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Imaging, Diagnosis, Prognosis |
Authors' Affiliations: 1 Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute and Hospital, Stockholm, Sweden; 2 Kyoto University Hospital, Breast Surgery, Kyoto, Japan; 3 Department of Molecular Sciences, Amgen, Inc., Seattle, Washington; 4 Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; and 5 Department of Clinical Trials and Research, Metropolitan Komagome Hospital, Tokyo Metropolitan Cancer and Infectious Disease Center, Tokyo, Japan
Requests for reprints: Stig Linder, Cancer Center Karolinska, R8:03, Karolinska Hospital, 17176 Stockholm, Sweden. Phone: 46-8-51772452; Fax: 46-8-339031; E-mail: Stig.Linder{at}cck.ki.se.
Purpose: With a widening arsenal of cancer therapies available, it is important to develop therapy-specific predictive markers and methods to rapidly assess treatment efficacy. We here evaluated the use of cytokeratin-18 (CK18) as a serum biomarker for monitoring chemotherapy-induced cell death in breast cancer.
Experimental Design: Different molecular forms of CK18 (caspase cleaved and total) were assessed by specific ELISA assays. Drug-induced release of CK18 was examined from breast carcinoma cells and tissue. CK18 protein composition was examined in serum. CK18 levels were determined in serum from 61 breast cancer patients during docetaxel or cyclophosphamide/epirubicin/5-fluorouracil (CEF) therapy.
Results: Caspase-cleaved CK18 molecules were released from monolayer cultures and tumor organ cultures to the extracellular compartment. CK18 was present in complexes with other cytokeratins in serum. Such CK18 protein complexes are remarkably stable, leading to favorable performance of CK18 biomarker assays for clinical investigations. Docetaxel induced increased levels of caspase-cleaved CK18 in serum from breast cancer patients, indicating apoptosis. CEF therapy led to increases predominantly in uncleaved CK18, indicating induction of necrotic cell death in many tumors. The increase in total CK18 at 24 h of the first treatment cycle correlated to the clinical response to CEF therapy (P < 0.0001).
Conclusions: Induction of necrotic cell death may explain the clinical efficacy of anthracycline-based therapy for breast carcinomas with defective apoptosis pathways. We suggest that CK18 biomarkers are useful for early prediction of the response to CEF therapy in breast cancer and may be useful biomarkers for clinical trials.
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