A polymorphism of EGFR extracellular domain is associated with progression free-survival in metastatic colorectal cancer patients receiving cetuximab-based treatment

doi:10.1186/1471-2407-8-169

BMC Cancer
Volume 8

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Gonçalves A
Esteyries S
Taylor-Smedra B
Lagarde A
Ayadi M
Monges G
Bertucci F
Esterni B
Delpero JR
Turrini O
Lelong B
Viens P
Borg JP
Birnbaum D
Olschwang S
Viret F

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Gonçalves A
Esteyries S
Taylor-Smedra B
Lagarde A
Ayadi M
Monges G
Bertucci F
Esterni B
Delpero JR
Turrini O
Lelong B
Viens P
Borg JP
Birnbaum D
Olschwang S
Viret F
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Research article

A polymorphism of EGFR extracellular domain is associated with progression free-survival in metastatic colorectal cancer patients receiving cetuximab-based treatment

Anthony Gonçalves^*¹^,2^,6^,7 , Séverine Esteyries^*³^,6^,7 , Brynn Taylor-Smedra²^,6^,7 , Arnaud Lagarde³^,7 , Mounay Ayadi¹ , Geneviève Monges⁴^,6^,7 , François Bertucci¹^,3^,6^,7 , Benjamin Esterni¹^,7 , Jean-Robert Delpero⁵^,6^,7 , Olivier Turrini⁵ , Bernard Lelong⁵ , Patrice Viens¹^,6^,7 , Jean-Paul Borg²^,6^,7 , Daniel Birnbaum³^,6^,7 , Sylviane Olschwang³^,7 and Frédéric Viret¹^,7

¹Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France

²Department of Molecular Pharmacology, Institut Paoli-Calmettes, Marseille, France

³Department of Molecular Oncology, Institut Paoli-Calmettes, Marseille, France

⁴Department of BioPathology, Institut Paoli-Calmettes, Marseille, France

⁵Department of Surgical Oncology, Institut Paoli-Calmettes, Marseille, France

⁶Université de la Méditerranée, UFR de Médecine, Marseille, France

⁷INSERM U891 ; Centre de Recherche en Cancérologie de Marseille, Marseille, France

author email corresponding author email* Contributed equally

BMC Cancer 2008, 8:169doi:10.1186/1471-2407-8-169


Published:	10 June 2008

Abstract

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.

Conclusion

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.