Eph A2 expression is a predictive biomarker of poorer activity and efficacy of FOLFIRI + cetuximab in RAS WT metastatic colorectal cancer (mCRC) patients (pts) in the CAPRI GOIM trial

Abstract

Background: Eph A2 promotes tumor growth, invasiveness and angiogenesis in mCRC. Targeting Eph A2 could overcome resistance to anti-epidermal growth factor receptor (EGFR) treatment in colon cancer preclinical models. Methods: Formalin-fixed paraffin-embedded tumor specimens from 82 RAS wild type (WT) mCRC pts treated with cetuximab + FOLFIRI as first line therapy in the CAPRI GOIM trial were assessed for Eph A2 expression by immunohistochemistry. Eph A2 levels were evaluated developing an HSCORE [1 × (% cells 1+) + 2 × (% cells 2+) + 3 × (% cells 3+)] (range: 0-300). A cut off was set by ROC analysis to define high (>50) and low (≤50) Eph A2 levels. Results: Eph A2 expression was found in 55/82 (67%) cases. According to HSCORE Eph A2 levels were low in 54 (66%) and high in 28 (34%) samples. Eph A2 expression resulted in mostly complete membranous staining. Tumor stroma was positive in 15/82 (18%) cases. In most of these cases an intense immune infiltrate was observed. Non-tumor adjacent normal mucosa was assessable in 34/82 samples. Eph A2 was expressed in 16/34 (47%), more frequently in dysplastic epithelial areas. A significant correlation between Eph A2 expression in tumor and stroma was found (p < 0.0001). Eph A2 was more frequently expressed in less differentiated tumors (p = 0.02), as well as in left-sided tumors compared to right-sided tumors [17/28 (61%), 11/28 (39%), respectively p = 0.04]. Eph A2 expression was associated with higher rate of disease progression (PD) 8/28 (29%) vs 5/54 (9%) (p = 0.02), and with worse median PFS [8.6 m (CI95% 6.4-10.8) vs 12.3 m (CI95% 10.4-14.2) p = 0.030], both in left and right-sided tumours. Moreover, median OS was 28.4 m (CI95% 13.1-43.7) vs 39.8 m (CI95% 30.2-49.4), although this result did not reach statistical significance (p = 0.23). Conclusion: Eph A2 levels were significantly associated with a worse PFS and an increase in PD in RAS WT mCRC pts treated with cetuximab + FOLFIRI as first line therapy in the CAPRI GOIM trial in both right and left-sided tumors. A similar trend was observed for OS. Eph A2 might represent an additional predictive biomarker of lack of efficacy in RAS WT mCRC pts treated with FOLFIRI + cetuximab.