Krebs von den Lungen 6 (KL-6) is a novel diagnostic and prognostic biomarker in pleural mesothelioma

Paul Stockhammer; Hannah Baumeister; Till Ploenes; Francesco Bonella; Dirk Theegarten; Balazs Dome; Christine Pirker; Walter Berger; Luca Hegedüs; Marcell Baranyi; Martin Schuler; Sophie Deshayes; Servet Bölükbas; Clemens Aigner; Christophe Blanquart; Balazs Hegedüs

doi:10.1016/j.lungcan.2023.107360

Krebs von den Lungen 6 (KL-6) is a novel diagnostic and prognostic biomarker in pleural mesothelioma

Lung Cancer. 2023 Nov:185:107360. doi: 10.1016/j.lungcan.2023.107360. Epub 2023 Sep 7.

Authors

Paul Stockhammer¹, Hannah Baumeister², Till Ploenes³, Francesco Bonella⁴, Dirk Theegarten⁵, Balazs Dome⁶, Christine Pirker⁷, Walter Berger⁷, Luca Hegedüs², Marcell Baranyi⁸, Martin Schuler⁹, Sophie Deshayes¹⁰, Servet Bölükbas², Clemens Aigner¹¹, Christophe Blanquart¹⁰, Balazs Hegedüs¹²

Affiliations

¹ Department of Thoracic Surgery, Ruhrlandklinik, West German Cancer Center, University Duisburg-Essen, Tueschener Weg 40, 45239 Essen, Germany; Yale School of Medicine, Yale University, 333 Cedar St, New Haven, CT 06510, USA.
² Department of Thoracic Surgery, Ruhrlandklinik, West German Cancer Center, University Duisburg-Essen, Tueschener Weg 40, 45239 Essen, Germany.
³ Department of Thoracic Surgery, Ruhrlandklinik, West German Cancer Center, University Duisburg-Essen, Tueschener Weg 40, 45239 Essen, Germany; Division of Thoracic Surgery, Department for Visceral-, Thoracic and Vascular Surgery, Medical Faculty Carl Gustav Carus and University Hospital, Technische Universität Dresden, Helmholtzstr. 10, 01069 Dresden, Germany.
⁴ Center for Interstitial and Rare Lung Disease Unit, Ruhrlandklinik University Hospital, University of Duisburg-Essen, Tueschener Weg 40, 45239 Essen, Germany.
⁵ Institute of Pathology, University Hospital Essen, University Duisburg-Essen, Hufelandstraße 55, 45147 Essen, Germany.
⁶ Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria; Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Ráth György u. 7-9, 1122 Budapest, Hungary; National Korányi Institute of Pulmonology, Korányi Frigyes út 1, 1122 Budapest, Hungary; Department of Translational Medicine, Lund University, Box 117, 221 00 Lund, Sweden.
⁷ Center for Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University Vienna, Spitalgasse 23, 1090 Vienna, Austria.
⁸ Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Üllöi ut 93, 195, Budapest, Hungary.
⁹ German Cancer Consortium (DKTK), Partner Site University Hospital Essen, 45122 Essen, Germany; Department of Medical Oncology, West German Cancer Center, University Duisburg-Essen, Hufelandstraße 55, 45147 Essen, German.
¹⁰ Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, F-44000 Nantes, France.
¹¹ Department of Thoracic Surgery, Ruhrlandklinik, West German Cancer Center, University Duisburg-Essen, Tueschener Weg 40, 45239 Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, 45122 Essen, Germany; Karl-Landsteiner-Institute for Clinical and Translational Thoracic Surgery Research, Bruenner Strasse 68, 1210 Vienna, Austria.
¹² Department of Thoracic Surgery, Ruhrlandklinik, West German Cancer Center, University Duisburg-Essen, Tueschener Weg 40, 45239 Essen, Germany. Electronic address: balazs.hegedues@rlk.uk-essen.de.

PMID: 37713954
DOI: 10.1016/j.lungcan.2023.107360

Abstract

Objectives: Pleural mesothelioma (PM) is a rare disease with dismal outcome. Systemic treatment options include chemotherapy and immunotherapy, but biomarkers for treatment personalization are missing. The only FDA-approved diagnostic biomarker is the soluble mesothelin-related protein (SMRP). Krebs von den Lungen-6 (KL-6) is a human mucin 1 (MUC1) glycoprotein, which has shown diagnostic and prognostic value as a biomarker in other malignancies. The present study investigated whether KL-6 can serve as a diagnostic and/or prognostic biomarker in PM.

Materials and methods: Using a fully-automated chemiluminescence enzyme immunoassay (CLEIA) for KL-6 and SMRP, pleural effusion samples from 87 consecutive patients with PM and 25 patients with non-malignant pleural disorders were studied. In addition, KL-6 and SMRP levels were determined in corresponding patient sera, and in an independent validation cohort (n = 122). MUC1 mRNA and protein expression, and KL-6 levels in cell line supernatants were investigated in PM primary cell lines in vitro.

Results: PM patients had significantly higher KL-6 levels in pleural effusion than non-malignant controls (AUC 0.78, p < 0.0001). Among PM patients, levels were highest in those with epithelioid or biphasic histologies. There was a strong positive correlation between pleural effusion levels of KL-6 and SMRP (p < 0.0001). KL-6 levels in sera similarly associated with diagnosis of PM, however, to a lesser extent (AUC 0.71, p = 0.008). PM patients with high pleural effusion KL-6 levels (≥303 IU/mL) had significantly better overall survival (OS) compared to those with low KL-6 levels (HR 0.51, p = 0.004). Congruently, high tumor cell MUC1 mRNA expression in primary cell lines associated with prolonged corresponding patient OS (HR 0.35, p = 0.004). These findings were confirmed in an independent validation cohort.

Conclusion: This is the first study demonstrating KL-6 as a potential novel liquid-based diagnostic and prognostic biomarker in PM.

Keywords: Biomarker; KL-6; Mucins; Pleural effusion; Pleural mesothelioma; SMRP.