Serum cytokine levels in breast cancer patients during neoadjuvant treatment with bevacizumab

Abstract

A high concentration of circulating vascular endothelial growth factor (VEGF) in cancer patients is associated with an aggressive tumor phenotype. Here, serum levels of 27 cytokines and blood cell counts were assessed in breast cancer patients receiving neoadjuvant chemotherapy with or without bevacizumab (Bev) in a randomized cohort of 132 patients with non-metastatic HER2-negative tumors. Cytokine levels were determined prior to treatment and at various time-points. The cytotoxic chemotherapy regimen of fluorouracil, epirubicin, and cyclophosphamide (FEC) had a profound impact on both circulating white blood cells and circulating cytokine levels. At the end of FEC treatment, the global decrease in cytokine levels correlated with the drop in white blood cell counts and was significantly greater in the patients of the Bev arm for cytokines, such as VEGF-A, IL-12, IP-10 and IL-10. Among patients who received Bev, those with pathological complete response (pCR) exhibited significantly lower levels of VEGF-A, IFN-g, TNF-a and IL-4 than patients without pCR. This effect was not observed in the chemotherapy-only arm. Certain circulating cytokine profiles were found to correlate with different immune cell types at the tumor site. For the Bev arm patients, the serum cytokine levels correlated with higher levels of cytotoxic T cells at the end of the therapy regimen, which was indicative of treatment response. The higher response rate for Bev-treated patients and stronger correlations between serum cytokine levels and infiltrating CD8T cells merits further investigation.

Serum levels of inflammation‐related markers and metabolites predict response to neoadjuvant chemotherapy with and without bevacizumab in breast cancers

“…We found that most of the significant changes occurred between screening and 12 weeks. We interpret this as a result of the potent effects of chemotherapy locally at the tumor site but also systemically as we previously reported …”

“…a – e ) with significantly different levels according to treatment arm (ANOVA FDR corrected p ‐value <0.05; Supplementary Table S3). We previously described a Bev‐induced significant decrease in VEGF‐A levels accompanied by a decrease in IL‐12 and IP‐10 . Here, we show that levels of ALCAM and AXL followed a similar pattern with marked decrease in serum levels induced by Bev (Figs.…”

“…We set up, based on levels of the molecules measured in the serum of the patients a logistic regression using the binomial distribution to predict categorical response of the two possible outcomes: minRT (less than 10% residual disease at 25 weeks) or residual disease (more than 10% residual disease). The levels of 17 inflammation‐related cytokines, 26 metabolites and 27 previously published cytokines were normalized together by Z ‐scores. The normalized levels of these 70 molecules were used to predict response at baseline (screening) or 12 weeks.…”

“…Vascular endothelial growth factor A (VEGF‐A), the main cytokine regulating angiogenesis, has been targeted in several cancer types . We recently demonstrated that anti‐VEGF‐A therapy in breast cancer affects the tumor immune contexture …”

“…In the NeoAva, a randomized clinical trial studying in a neoadjuvant setting the effects of chemotherapy ± bevacizumab (Bev; VEGF‐A inhibition), we recently demonstrated that Bev decreased serum levels of interleukin (IL)‐12, interferon‐gamma inducible protein 10 (IP‐10/CXCL10) and IL‐10 …”