Abstract
PurposeSince the KRAS mutation is not responsible for all metastatic colorectal cancer (mCRC) patients with resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy, new predictive and prognostic factors are actively being sought. MethodsWe retrospectively evaluated the efficacy of anti-EGFR MoAb-based therapies in 91 patients with mCRC according to KRAS, BRAF, and PIK3CA mutational status as well as PTEN and MET expression.ResultsIn the patient group with wild-type KRAS, the presence of BRAF mutation or PIK3CA mutations was associated with lower disease control rate (DCR), shorter progression-free survival (PFS), and shorter overall survival. Patients with MET overexpression also showed lower DCR and shorter PFS when compared with patients with normal MET expression. In a separate analysis, 44 patients harboring wild-type KRAS tumors were sorted into subgroups of 25 patients without abnormality in three molecules (BRAF, PIK3CA and MET) and 19 patients with abnormality in at least one of these three molecules. The former group showed significantly higher DCR and longer PFS following anti-EGFR therapy than the latter group.ConclusionsOur data point to the usefulness of MET overexpression, in addition to BRAF and PIK3CA mutations, as a new predictive marker for responsiveness to anti-EGFR MoAbs in mCRC patients with wild-type KRAS. This study also suggests that application of multiple biomarkers is more effective than the use of a single marker in selecting patients who might benefit from anti-EGFR therapy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-014-2401-4) contains supplementary material, which is available to authorized users.
Highlights
Cetuximab and panitumumab are monoclonal antibodies (MoAbs) that inhibit the activation of the epidermal growth factor receptor (EGFR) and its downstream pathways, namely the RAS/RAF/MAPK and the PI3K/PTEN/Akt axes [1, 2]
As the response rate (RR) to anti-EGFR MoAbs remains as low as 10–20 % in patients with metastatic colorectal cancer [2], several studies have been performed to identify markers predicting the efficacy of these agents
The MET expression, PTEN expression, and mutations of BRAF and PIK3CA in metastatic colorectal cancer (mCRC) patients with wild-type KRAS were investigated in association with clinical response to anti-EGFR MoAb therapy
Summary
Cetuximab and panitumumab are monoclonal antibodies (MoAbs) that inhibit the activation of the epidermal growth factor receptor (EGFR) and its downstream pathways, namely the RAS/RAF/MAPK and the PI3K/PTEN/Akt axes [1, 2]. 40–60 % of patients with wild-type KRAS tumors respond to anti-EGFR MoAb therapy, new predictive and prognostic factors are actively being sought [5, 6]. In this regard, the presence of oncogenic deregulation of EGFR and other members of its downstream signaling pathways, such as BRAF, PIK3CA, and PTEN, has been shown to influence the responsiveness to cetuximab and panitumumab and could, help to identify nonresponder patients [4, 6,7,8,9,10]. Analysis of these genetic markers in different patient populations, in particular in different ethnic groups, will help determine their clinical significance
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