Abstract
The HER-2/neu oncogene and its p185 receptor protein are indicators of a more aggressive form of breast cancer. The HER-2/neu status of the tumour guides trastuzumab (Herceptin ®) therapy, a monoclonal antibody directed against the extracellular domain (ECD) of the HER-2/neu oncoprotein. The HER-2/neu ECD is shed from cancer cells into the circulation and is measurable by immunoassay (HER-2/neu Manual Elisa, Oncogene Science, Cambridge, MA, USA). Currently, the HER-2 status of the tumour is evaluated either by morphological techniques, immunocytochemistry or fluorescent in situ hybridization. We studied serum HER-2 ECD before and after primary treatment in a series of 701 primary breast cancers at diagnosis and before first metastases ( N =128). At diagnosis, elevated HER-2 ECD (>12 ng/ml, cut-off level) was found in only 47 (6.7%) patients. Before first metastases, 45% of the samples were over 12 μg/l of HER-2 ECD (cut-off) and were significantly related with pre -and post treatment values ( P =0.0350 and P <0.0001 respectively). Concordance with CA 15.3 was 56.25% (weak correlation, rho =0.263). HER-2 ECD levels differed according to the sites of metastases ( P =0.0199, highest levels found in liver and lung). A median HER-2 ECD lead time of 254 days was found in 18/28 (64.3%) of recurring patients. Premetastatic HER-2 ECD levels showed a strong univariate (Kaplan-Meier method, P =0.0014) and multivariate prognostic values (Cox model, P <0.0001) for survival. We monitored the longitudinal changes in HER-2 ECD values of 33 women with metastatic breast cancer treated with trastuzumab and chemotherapy. Changes in HER-2 ECD serial concentrations reflected the clinical course of disease, increasing HER-2 ECD indicated breast cancer progression while decreasing serum values were indicative of response to therapy. We constructed a model (GEE, generalised estimated equation) that can be used to emulate patients’ response and we found pre-treatment HER-2 ECD to be predictive of the response to trastuzumab : when over 30ng/ml, pretreatment HER-2 ECD is predictive of treatment failure. In recurrent breast cancer, elevated levels of HER-2 ECD allow an early detection of occult metastases and the identification of patients with a high probability of shortened survival. Monitoring HER-2/ neu ECD levels during metastatic breast cancer can provide a real time assessment of a woman’s HER-2/ neu status and can provide important information for therapeutic decisions.
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