Right- versus left-side metastatic colorectal cancer: Differences in tumor biology and bevacizumab efficacy

Abstract

Introduction: Recent evidences have highlighted a different response to chemotherapy in metastatic colorectal cancer (mCRC) patients with regard to the tumor localization (right‐ versus left‐side). Different molecular profiles could explain this difference. We analyzed the different outcome in relation to the tumor localization, the molecular characteristics and the expression of inflammatory and angiogenic biomarkers, in a case series of mCRC patients randomized to receive chemotherapy (CT) or CT plus bevacizumab (CT+B) in the first line setting. Methods: One hundred and twenty‐two patients enrolled onto the phase III prospective multicentre randomized “Italian Trial in Advanced Colorectal Cancer (ITACa)” trial were evaluated. Sixty patients received CT plus B, whereas 62 received only CT. RAS and BRAF mutation analysis was performed by MassARRAY (Sequenom). Baseline VEGF, eNOS, COX2, EPHB4 and HIF‐1alpha peripheral blood expression were evaluated by Real‐Time PCR. Inflammatory indexes such as neutrophil‐tolymphocyte ratio (NLR), platelet‐lymphocyte rate (PLR) and systemic immune inflammation index (SII) were also evaluated at baseline. All parameters were analyzed in relation to right‐ and side‐colon tumor location and in relation to patient outcome in terms of progression free survival (PFS) and overall survival (OS). Results: Overall, no differences in terms of PFS and OS were observed between rightand left‐side tumors. Among patients with right‐side tumors, a longer PFS was observed in the CT+B group (12.6 months [95% CI 8.6‐16.0]) with respect to the CT group (9.0 months [95% CI 6.5‐10.3], p=0.017. A higher OS was also shown (27.5 months [15.9‐35.7] vs 20.4 months [13.8‐26.4], respectively), although not statistically significant (p=0.380). As regards left‐side tumors, no differences in terms of OS and PFS were seen between the CT+B and the CT group. Baseline inflammatory indexes were significantly higher in left‐side tumors (NLR 3.19 [95% CI 0.78‐12.32], PLR 192.07 [38.11‐909.75], SII 876.77 [140.36‐8069.24] with respect to the right‐side ones (NLR 2.37 [95% CI 0.90‐10.73], PLR 161.76 [64.73‐310.45], SII 641.47 [175.42‐3614.67], p=0.003, p=0.020 and p=0.005, respectively. Conversely, eNOS and EPHB4 blood expression were significantly higher in right‐side vs left‐side tumors (p=0.027 and p=0.036, respectively). RAS and BRAF mutations did not show a different distribution in right‐side and left‐side tumors. Conclusion: Our data suggest a higher efficacy of CT and B combination in right‐side with respect to left‐side mCRC. The higher sensitivity to B could be attributable to a lower inflammatory status, together with a higher expression of pro‐angiogenic factors, that seem to characterize right‐side tumors.