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

Abstract

Angiogenesis is necessary for tumor growth and has been targeted in breast cancer; however, it is unclear which patients will respond and benefit from antiangiogenic therapy. We report noninvasive monitoring of patient response to neoadjuvant chemotherapy given alone or in combination with anti‐vascular endothelial growth factor (bevacizumab) in a randomized clinical trial. At four time points during neoadjuvant chemotherapy ± bevacizumab of receptor tyrosine‐protein kinase erbB‐2‐negative breast cancers, we measured metabolites and inflammation‐related markers in patient's serum. We report significant changes in the levels of several molecules induced by bevacizumab, the most prominent being an increase in pentraxin 3 (PTX3) and von Willebrand factor (VWF). Serum levels of AXL, VWF and pulmonary and activation‐regulated cytokine (PARC/CCL18) reflected response to chemotherapy alone or in combination with bevacizumab. We further analyzed serum cytokines in relation to tumor characteristics such as gene expression, tumor metabolites and tumor infiltrating leukocytes. We found that VWF and growth‐differentiation factor 15 tumor mRNA levels correlated with their respective serum protein levels suggesting that these cytokines may be produced by tumors and outflow to the bloodstream while influencing the tumor microenvironment locally. Finally, we used binomial logistic regression which allowed to predict patient's response using only 10 noninvasive biomarkers. Our study highlights the potential of monitoring circulating levels of cytokines and metabolites during breast cancer therapy.

Circulating biomarkers and cardiac function over 3 years after chemotherapy with anthracyclines: the ICOS‐ONE trial

“…PTX3 which was supra‐normal at baseline, possibly because of the underlying cancer, seemed to weakly increase after CT but did not show any relation with type of chemotherapy, dose, or echocardiographic variables. PTX3 was significantly higher at baseline and during CT in patients with leukaemia or lymphoma than in those with breast cancer, in agreement with previous observations 27,28 . The higher concentration in younger patients is probably due to a higher prevalence of leukaemia in this age group.…”

“…PTX3 was significantly higher at baseline and during CT in patients with leukaemia or lymphoma than in those with breast cancer, in agreement with previous observations. 27,28 The higher concentration in younger patients is probably due to a higher prevalence of leukaemia in this age group. It may be speculated that the depression in circulating white blood cells induced by CT may have decreased a major storage compartment for circulating PTX3.…”

Von Willebrand factor and cancer; metastasis and coagulopathies

“…Within the tumor microenvironment, infiltrating immune cells produce an array of pro‐inflammatory cytokines, pro‐angiogenic factors which serve to contribute to tumor growth, migration, and dissemination. Interestingly, a recent study found that plasma VWF:Ag levels in breast cancer patients positively correlated with tumor infiltrating mast cells suggesting perhaps VWF may contribute to immune cell recruitment within tumor tissues 52 . Further studies are warranted to confirm these observations.…”

Life after Cell Death—Survival and Survivorship Following Chemotherapy

“…The effects of chemotherapy on intestinal epithelium, an inevitable target due to its high turnover rate, results in massive endotoxin release from gut microflora into circulation [135]. Inflammatory mediators, in turn, further contribute to microvascular remodelling, activation and increased permeability, perpetuating the cycle of vascular pathology, cardiovascular disease and oedema [136], as well as affecting the response to treatment [137] and potential for relapse [99].…”