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PIK3CA Mutations in Colorectal Cancer Are Associated with Clinical Resistance to EGFR-Targeted Monoclonal Antibodies

¹ The Falck Division of Medical Oncology, ² Division of Pathology, and ³ Service of Biostatistics, Ospedale Niguarda Ca' Granda, and ⁴ FIRC Institute of Molecular Oncology, Milan, Italy; ⁵ Laboratory of Molecular Genetics, The Oncogenomics Center, Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo, Italy; ⁶ Laboratory of Molecular Diagnostic, Istituto Cantonale di Patologia, Locarno, Switzerland; and ⁷ Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland

Requests for reprints: Salvatore Siena, Divisione Oncologia Falck, Ospedale Niguarda Ca' Granda, Piazza Ospedale Maggiore 3, 20162 Milan, Italy. E-mail: salvatore.siena{at}ospedaleniguarda.it and Alberto Bardelli, Laboratory of Molecular Genetics, The Oncogenomics Center, Institute for Cancer Research and Treatment, University of Torino, Medical School, Strada Provinciale 142 Km 3.95, 10060 Candiolo, Torino, Italy. Phone: 00390119933235; Fax: 00390119933225; E-mail: a.bardelli{at}unito.it.

Key Words: colorectal cancer • EGFR • PIK3CA • PTEN • KRAS • mutations • cetuximab • panitumumab

The monoclonal antibodies (moAb) panitumumab and cetuximab target the epidermal growth factor receptor (EGFR) and have proven valuable for the treatment of metastatic colorectal cancer (mCRC). EGFR-mediated signaling involves two main intracellular cascades: on one side KRAS activates BRAF, which in turn triggers the mitogen-activated protein kinases. On the other, membrane localization of the lipid kinase PIK3CA counteracts PTEN and promotes AKT1 phosphorylation, thereby activating a parallel intracellular axis. Constitutive activation of KRAS bypasses the corresponding signaling cascade and, accordingly, patients with mCRC bearing KRAS mutations are clinically resistant to therapy with panitumumab or cetuximab. We hypothesized that mutations activating PIK3CA could also preclude responsiveness to EGFR-targeted moAbs through a similar mechanism. Here, we present the mutational analysis of PIK3CA and KRAS and evaluation of the PTEN protein status in a cohort of 110 patients with mCRC treated with anti-EGFR moAbs. We observed 15 (13.6%) PIK3CA and 32 (29.0%) KRAS mutations. PIK3CA mutations were significantly associated with clinical resistance to panitumumab or cetuximab; none of the mutated patients achieved objective response (P = 0.038). When only KRAS wild-type tumors were analyzed, the statistical correlation was stronger (P = 0.016). Patients with PIK3CA mutations displayed a worse clinical outcome also in terms of progression-free survival (P = 0.035). Our data indicate that PIK3CA mutations can independently hamper the therapeutic response to panitumumab or cetuximab in mCRC. When the molecular status of the PIK3CA/PTEN and KRAS pathways are concomitantly ascertained, up to 70% of mCRC patients unlikely to respond to EGFR moAbs can be identified. [Cancer Res 2009;69(5):1851–7]

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