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 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 HER2ECD levels were stable within 24 h 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 (> 35 ng/ml) had the worst overall survival (P = 0.03) if treated with upfront combination therapy. Conversely, patients with low HER2ECD baseline values (< 15 ng/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.

Trial registration: Registration Number by ClinicalTrials.gov: NCT00004935, Trial number: SAKK22/99. Registered on 27 January 2003.

Keywords: Baseline; HER2+ breast cancer; Plasma HER2ECD levels; Sequential therapy; Trastuzumab; Upfront combined therapy.

Conflict of interest statement

Dirk Klingbiel performed the statistical analysis of the data working for the SAKK Swiss Group for Clinical Cancer Research Coordinating Center, Bern, Switzerland. Thereafter, before submission of the manuscript, he joined F. Hoffmann-La Roche Ltd. (F. Hoffmann-La Roche Ltd., Global Product Development Medical Affairs (Biometrics), CH-4053 Basel).

D.A. Rufle joined Ausbilder Biologie, AZM-2202.2.04, Lachmattstrasse 81, 4132 Muttenz after complete performance of all laboratory analyses.

B. Thürlimann holds stock of Roche and received honoraria for consultations from Roche.

All other authors declare that they have no competing interests.

Figures

Fig. 1

Comparison of baseline ECDHER2 values as detected in plasma (n = 47) or serum (n = 13) in two SAKK studies. Median values of plasma ECDHER2 levels of selected postmenopausal patients with ER positive tumors (left) compared to the one detected in serum of patients entering the SAKK23/04 (in both studies median: 21 ng/ml; P = 0.42)

Fig. 2

Kaplan–Meyer curves of the overall study population with respect to a TTP, b TTP-TChemo; c OS using the threshold of 15 ng/ml; and d OS using the calculated threshold of 35 ng/ml

Fig. 3

Kaplan–Meyer curves of patients’ subsets with respect to OS (a-b) and TTP-TChemo (c-d). Baseline HER2ECD threshold values are 35 ng/ml in (a-b), and 15 ng/ml in (c-d)

Fig. 4

Spaghetti plots with summary of plasma HER2ECD levels of the two arms’ cohort behavior: red lines Arm A and turquoise lines Arm B. Observation time points: Base: Baseline mean values before-after first injection; d1c2: day 1 s cycle (after 3 weeks); ass1: first assessment at 8–9 weeks; PD1: first progression; PD2: second progression

Fig. 5

Kaplan-Meier curves depicting the OS of patients in Arm A with no change (green), increased (red), and decreased (black) ECDHER2 values at first assessment compared to baseline values