetuximab. Results were analyzed according to different score systems previously reported in colorectal and lung cancers. The primary end point of the study was identification of the EGFR FISH score that best associates with response rate (RR).

Results: Using receiver operating characteristic (ROC) analysis, the cut-off that best discriminated responders versus nonresponders to cetuximab was a mean of 2.92 EGFR gene copies per cell. This model showed sensitivity of 58.6% [95% confidence interval (CI) = 47.1–70.1) and specificity of 93.3% (95% CI = 80.6–100). EGFR FISH-positive patients (N = 43, 50.6%) had significantly higher RR (P = 0.0001) and significantly longer time to disease progression (P = 0.02) than EGFR FISH negative (N = 42, 49.4%). Other scoring systems resulted less accurate in discriminating patients with the highest likelihood of response to cetuximab therapy.

Conclusions: CRC patients with high EGFR gene copy number have an increased likelihood to respond to cetuximab therapy. Prospective clinical trials with a careful standardization of assay conditions and pattern interpretation are urgently needed.

Key words: cetuximab, colon cancer, EGFR, fluorescence in situ hybridization

Received for publication August 10, 2007. Revision received September 18, 2007. Accepted for publication September 19, 2007.


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