A polymorphism of EGFR extracellular domain is associated with progression free-survival in metastatic colorectal cancer patients receiving cetuximab-based treatment.
BACKGROUND
Cetuximab, a monoclonal antibody targeting Epidermal Growth Factor Receptor (EGFR), is currently used in metastatic colorectal cancer (mCRC), but predictive factors for therapeutic response are lacking. Mutational status of KRAS and EGFR, and EGFR copy number are potential determinants of cetuximab activity.


METHODS
We analyzed tumor tissues from 32 EGFR-positive mCRC patients receiving cetuximab/irinotecan combination and evaluable for treatment response. EGFR copy number was quantified by fluorescence in situ hybridization (FISH). KRAS exon 1 and EGFR exons coding for extracellular regions were sequenced.


RESULTS
Nine patients experienced an objective response (partial response) and 23 were considered as nonresponders (12 with stable disease and 11 with progressive disease). There was no EGFR amplification found, but high polysomy was noted in 2 patients, both of which were cetuximab responders. No EGFR mutations were found but a variant of exon 13 (R521K) was observed in 12 patients, 11 of which achieved objective response or stable disease. Progression-free and overall survivals were significantly better in patients with this EGFR exon 13 variant. KRAS mutations were found in 14 cases. While there was a trend for an increased KRAS mutation frequency in nonresponder patients (12 mutations out of 23, 52%) as compared to responder patients (2 out of 9, 22%), authentic tumor response or long-term disease stabilization was found in KRAS mutated patients.


CONCLUSIONS
This preliminary study suggests that: an increase in EGFR copy number may be associated with cetuximab response but is a rare event in CRC, KRAS mutations are associated with low response rate but do not preclude any cetuximab-based combination efficacy and EGFR exon 13 variant (R521K) may predict for cetuximab benefit.
Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France. goncalves.anthony2@orange.fr
Anthony
A
Gonçalves
Séverine
S
Esteyries
Brynn
B
Taylor-Smedra
Arnaud
A
Lagarde
Mounay
M
Ayadi
Geneviève
G
Monges
François
F
Bertucci
Benjamin
B
Esterni
Jean-Robert
JR
Delpero
Olivier
O
Turrini
Bernard
B
Lelong
Patrice
P
Viens
Jean-Paul
JP
Borg
Daniel
D
Birnbaum
Sylviane
S
Olschwang
Frédéric
F
Viret
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D005091:Exons; D005260:Female; D018628:Gene Dosage; D011905:Genes, ras; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D012189:Retrospective Studies; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000077146:Irinotecan; D066246:ErbB Receptors; D000068818:Cetuximab; D002166:Camptothecin