Prospective evaluation of BRAF, PI3K and PTEN as predictive and prognostic biomarkers in first-line advanced KRAS wild-type colorectal cancer treated with FOLFOX or FOLFIRI plus bi-weekly cetuximab. GEMCAD 10-02

Background

In metastatic colorectal cancer (mCRC), mutation testing for KRAS exon 2 and recently exon 2, 3 and 4 KRAS and NRAS is widely implemented to select patients, sensitive to anti-EGFR therapies, i.e. cetuximab. The added predictive value of BRAF-ERK and PI3K- AKT signaling pathways remains controversial, mostly due to the retrospective nature and second-third lines studies.

Methods

We conducted a biomarker-evaluation phase II trial (ClinicalTrials.gov id: NCT01276379). We included 221 KRAS exon 2 WT patients and evaluated whole KRAS and NRAS mutations by pyrosequencing, BRAF and PI3K mutations by RT-qPCR and PTEN expression by immunohistochemistry. We followed patients every 3 months with abdominopelvic CT scan and clinical examination. We analyzed progression-free survival (PFS, time from inclusion to progression or death) and overall survival (OS, time from inclusion to death) in patients with BRAF wild-type (WT) vs. BRAF mutant and in patients with increased PI3K pathway activation (PI3K mutant or loss of PTEN expression) vs. low PI3K pathway activation (PI3K WT and preserved PTEN expression).

Results

BRAF mutational status was evaluable in 207 patients (20 mutated) and PI3K pathway activation status was evaluable in 193 (108 PI3K mutant or loss of PTEN expression). Patients were treated either with FOLFOX-Cetuximab (53%) or with FOLFIRI-Cetuximab (47%). Median follow-up was 24 (range 0.3-54) months. Patients had a median PFS of 11.4 (95% 9.8-13.2) months if BRAF WT and of 6.1 (3.5-8.3) months if BRAF mutant (adjusted HR = 2.00, 95% CI 1.16-3.46). Median OS for BRAF WT patients was 34.4 (95% 26.8-43.1) months and 9.7 (7.2-23.5) months for BRAF mutant patients (adjusted HR = 3.21, 95% CI 1.80-5.74). PI3K pathway activation status did not discriminate neither PFS (adjusted HR 0.83, 95% CI 0.61-1.13) nor OS (adjusted HR 1.24, 95% CI 0.80-1.91).

Conclusions

BRAF mutational status is both predictive and prognostic in patients with advanced KRAS WT colorectal cancer receiving Cetuximab-containing regimes as first line of therapy. PI3K pathway activation is not associated with Cetuximab resistance.

Clinical trial identification

EudraCT 2010-019236-12

Legal entity responsible for the study

Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD)

Funding

Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD)

Disclosure

All authors have declared no conflicts of interest.