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 (HER2 ECD ) is reported to rise and fall in parallel with HER2+ breast cancer behavior. In this study, we evaluated the clinical relevance of plasma HER2 ECD 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 HER2 ECD 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 HER2 ECD levels were stable within 24 hours after the first trastuzumab injection. These plasma values correlated positively with the HER2 gene ratio (r s =0.39, P <0.001) and HER2 protein expression levels (r s =0.36, P <0.001) but not with ER/PR status of the primary tumor. HER2 ECD 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 HER2 ECD baseline values (<15ng/ml) had longer time to progression on combined trastuzumab-chemotherapy when first treated with trastuzumab monotherapy ( P =0.02). Monitoring HER2 ECD 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 HER2 ECD levels remained stable until just before disease progression. In patients responding to combination treatment HER2 ECD levels decreased to > 20%. Conclusions Plasma HER2 ECD 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 HER2 ECD levels during trastuzumab monotherapy could help defining the optimal time to introduce chemotherapy.