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Molecular Oncology, Markers, Clinical Correlates |
Medical Oncology Division, Hospital 12 de Octubre, 28041 Madrid [R. C., S. M., H. C-F.]; Hematology and Medical Oncology Division, Hospital Clínic, 46010 Valencia [A. L.]; Medical Oncology Division, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona [B. O.]; Medical Oncology Division, Hospital Germans Trias i Pujol, 08916 Barcelona [A. B.]; Medical Oncology Division, Hospital Clínico, 28040 Madrid [A. C.]; Medical Oncology Division, Hospital General, 03010 Alicante [B. M.]; Pathology Department, Institut Català d’Oncologia, 08907 Barcelona [B. L.], Spain
To test the hypothesis of an association between HER2 and chemotherapy resistance, we performed a prospective assessment of the predictive value of the circulating HER2 extracellular domain (ECD) in patients with advanced breast carcinoma in the setting of a multicenter Phase II trial using paclitaxel and doxorubicin. Serum samples were collected from 58 patients with metastatic breast carcinoma before first-line chemotherapy for advanced disease, and the levels of circulating HER2 ECD were measured using an enzyme immunoassay. Immunohistochemistry with anti-HER2 monoclonal antibody CB11 was used to assess the overexpression of HER2 in the primary tumors. When 450 fmol/ml was used as a cutoff, 24 cases (41%) had elevated HER2 ECD levels. Elevated levels of circulating HER2 ECD were associated with the expression of HER2 in the primary tumor tissue and with the metastatic tumor burden (evaluated 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 circulating HER2 ECD correlated inversely with the response to treatment. The probability of obtaining a complete response to chemotherapy was significantly lower (P = 0.021) in patients with elevated HER2 ECD levels (0%; 95% confidence interval, 0–13%) compared with patients with nonelevated HER2 (26%; 95% confidence interval, 12–45%). In addition, the duration of clinical response was significantly shorter in patients with elevated HER2 ECD, compared with the cases with nonelevated HER2 (7.5 versus 11 months; P = 0.035). In conclusion, elevated levels of circulating HER2 ECD in patients with metastatic breast cancer correlate with reduced efficacy of a paclitaxel-doxorubicin chemotherapy combination. We suggest that the poor response rate associated with HER2 expression in advanced breast cancer may not be reversed by aggressive chemotherapy alone.
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