Abstract 1337: Circulating angiogenic factors predict metastatic liver progression in rectal cancer patients given curative-intent oxaliplatin-containing neoadjuvant therapy
Authors: Meltzer Sebastian , Redalen Kathrine Røe , Dueland Svein , Kristensen Annette Torgunrud , Solbakken Arne Mide , Flatmark Kjersti , Ree Anne Hansen 
Published: August 2019

Purpose: Systemic failure remains a challenge in rectal cancer. Our recent data from a prospective study of intensified treatment in locally advanced rectal cancer indicated that neoadjuvant chemotherapy (NACT) and sequential long-course chemoradiotherapy (CRT), both modalities containing oxaliplatin, may have eradicated hypoxic tumor components and promoted an immune response that favored survival without metastatic progression. Because a tumor microenvironment with aberrant vasculature and hypoxia provokes immune tolerance, which is frequently connected to systemic inflammation, we hypothesized that circulating angiogenic factors may predict development of metastatic disease in rectal cancer patients given curative-intent treatment. Recognizing that angiopoietin 2 (ANGPT2) disrupts vascular remodeling by inducing endothelial cell apoptosis, we analyzed the soluble ANGPT2 and its endothelial receptor TEK at diagnosis and their linkage to inflammatory factors and progression-free survival (PFS).

Experimental procedures: We used clinical data from 275 rectal cancer patients prospectively enrolled onto three studies. In two of the studies, patients were referred either directly to pelvic surgery or to standard CRT (without oxaliplatin) or short-course radiotherapy before surgery. In the third, introduced above, 80 patients received oxaliplatin-based therapy (two cycles of NACT followed by CRT) before resection. PFS was defined as time from study enrolment until the first metastatic event or up to five years after surgery in the case of no event. Serum ANGPT2 and TEK were measured by immunoassays. The measures (range of 1.60-8.16 ng/ml for ANGPT2 and 1.42-2.97 ng/ml for TEK) were normalized according to each intracohort mean value to enable analysis of pooled samples. Statistical methods were Pearson product correlation and Cox regression.

Results: A correlation was seen between ANGPT2 and TEK levels (r = 0.34, p &lt; 0.001), and each factor correlated with C-reactive protein (for ANGPT2: r = 0.29, p &lt; 0.01; for TEK: r = 0.19, p &lt; 0.01). The higher ANGPT2 or TEK, the higher risk of developing liver metastasis (for ANGPT2: hazard ratio 1.01, p = 0.002; for TEK: hazard ratio 1.01, p = 0.039) in the oxaliplatin-exposed cohort. No such association was found for patients given treatment devoid of oxaliplatin.

Conclusions: High circulating ANGPT2 and TEK at diagnosis were associated with systemic inflammation and metastatic progression to the liver in rectal cancer patients receiving oxaliplatin-containing neoadjuvant therapy. Since we have previously shown that oxaliplatin may have breached the immune tolerance in patients with favorable outcome, there is a rationale for adding an anti-angiogenic agent in patients with hypoxic tumors as reflected by elevated circulating angiogenic factors.

Citation Format: Sebastian Meltzer, Kathrine Røe Redalen, Svein Dueland, Annette Torgunrud Kristensen, Arne Mide Solbakken, Kjersti Flatmark, Anne Hansen Ree. Circulating angiogenic factors predict metastatic liver progression in rectal cancer patients given curative-intent oxaliplatin-containing neoadjuvant therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1337.