CD31‐labeled circulating endothelial cells as predictor in anlotinib‐treated non‐small‐cell lung cancer: Analysis on ALTER‐0303 study

Abstract

Our previous studies revealed that the level of activated circulating endothelial cells (aCECs) was correlated with the progression‐free survival (PFS) in antiangiogenesis therapy. Anlotinib displayed affirmatory efficacies in several clinical trials of non‐small‐cell lung cancer (NSCLC). To find a marker predicting the efficacy of anlotinib treatment, we investigated the correlations of aCECs with PFS and overall survival (OS) in patients with NSCLC treated with anlotinib and the impact of anlotinib on human umbilical vascular endothelial cells (HUVECs). The blood samples of 78 patients with NSCLC were collected. aCECs were identified by flow cytometry as CD45−/CD146+/CD31+ cells and CD45−/CD146+/CD105+ cells. The mean value of baseline aCECs counts was defined as the cutoff value, according to which patients were divided into high and low baseline groups. Statistical correlation between high baseline CD31‐labeled aCECs counts and number of metastatic lesions (>3) (χ2 = 4.905, P = .027) was analyzed. The 49 patients treated with anlotinib were stratified according to the ratio of minimal aCECs counts at any time points to baseline (aCECs min/baseline) as <1 or ≥1. Interestingly, the patients with aCECs (CD31) min/baseline <1 displayed longer PFS [HR = 0.439, 95%CI (0.211‐0.912), P = .023]. The biological effect of anlotinib on HUVECs was investigated using MTT assays. Western blot analysis was conducted to evaluate the expression levels of CD31 and CD105 under anlotinib treatment and the underlying mechanisms. In vitro experiment data demonstrated that CD31 exhibited more sensitive changes than CD105 under anlotinib treatment through PI3K‐AKT pathway. Thus, our finding provides new insights into the mechanism by which the CD31‐labeled aCECs are a more sensitive marker for predicting the efficiency of anlotinib treatment.

Salvage anlotinib showed sustained efficacy in heavily pretreated EGFR wild-type lung adenocarcinoma

“…[ 10 ] The CD31-labeled activated circulating endothelial cell is a potential indicator for predicting the efficiency of anlotinib in NSCLC, although it requires further validation. [ 11 ] CEA of the present patient seems to be an informative indicator of anlotinib because the change of serum CEA was to some extent parallel with the radiographic changes of the pulmonary lesions. More reliable biomarkers such as circulating DNA which is capable of predicting and monitoring the response to anlotinib require further validation.…”

Durable efficacy of anlotinib in a patient with advanced thymic squamous cell carcinoma after multiline chemotherapy and apatinib: A case report and literature review

“…Nowadays, the potential predictive biomarkers of anlotinib are still unclear, and identifying the ideal predictive efficacy biomarkers with which to screen the patient population will maximize the benefits to patients. In NSCLC, Liu et al 18 found CD31-labeled activated circulating endothelial cells (aCECs) could be used as a sensitive marker for the efficacy of anlotinib. Another study suggested serum levels of KLK5 and L1CAM had preferable predictive value for anlotinib response in NSCLC patients receiving third-line treatment.…”

Plasma Proteomics Analysis for Screening Anlotinib Responders in Non-small Cell Lung Cancer

“…As same as previous procedure, other 7 plasma samples (patient No. [8][9][10][11][12][13][14] from responders at baseline mixed together as a duplicate for protein extraction (Supplementary Table 1 and Supplementary Table 3). Therefore, we prepared two mixed samples from responders at baseline for proteomics analysis.…”

“…Importantly, we thought that next generation sequencing (NGS) for plasma cell free DNA (cfDNA) plays a role in anlotinib responsive strati cation, and found that the biomarker tumor mutation index (TMI) plus IDH1 exon4 mutation status can signi cant stratify the anlotinib responders [11]. In addition, other recent studies introduced predictors including CD31-labeled circulating endothelial cells and baseline characteristics of patients, for the strati cation of those patients treated with anlotinb [12,13]. Due to complex architecture of anlotinib anti-angiogenic signaling pathway [14], as far as possible screen biomarker from omics analysis will contribute to multiple cancer (NSCLC, SCLC, RCC, and so on) treatments with anlotinib.…”