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Pharmacogenetic Profiling for Cetuximab Plus Irinotecan Therapy in Patients With Refractory Advanced Colorectal Cancer

Francesco Graziano, Annamaria Ruzzo, Fotios Loupakis, Emanuele Canestrari, Daniele Santini, Vincenzo Catalano, Renato Bisonni, Umberto Torresi, Irene Floriani, Gaia Schiavon, Francesca Andreoni, Paolo Maltese, Eliana Rulli, Bostjan Humar, Alfredo Falcone, Lucio Giustini, Giuseppe Tonini, Andrea Fontana, Gianluca Masi, Mauro Magnani

From the Medical Oncology Unit, Hospital of Pesaro, Pesaro; Institute of Biochemistry "G. Fornaini," and Institute of Biotechnology, University of Urbino, Urbino; Medical Oncology Unit, Azienda USL-6 Livorno, Livorno; University of Pisa, Istituto Toscano Tumori, Pisa; Medical Oncology Unit, University Campus Biomedico, Rome; Medical Oncology Unit, Hospital of Fermo, Fermo; Medical Oncology Unit, Hospital of Macerata, Macerata; Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy; and Cancer Genetics Laboratory, University of Otago, Otago, New Zealand

Corresponding author: Francesco Graziano, MD, Medical Oncology Unit, Hospital of Urbino, via Bonconte da Montefeltro, 61029, Urbino, Italy; e-mail: frada{at}tin.it

Purpose: Regulation of epidermal growth factor receptor (EGFR) signaling pathways may play a relevant role in determining the activity of cetuximab therapy in patients with metastatic colorectal cancer (MCRC). We investigated possible associations between genetic variants and clinical outcomes of MCRC patients treated with cetuximab-irinotecan salvage therapy.

Patients and Methods: Patients who underwent cetuximab-irinotecan salvage therapy after disease progression during or after first-line bolus/infusional fluorouracil, leucovorin, and oxaliplatin chemotherapy and a second-line irinotecan-based regimen were considered eligible for analysis of polymorphisms with putative influence on cetuximab-related pathways. Epidermal growth factor (EGF) 61A>G, EGF receptor (EGFR) 216G>T, EGFR 497G>A, EGFR intron-1 (CA)_n dinucleotide short (S)/long (L) variant, cyclin-D1 870A>G, immunoglobulin-G fragment-C receptors RIIIa 158G>T, and RIIa 131G>A were studied for a possible association with overall survival (OS) as the primary end point. Additional analyses were addressed at possible associations among polymorphisms and EGFR expression, toxicity, and response.

Results: In 110 assessable patients, significant association with favorable OS was observed for EGFR intron-1 S/S and EGF 61 G/G genotypes. In the multivariate model, EGFR intron-1 S/S and EGF 61 G/G genotypes showed a hazard ratio of 0.41 (95% CI, 0.21 to 0.78; P = .006) and 0.44 (95% CI, 0.23 to 0.84; P = .01), respectively. EGFR intron-1 S/S carriers showed more frequent G2-G3 skin toxicity (² test = 12.7; P = .001) and treatment response (² test = 9.45; P = .008) than EGFR intron-1 L/L carriers.

Conclusion: Although additional studies are required for confirmation, our findings could optimize the use of cetuximab in MCRC patients.

Supported by Consorzio Interuniversitario per le Biotecnologie and Fanoateneo.

F.G. and A.R. contributed equally to this study.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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