Elevation in inflammatory serum biomarkers predicts response to trastuzumab-containing therapy

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.

Figure 1. Serum ferritin (A) and CRP (B) levels in HER2/neu-overexpressing patients before undergoing trastuzumab-containing therapy (n = 66).

The pretreatment values were moderately correlated (C).

Figure 2. Serum ferritin and CRP predict response to trastuzumab-containing therapy.

Pre-treatment serum ferritin and CRP predict overall survival (A&C respectively) and progression-free survival (PFS; B&D respectively) in patients receiving trastuzumab-containing therapy. Low serum ferritin or CRP (<250 ng/ml and <7.25 mg/l respectively) had an overall better clinical outcome than high ferritin or CRP. Difference in OS and PFS were analyzed by Kaplan-Meier survival model with the median serum ferritin or CRP value as a cutoff point.

Figure 3. Patients with elevation in both serum ferritin and CRP have the poorest response to trastuzumab-containing therapy.

Kaplan-Meier analysis of overall survival (A) and progression-free survival (B) in trastuzumab-treated patients stratified by their CRP and serum ferritin levels. High CRP (>7.25 mg/l); High Ferritin (>250 ng/ml).