Originally published as JCO Early Release 10.1200/JCO.2008.20.2796 on April 27 2009

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PTEN Expression and KRAS Mutations on Primary Tumors and Metastases in the Prediction of Benefit From Cetuximab Plus Irinotecan for Patients With Metastatic Colorectal Cancer

From the Department of Oncology, Azienda Unità Sanitaria Locale 6, Istituto Toscano Tumori, Livorno; Division of Pathology; and Medical Oncology Unit, Azienda Ospedaliero-Universitaria and University of Pisa; and Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Pisa; Department of Biomolecular Sciences, University of Urbino, Urbino; Clinica di Oncologia Medica, Azienda Ospedaliera Ospedali Riuniti, Università Politecnica delle Marche, Ancona; Medical Oncology Unit, University Campus Biomedico, Rome; Medical Oncology Unit, San Salvatore Hospital, Pesaro; and Istituto di Ricerche Farmacologiche Mario Negri, Milan.

Corresponding author: Fotios Loupakis, MD, Department of Oncology, Azienda USL 6, Istituto Toscano Tumori, Livorno, Department of Oncology, Transplants and New Techologies in Medicine, University of Pisa, Viale Alfieri 36, 57124 Livorno, Italy; e-mail: fotiosloupakis{at}gmail.com.

Purpose PTEN, AKT, and KRAS are epidermal growth factor receptor (EGFR) downstream regulators. KRAS mutations confer resistance to cetuximab. This retrospective study investigated the role of PTEN loss, AKT phosphorylation, and KRAS mutations on the activity of cetuximab plus irinotecan in patients with metastatic colorectal cancer (mCRC).

Patients and Methods A cohort of patients with irinotecan-refractory mCRC who were treated with cetuximab plus irinotecan was tested for PTEN immunoreactivity (ie, immunohistochemistry; IHC), pAKT IHC, and KRAS mutations. Analyses were performed both on primary tumors and on related metastases, and the association among IHC, mutational results, and treatment outcomes was investigated.

Results One-hundred two patients were eligible. Ninety-six primary tumors, 59 metastases, and 53 paired samples were available. Forty-nine primary tumors (58% of assessable samples) had a preserved PTEN expression (PTEN-positive), whereas 35 (40% of assessable samples) were pAKT-positive. Levels of concordance between primary tumors and metastases were 60%, 68%, and 95% for PTEN, pAKT, and KRAS, respectively. PTEN status on primary tumors and pAKT status both on primary tumors and on metastases did not predict response or progression-free survival (PFS). On metastases, 12 (36%) of 33 patients with PTEN-positive tumors were responders compared with one (5%) of 22 who had PTEN-negative tumors (P = .007). The median PFS of patients with PTEN-positive metastases was 4.7 months compared with 3.3 months for those with PTEN-negative metastases (hazard ratio [HR], 0.49; P = .005). Patients with PTEN-positive metastases and KRAS wild type had longer PFS compared with other patients (5.5 months v 3.8 months; HR, 0.42; P = .001).

Conclusion PTEN loss in metastases may be predictive of resistance to cetuximab plus irinotecan. The combination of PTEN IHC and KRAS mutational analyses could help to identify a subgroup of patients with mCRC who have higher chances of benefiting from EGFR inhibition.

Supported by the Fondazione Associazione Ricerche e Cure in Oncologia (ARCO) and FanoAteneo.

Presented at the 2008 Gastrointestinal Cancers Symposium, Orlando, Florida, January 25-27, 2008; and at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL.

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

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