Cytokeratin-18 Is a Useful Serum Biomarker for Early Determination of Response of Breast Carcinomas to Chemotherapy

• Published in: Clinical cancer research Vol. 13; no. 11; pp. 3198 - 3206
• Main Authors: HÄGG OLOFSSON, Maria, UENO, Takayuki, ANDERSSON, Elina, SHOSHAN, Maria C, MANDIC HAVELKA, Aleksandra, TOI, Masakazu, LINDER, Stig, YANG PAN, REN XU, FENG CAI, VAN DER KUIP, Heiko, MUERDTER, Thomas E, SONNENBERG, Maike, AULITZKY, Walter E, SCHWARZ, Stephan
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-06-2007
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis; Biological and medical sciences; Biomarkers, Tumor; Breast Neoplasms - blood; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cell Line, Tumor; clinical response; Female; Gene Expression Regulation, Neoplastic; Gynecology. Andrology. Obstetrics; Humans; Keratin-18 - blood; Keratin-18 - genetics; Mammary gland diseases; Medical sciences; Medicin och hälsovetenskap; Models, Genetic; Necrosis; Neoplasm Metastasis; Pharmacology. Drug treatments; Reproducibility of Results; serum biomarker; Taxoids - pharmacology; Time Factors; Treatment Outcome; Tumors; Mammary gland diseases; Breast carcinoma; Cytokeratin; Biological fluid; Chemotherapy; Treatment; Biological marker; Early; Serum; Breast cancer; Malignant tumor; Quantitative analysis
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-0009

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.