Background: Amplification or overexpression of HER2 has been shown to play an important role in approximately 30% of breast cancers and is strongly associated with increased recurrence and a worse prognosis. The HER2 extracellular domain (ECD) may be cleaved and shed from the surface of breast cancer cells and serum HER2 ECD levels can be detected by enzyme-linked immunosorbent assay (ELISA). In this study, we explored the relationship between circulating HER2 ECD and tissue HER2 status, then we also examined its predictive value in a cohort of metastatic breast cancer patients. Methods: Two hundred and seven metastatic breast cancer patients from March 2009 to July 2011 were involved in this prospective study at Zhejiang Cancer Hospital. The patients were identified histopathologically as having breast cancer by pathologists and staged mainly based on the pathology, the clinical manifestation, and the imaging findings of CT and MRI according to the classification system of the International Union Against Cancer. Serum HER2 ECD levels were measured by ELISA. Tissue HER2 was determined by IHC and FISH in tumor samples, respectively. Results: The level of serum HER2 ECD was at least more than 15 ng/ml in 31.4% (65/207) metastatic breast cancer patients, 39.1%(43/110) in HER2-positive patients and 23.4%(22/94) in HER2-negative cases, respectively, P = 0.017. We also found that high serum HER2 ECD levels (≥15 ng/ml) were significantly associated with elevated serum CEA (52.1% v 21.5%, OR 3.978, 95%CI 2.138–7.401, P = 0.000), CA125 (48.5% v 23.5%, OR 3.064, 95%CI 1.650–5.691, P = 0.000), CA153 (53.2% v 17.1%, OR 5.48, 95%CI 2.897–10.366, P = 0.000), LDH (53.3% v 23.1%, OR 3.798, 95%CI 2.011–7.173, P = 0.000) and AKP (51.2% v 26.5%, OR 2.911, 95%CI 1.442–5.879, P = 0.002), respectively. For the effect of HER2 ECD on the site of relapse, still there were statistically significant correlation between increased serum HER2 ECD levels and liver involvement (42.7% v 24.0%, OR 2.358, 95%CI 1.294–4.297, P = 0.005), brain metastasis (50.0% v 26.7%, OR 2.744, 95%CI 1.397–5.391, P = 0.003) and visceral involved (37.9% v 14.8%, OR 3.511, 95%CI 1.548–7.961, P = 0.002), respectively. While serum HER2 ECD levels were not related to age, BMI, tumor size, lymph node involvement and hormone receptors status, respectively (P>0.05). Conclusions: Monitoring the circulating levels of the HER2 ECD in patients with metastatic breast cancer provides a real-time assessment of tumor burden and indicates poor prognosis, and may provide important information for reassessment of HER2 in HER2-negative metastatic breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-05-05.

Background: The human epidermal growth factor (HER2/neu) oncoprotein is composed of an intracellular tyrosine kinase portion, a short transmembrane section, and an extracellular ligand-binding domain (ECD). The latter is frequently cleaved from the surface of breast cancer cells and the serum HER2 ECD levels can be detected by enzyme-linked immunosorbent assay (ELISA). Consistent with majority of reports, our prior study showed that high circulating levels of the HER2 ECD indicates poor prognosis in 207 patients with metastatic breast cancer. In the present study, we aimed to elucidate whether serum HER2 ECD levels would predict the clinical outcome of metastatic breast cancer patients. Methods: Till May 19, 2012, one hundred ninty metastatic breast cancer patients were followed up. Serum was available from 190 patients at baseline, 46 patients in the assessment of time. Serum HER2 ECD levels were measured by ELISA. Disease state was assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Progression-free survival (PFS) was defined as the interval from the time of randomization until the first documentation of disease progression or death due to any cause. PFS and median PFS were generated by Kaplan-Meier spots. Results: Elevated baseline HER2 ECD levels (bECD) (≥15 ng/ml) were observed in 40% (40/100) of patients with HER2-amplified tumors and 21.8% (19/87) of patients with HER2-negative tumors. Patients with bECD-elevated disease had a median PFS of 356 days compared with 229 days for patients with bECD-low disease(P = 0.001). In HER2-amplified cohort, median PFS for patients with low bECD levels was longer than those with bECD-elevated disease (391 days v 226 days, P = 0.005). And patients with low bECD levels treated with Herceptin-based regimen (n = 36) had a trend of longer PFS than patients(n = 24) treated with non-Herceptin regimen(447 days v 298 days, P = 0.227). Moreover, bECD-low patients (n = 36) showed a significantly longer median PFS than bECD-elevated patients(n = 22) when treated with Herceptin-based scheme (447 days v 229 days, P = 0.004). While, in patients with increased bECD levels, there was no statistical difference between Herceptin-treated groups (n = 22) and non-Herceptin-treated groups (n = 14) (229 days v 173 days, P = 0.761). In the HER2-negative group, patients with bECD-low disease had a median PFS of 313 days compared with 206 days for patients with bECD-elevated disease (P = 0.02). In a cohort of 46 patients whose HER2 ECD levels were monitored during treatment, 29 patients remains low ECD levels, 12 patients convert from elevated to low, 2 patients convert from low to high, and 3 patients remains elevated HER2 ECD levels. The patients who remained low ECD levels or achieved low ECD leves have significantly longer PFS than those whose levels remained above 15ng/mL or converted from low to high regardless of treatment given (440 days v 192days, P = 0.019). Conclusion: Elevated HER2 bECD predicts poor median PFS irrespective of HER2 status. HER2-amplified patients with low-HER2 ECD levels may get more benefit from Herceptin-based scheme. Remained low-HER2 ECD levels or decreases in serum HER2 ECD levels during treatment were associated with longer median PFS in metastatic breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-09-09.