Abstract
Approximately half of all HER2/neu-overexpressing breast cancer patients do not respond to trastuzumab-containing therapy. Therefore, there remains an urgent and unmet clinical need for the development of predictive biomarkers for trastuzumab response. Recently, several lines of evidence have demonstrated that the inflammatory tumor microenvironment is a major contributor to therapy resistance in breast cancer. In order to explore the predictive value of inflammation in breast cancer patients, we measured the inflammatory biomarkers serum ferritin and C-reactive protein (CRP) in 66 patients immediately before undergoing trastuzumab-containing therapy and evaluated their progression-free and overall survival. The elevation in pre-treatment serum ferritin (>250 ng/ml) or CRP (>7.25 mg/l) was a significant predictor of reduced progression-free survival and shorter overall survival. When patients were stratified based on their serum ferritin and CRP levels, patients with elevation in both inflammatory biomarkers had a markedly poorer response to trastuzumab-containing therapy. Therefore, the elevation in inflammatory serum biomarkers may reflect a pathological state that decreases the clinical efficacy of this therapy. Anti-inflammatory drugs and life-style changes to decrease inflammation in cancer patients should be explored as possible strategies to sensitize patients to anti-cancer therapeutics.
Highlights
Inflammation plays a critical role in breast cancer development and progression [1,2]
In order to examine the predictive value of inflammatory biomarkers in breast cancer patients, we measured serum ferritin and Creactive protein (CRP) in HER2/neu-overexpressing patients before undergoing trastuzumab-containing therapy (Table 1)
Of the 66 patients, 33 (50%) had elevated pre-treatment serum ferritin levels which were defined as being greater than the median, which at 250 ng/ml is near the upper limit of the normal range reported for serum ferritin [18,19] (Table 2, Fig. 1A)
Summary
Inflammation plays a critical role in breast cancer development and progression [1,2]. Epidemiological studies have consistently demonstrated that the chronic use of anti-inflammatory drugs is associated with reduced breast cancer incidence and mortality [3,4,5]. The role of the inflammatory microenvironment in modulating response to cancer therapy has only been recently appreciated [11,12,13]. Imaging studies have provided further evidence showing that infiltration of myeloid cells into tumors impedes therapy response [13]. Taken together, these studies suggest that drug distribution within the tumor increases with vascular permeability, which can be negatively influenced by macrophage-derived factors [11,13,14]
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