Epidermal growth factor receptor gene copy number in 101 advanced colorectal cancer patients treated with chemotherapy plus cetuximab.
BACKGROUND
Responsiveness to Cetuximab alone can be mediated by an increase of Epidermal Growth factor Receptor (EGFR) Gene Copy Number (GCN). Aim of this study was to assess the role of EGFR-GCN in advanced colorectal cancer (CRC) patients receiving chemotherapy plus Cetuximab.


METHODS
One hundred and one advanced CRC patients (43 untreated- and 58 pre-treated) were retrospectively studied by fluorescence in situ hybridization (FISH) to assess EGFR-GCN and by immunohistochemistry (IHC) to determine EGFR expression. Sixty-one out of 101 patients were evaluated also for k-ras status by direct sequencing. Clinical end-points were response rate (RR), progression-free survival (PFS) and overall survival (OS).


RESULTS
Increased EGFR-GCN was found in 60/101 (59%) tumor samples. There was no correlation between intensity of EGFR-IHC and EGFR-GCN (p = 0.43). Patients receiving chemotherapy plus Cetuximab as first line treatment had a RR of 70% (30/43) while it was 18% (10/56) in the group with previous lines of therapy (p < 0.0001). RR was observed in 29/60 (48%) of patients with increased EGFR-GCN and in 6/28 (21%) in those without (p = 0.02). At multivariate analyses, number of chemotherapy lines and increased EGFR-GCN were predictive of response; EGFR-IHC score, increased EGFR-GCN and number of chemotherapy lines were significantly associated with a significant better PFS. Response to therapy was the only prognostic predictive factor for OS. In the 60 patients analyzed for k-ras mutations, number of chemotherapy lines, increased EGFR-GCN and k-ras wild type status predicted a better PFS.


CONCLUSIONS
In metastatic CRC patients treated with chemotherapy plus Cetuximab number of chemotherapy lines and increased EGFR-GCN were significantly associated with a better clinical outcome, independent of k-ras status.
Campanella
Carla
C
Department of Medical Oncology, Regina Elena Institute, Rome, Italy.
Mottolese
Marcella
M
Cianciulli
Anna
A
Torsello
Angela
A
Merola
Roberta
R
Sperduti
Isabella
I
Melucci
Elisa
E
Conti
Salvatore
S
Diodoro
Maria Grazia
MG
Zeuli
Massimo
M
Paoletti
Giancarlo
G
Cognetti
Francesco
F
Garufi
Carlo
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D016896:Treatment Outcome; D018631:ras Proteins / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab
Clin Cancer Res. 2008 Aug 1;14(15):4830-5
18676755
Drugs Today (Barc). 2003;39 Suppl C:1-16
14988743
Ann Oncol. 2008 Apr;19(4):717-23
17974556
N Engl J Med. 2007 Nov 15;357(20):2040-8
18003960
Radiother Oncol. 2005 Aug;76(2):157-61
16024112
Clin Cancer Res. 2008 Sep 15;14(18):5869-76
18794099
Drugs. 2006;66(11):1441-63
16906777
J Clin Oncol. 2007 Aug 1;25(22):3238-45
17664472
Lancet Oncol. 2008 May;9(5):402-3
18452847
J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
10655437
N Engl J Med. 2008 Oct 23;359(17):1757-65
18946061
N Engl J Med. 2004 Jun 3;350(23):2335-42
15175435
J Clin Oncol. 2008 May 10;26(14):2311-9
18390971
Clin Cancer Res. 2002 May;8(5):994-1003
12006511
Adv Cancer Res. 2000;77:25-79
10549355
N Engl J Med. 2009 Apr 2;360(14):1408-17
19339720
J Clin Oncol. 2008 Jan 20;26(3):374-9
18202412
Lancet Oncol. 2005 May;6(5):279-86
15863375
N Engl J Med. 2004 Jul 22;351(4):337-45
15269313
J Clin Oncol. 2005 Mar 20;23(9):1803-10
15677699
J Clin Oncol. 2007 Nov 20;25(33):5225-32
18024868