RAS testing is used to select patients sensitive to anti-EGFR therapies in metastatic colorectal cancer (mCRC) but other biomarkers such as BRAF, PIK3CA/PTEN and p-IGF-1R+/MMP7 + (DP phenotype) have not prospectively assessed to predict anti-EGFR resistance.
We designed a multicenter prospective trial (NCT01276379) to evaluate if the following biomarkers BRAF mutation, PIK3CA mutation/PTEN loss and DP phenotype can improve the prediction of 12-months progression-free survival (PFS) over the use of only clinical variables in patients with RAS WT mCRC treated with standard chemotherapy plus biweekly Cetuximab as first-line therapy. The planned sample size was 170 RAS WT patients to detect a 20% difference in 12-month PFR based on analysis of clinical and selected biomarkers (alpha=.05, beta=.2). The discriminatory capacity of the biomarkers was evaluated using ROC curves.
We included 181 RAS WT patients. The biomarker distribution was: BRAF mutant 20 patients (11%), PIK3CA mutated/PTEN loss 98 patients (58%) and DP 23 patients (12.7%). Median PFS: BRAF WT 11.4 vs BRAF mutant 5.9 months (p = 0.004). PIK3CA/PTEN pathway and DP phenotype did not discriminate PFR (p=NS). Baseline clinical variables with good prognosis in a multivariable model were PS = 0, left sided tumor and resectable liver metastases (i.e. liver only metastases (<3 nodules and <5cm)).
A clinical score discriminates between two groups of patients who benefitted differently from chemotherapy plus cetuximab. The addition of BRAF, PIK3CA/PTEN and DP to the clinical score does not improve the prediction of 12m PFS.
Clinical trial identification
Legal entity responsible for the study
Grupo Español Multidisciplinar de Cáncer Digestivo.
All authors have declared no conflicts of interest.