Combining bevacizumab and chemoradiation in rectal cancer. Translational results of the AXEBeam trial

Abstract

Background:This study characterises molecular effect of bevacizumab, and explores the relation of molecular and genetic markers with response to bevacizumab combined with chemoradiotherapy (CRT).Methods:From a subset of 59 patients of 84 rectal cancer patients included in a phase II study combining bevacizumab with CRT, tumour and blood samples were collected before and during treatment, offering the possibility to evaluate changes induced by one dose of bevacizumab. We performed cDNA microarrays, stains for CD31/CD34 combined with α-SMA and CA-IX, as well as enzyme-linked immunosorbent assay (ELISA) for circulating angiogenic proteins. Markers were related with the pathological response of patients.Results:One dose of bevacizumab changed the expression of 14 genes and led to a significant decrease in microvessel density and in the proportion of pericyte-covered blood vessels, and a small but nonsignificant increase in hypoxia. Alterations in angiogenic processes after bevacizumab delivery were only detected in responding tumours. Lower PDGFA expression and PDGF-BB levels, less pericyte-covered blood vessels and higher CA-IX expression were found after bevacizumab treatment only in patients with pathological complete response.Conclusions:We could not support the ‘normalization hypothesis' and suggest a role for PDGFA, PDGF-BB, CA-IX and α-SMA. Validation in larger patient groups is needed.

Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients

“…Nonetheless, we reasoned that HRBC patients with baseline MVD greater than or equal to that of TNBC patients with pCR might follow a pattern similar to that of TNBC patients. Of note, this high MVD threshold in HRBC is lower than the lowest MVD of all patients assessed in a recent colorectal study (27). In this descriptive analysis of high baseline tumor MVD in the HRBC cohort, the majority of patients with a good response in the primary tumor after combination therapy (MP >3) had maintained or increased PC-MVD (Table S8 and Fig.…”

“…A phase II trial in 20 BC patients also noted an association between expression of the endothelial cell marker CD31 and tumor regression (23). In patients with other tumor types treated with bevacizumab and cytotoxic therapy, correlations between baseline MVD and response have also been documented (24,25), whereas other studies have found no relationship between MVD or MVD surrogates and response (26,27). The exploratory nature of our current analysis notwithstanding, the association between MVD and tumor regression scores is consistent with the notion that vascular remodeling postbevacizumab can convert some nonfunctional vessels into functional ones, but it cannot create new vessels.…”

Prospective patient stratification into robust cancer‐cell intrinsic subtypes from colorectal cancer biopsies

“…Additionally, we assessed subtyping robustness in a meta‐analysis of publicly available rectal cancer biopsy datasets. We also performed temporal/spatial assessment of the stability of these classifiers, using both patient‐matched serial biopsies collected over a 3‐week period from the phase II AXEBeam study and multi‐region‐of‐origin colon biopsies from the Biopsies of Surgical Specimens (BOSS) study . Finally, as part of the S:CORT (Stratification in COloRecTal cancer) research programme , we assessed the ability of CRISs and CMSs to classify histologically‐diverse rectal biopsy samples from the phase II COPERNICUS study.…”

An enzyme-linked immunosorbent assay with a new way to control the edge effect and its application for bevacizumab pharmacokinetic studies in beagle dogs by fitting with a new pharmacokinetic model

“…18,19 The PK data of mAb drugs are usually obtained using ELISA, which is sensitive to outside interference. 4,5 However, the details of assay validations were oen unavailable in those publications since the assay validations were usually not the key point in those studies, and there were few detailed reports about the interference of the edge effect on detection results. For this reason, controlling the edge effect will be valuable for improving the accuracy and precision of ELISA.…”

“…2 mL blood was collected from the foreleg vein into heparinized centrifuge tubes, before and at 0.083, 2, 6, 12 h, 1,3,5,7,9,11,14,17,21,25,29,33,34,35,38,45,52,59, and 66 d aer administration. 2 mL blood was collected from the foreleg vein into heparinized centrifuge tubes, before and at 0.083, 2, 6, 12 h, 1,3,5,7,9,11,14,17,21,25,29,33,34,35,38,45,52,59, and 66 d aer administration.…”