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

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 h; 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 h 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 ( > 35 ng/ml) had the worst overall survival ( P = 0.03) if treated with upfront combination therapy. Conversely, patients with low HER2 ECD baseline values (< 15 ng/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. Trial registration Registration Number by ClinicalTrials.gov: NCT00004935 , Trial number: SAKK22/99. Registered on 27 January 2003.