Predictive role of multiple gene alterations in response to cetuximab in metastatic colorectal cancer: A single center study

Paola Ulivi,Dino Amadori,Wainer Zoli,Laura Capelli,Alessandro Passardi,Emanuela Scarpi,Giovanni Luca Frassineti,Elisa Chiadini,Daniele Calistri,Andrea Casadei Gardini,Martina Valgiusti,Paola Rosetti,Sara Bravaccini,Luca Saragoni,Angela Ragazzini

doi:10.1186/1479-5876-10-87

Abstract

BackgroundKRAS mutations negatively affect outcome after treatment with cetuximab in metastatic colorectal cancer (mCRC) patients. As only 20% of KRAS wild type (WT) patients respond to cetuximab it is possible that other mutations, constitutively activating the EGFR pathway, are present in the non-responding KRAS WT patients. We retrospectively analyzed objective tumor response rate, (ORR) progression-free (PFS) and overall survival (OS) with respect to the mutational status of KRAS, BRAF, PIK3CA and PTEN expression in mCRC patients treated with a cetuximab-based regimen.Methods67 mCRC patients were enrolled onto the study. DNA was extracted from paraffin-embedded sections derived from primary or metastatic lesions. Exon 2 of KRAS and exon 15 of BRAF were analyzed by direct sequencing, PIK3CA was evaluated by pyrosequencing and PTEN expression by immunohistochemistry.ResultsBRAF and PIK3CA mutations were independently associated with worse PFS (p = 0.006 and p = 0.028, respectively) and OS (p = 0.008 and p = 0.029, respectively). No differences in clinical outcome were found between patients who were positive or negative for PTEN expression. Conversely, patients negative for KRAS, BRAF and PIK3CA mutations were characterized by significantly better ORR, PFS and OS than patients with at least one of these mutations.ConclusionsBRAF and PIK3CA mutations would seem to be independent predictors of anti-EGFR therapy effectiveness and could be taken into consideration during treatment decision making.

Highlights

KRAS mutations negatively affect outcome after treatment with cetuximab in metastatic colorectal cancer patients
Patients treated before June 2009 were selected for CTX on the basis of epidermal growth factor receptor (EGFR) expression alone as KRAS mutational status evaluation had still not been made mandatory by the Italian Regulatory Authority
Molecular alterations Among the 39 patients treated with CTX-based treatment before June 2009 we detected 14 (36%) KRAS mutations, whereas all 28 patients treated after June 2009 had wild type (WT) KRAS

Summary

Introduction

KRAS mutations negatively affect outcome after treatment with cetuximab in metastatic colorectal cancer (mCRC) patients. As only 20% of KRAS wild type (WT) patients respond to cetuximab it is possible that other mutations, constitutively activating the EGFR pathway, are present in the non-responding KRAS WT patients. Relatively few patients benefit from CTX: ORRs are around 13% (vs about 1% in KRAS mutated) for monotherapy [9] and about 60% (vs 35% in KRAS mutated) when combined with chemotherapy [10,11]. These findings clearly suggest that other resistance mediators exist in non-responding WT patients. The predictive value of additional mutations and deregulations of signaling pathways downstream of EGFR such as BRAF, PIK3CA, or PTEN is currently under intensive investigation

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Results

Discussion

Conclusion