Plasma HER2ECD a promising test for patient prognosis and prediction of response in HER2 positive breast cancer: Results of a randomized study - SAKK 22/99.

Abstract Background: The HER2 extracellular domain shed in blood (HER2ECD) is reported to rise and fall in parallel with HER2+ breast cancer behavior. In this study, we evaluated the clinical relevance of plasma HER2ECD values in patients with metastatic breast cancer treated in the SAKK22/99 trial comparing trastuzumab monotherapy followed by trastuzumab-chemotherapy combination at progression versus upfront combination therapy. Methods : Quantitative assessment of plasma HER2ECD was performed in 133 patients at baseline; after 2-24 hours; at 3 weeks; at first response evaluation (8-9 weeks); and at tumor progression. Associations with tumor characteristics, disease course and trial treatment were evaluated.Results: Baseline HER2ECD levels were stable within 24 hours after the first trastuzumab injection. These plasma values correlated positively with the HER2 gene ratio (rs=0.39, P<0.001) and HER2 protein expression levels (rs=0.36, P<0.001) but not with ER/PR status of the primary tumor. HER2ECD baseline levels were positively associated with the presence of visceral disease (P=0.05) and poor patients’ outcome (Cox-regression: P=0.009). Patients with high baseline levels (>35ng/ml) had the worst overall survival (P=0.03) if treated with upfront combination therapy. Conversely, patients with low HER2ECD baseline values (<15ng/ml) had longer time to progression on combined trastuzumab-chemotherapy when first treated with trastuzumab monotherapy (P=0.02). Monitoring HER2ECD levels during the course of the trial revealed significant time (P=0.001) and time-treatment arm interactions (P=0.0007). Under upfront trastuzumab alone, the HER2ECD levels remained stable until just before disease progression. In patients responding to combination treatment HER2ECD levels decreased to >20%. Conclusions: Plasma HER2ECD levels in patients with metastatic breast cancer reflect HER2 disease status. This robust biomarker might help identifying patients without visceral disease profiting from a sequential treatment’s modality. Monitoring HER2ECD levels during trastuzumab monotherapy could help defining the optimal time to introduce chemotherapy.