Additional value of EGFR downstream signaling phosphoprotein expression to KRAS mutation for response prediction to cetuximab in colorectal cancer (CRC).

4126 Background: KRAS mutations have been implicated in the resistance of CRC to cetuximab (Lievre et al, J Clin Oncol, 2007) and key mechanisms involved in the resistance to anti-EGFR therapy appear to come from the constitutive activation of EGFR downstream signaling.,EGFR downstream signaling phosphoproteins expression, belonging to MAP kinase (p-MEK, p- ERK1/2) and AKT (p-AKT, p-GSK3, p-P70S6K) pathways were analyzed using Bioplex phosphoprotein array in 42 patients treated for advanced CRC by cetuximab (41) or panitumumab (1) then confronted to KRAS mutation previously analyzed.,Among the 42 patients analyzed (M/F: 24/18; mean age: 61.8 years), 12 (28.5%) had an objective response to anti EGFR antibodies (CR: 1, PR: 11), administered in monotherapy (n=3) or in combination with irinotecan (alone, n=37; FOLFIRI regimen, n=2). Median progression-free survival (PFS) was 15.3 weeks. KRAS mutations were observed in 45.2% of the cases (n=19) and were significantly associated with the absence of response to cetuximab (0 responder among the 19 mutated patients versus 12 (52%) among the 23 non-mutated patients; p<10). In univariate analysis, PFS was longer when tumor was not mutated (median: 32 vs 8.6 weeks, Log-rank p<10). Expression of p-P70S6K was lower in responder than in non-responder patients (p=0.02). In Cox univariate analysis adjusted on age and gender progression free survival (PFS) was longer for patients with low expression of p-P70S6K and p-MEK with an hazard ratio (HR) of 2.44 (p=0.007) and 1.89 respectively (p=0.025). In a stepwise estimation of a Cox proportional hazard model including the 5 phosphoprotein tested p-MEK was the only retained protein to predict PFS. p-MEK expresion was higher in KRAS mutated tumors than in non mutated tumors (p<.04). In Cox multivariate analysis adjusted for age and gender KRAS and pMEK are two independent prognostic markers of patients treated by anti-EGFR antobodies (HR 4.4, P<10 and 2.15, p=0.03 respectively).,This study shows the interest of measuring EGFR downstream signaling phosphosproteins expression in CRC. Adding functional data to KRAS mutation analysis, such data could be helpful to predict response to cetuximab and PFS in CRC. [Table: see text].