PTEN Expression and KRAS Mutations on Primary Tumors and Metastases in the Prediction of Benefit From Cetuximab

J Clin Oncol. 2009 Apr 27. [Epub ahead of print]

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.

Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, Masi G, Graziano
F, Cremolini C, Rulli E, Canestrari E, Funel N, Schiavon G, Petrini I, Magnani M,
Tonini G, Campani D, Floriani I, Cascinu S, Falcone A.

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.

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.

PMID: 19398573 [PubMed - as supplied by publisher]