121PAXL expression predicts poor prognosis and lack of efficacy of anti-angiogenic and anti-epidermal growth factor receptor (EGFR) agents in patients (pts) with RAS wild type (WT) metastatic colorectal cancer (mCRC)

Abstract Background Activation of AXL receptor tyrosine kinase is a key mediator of epithelial to mesenchymal transition (EMT). AXL is overexpressed in several human cancers, including CRC. Methods AXL expression was assessed by immunohistochemistry in tumor samples from 346 mCRC pts treated at three Institutions and enrolled in different clinical trials (CAPRI, MACBETH, MOMA, TRIBE2). In silico data of AXL RNA levels were obtained from GSE5851 dataset, including 80 pts with advanced mCRC treated with cetuximab in a later line. Results AXL expression was found in 18% of cases within tumor cells, with no difference among RAS cohorts. In the RAS WT group, AXL positive pts had a worse mPFS whether treated with chemotherapy (CT) + anti-EGFR [6.2 m (CI95% 4.2- 8.2) vs 12.1 m (CI95% 10.6 – 13.6) p 0.012] or CT+anti-angiogenic agent [6.7 m (CI95% 8.9- 19.3) vs 14.1 m (CI95% 9.4– 13.0) p 0.007], whereas in RAS mutant pts no impact on PFS was observed. AXL expression correlated with worse mOS in both cohorts; notably, in RAS WT pts mOS was 19.9 m (CI95% 10.5- 29.2) vs 37.6 m (CI95% 31.1– 44.1) p 0.006]. In tumor stroma, assessable in 334 samples, AXL was expressed in 80% of cases, with no difference among RAS groups. AXL expression correlated with lower mOS in both cohorts. (Table) Intriguingly, AXL expression in tumor and stroma (+/+) correlated with shorter mOS; in particular, RAS WT pts (+/+) had a mOS of 19.9 m (CI95% 8.0- 31.7) vs (-/-) 50.1 m (CI95% 43.9- 56.2) p 0.004]. In silico analyses showed high AXL RNA levels in 50% of pts. Moreover, in this population treated with cetuximab, in the KRAS exon2 WT cohort (N = 43) AXL high pts had worse mPFS [1.9 m (CI95% 1.7 -2.0) vs 3.8 m (CI95% 0.7-6.7) p 0.59]. Conclusions AXL expression in tumor and stroma might have a negative prognostic relevance in mCRC. In RAS WT pts, AXL expression might represent a predictive biomarker of lack of efficacy for both anti-EGFR and anti-angiogenic agents. Legal entity responsible for the study Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli". Funding AIRC MFAG-2015-ID: 7778. Table: 121PCohortAXL expression in tumor cellsAXL expression in stromaNNegative