Circulating HER2 extracellular domain and resistance to chemotherapy in advanced breast cancer

To test the hypothesis of an association between HER2 and chemotherapy resi stance, we performed a prospective assessment of the predictive value of th e circulating HER2 extracellular domain (ECD) in patients with advanced bre ast carcinoma in the setting of a multicenter Phase II trial using paclitax el and doxorubicin. Serum samples were collected from 58 patients with meta static breast carcinoma before first-line chemotherapy for advanced disease , and the levels of circulating HER2 ECD were measured using an enzyme immu noassay. Immunohistochemistry with antiHER2 monoclonal antibody CB11 was us ed to assess the overexpression of HER2 in the primary tumors, When 450 fmo l/ml was used as a cutoff, 24 cases (41%) had elevated HER2 ECD levels. Ele vated levels of circulating HER2 ECD were associated with the expression of HER2 in the primary tumor tissue and with the metastatic tumor burden (eva luated with the marker CA 15-3; P = 0.032 and P = 0.002, respectively) but not with variables such as menopausal status, stage at diagnosis, previous adjuvant therapy, or the number of metastatic sites. The levels of circulat ing HER2 ECD correlated inversely with the response to treatment. The proba bility of obtaining a complete response to chemotherapy was significantly l ower (P = 0.021) in patients with elevated HER2 ECD levels (0%; 95% confide nce interval, 0-13%) compared with patients with nonelevated HER2 (26%; 95% confidence interval, 12-45%). In addition, the duration of clinical respon se was significantly shorter in patients with elevated HER2 ECD, compared w ith the cases with nonelevated HER2 (7.5 versus 11 months; P = 0.035), In c onclusion, elevated levels of circulating HER2 ECD in patients with metasta tic breast cancer correlate with reduced efficacy of a paclitaxel-doxorubic in chemotherapy combination. We suggest that the poor response rate associa ted with HER2 expression in advanced breast cancer may not be reversed by a ggressive chemotherapy alone.