Folic acid phenotype (FAP) is a superior biomarker predicting response to pemetrexed-based chemotherapy in malignant pleural mesothelioma

// Fabian Dominik Mairinger 1 , Claudia Vollbrecht 2, 3, 4 , Elena Flom 1 , Daniel Christian Christoph 5 , Kurt-Werner Schmid 1 , Jens Kollmeier 6 , Helmut Hans Popper 7 , Thomas Mairinger 8 and Robert Fred Henry Walter 1, 9 1 Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 2 Institute of Pathology, Division of Molecular Pathology, Charite, Berlin, Germany 3 German Cancer Consortium (DKTK), Germany 4 German Cancer Research Center (DKFZ), Heidelberg, Germany 5 Department of Medical Oncology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 6 Department of Pneumology, Helios Klinikum Emil von Behring, Berlin, Germany 7 Department of Pathology, Division of Molecular Lung- and Pleurapathology, Medical University of Graz, Graz, Austria 8 Department of Pathology, Helios Klinikum Emil von Behring, Berlin, Germany 9 Ruhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany Correspondence to: Fabian Dominik Mairinger, email: fabian.mairinger@uk-essen.de Keywords: pleural mesothelioma, pemetrexed, thymidylate synthethase, folylpolyglutamate synthase, personalized therapy Received: October 12, 2016 Accepted: March 01, 2017 Published: March 21, 2017 ABSTRACT Background: Malignant pleural mesothelioma (MPM) is a rare tumor linked to a dismal prognosis. Even the most effective chemotherapeutical regime of pemetrexed combined with cisplatin leads to a remission-rate of only about 40%. The reasons for the rather poor efficacy remain largely unknown. Results: Phenotypes were significantly associated with progression (p=0.0279) and remission (p=0.0262). Cox-regression revealed significant associations between SLC19A1 / TYMS -ratio (p=0.0076) as well as FPGS / TYMS -ratio (p=0.0026) and OS. For differentiation by risk-groups, COXPH identified a strong correlation (p=0.0008). Methods: 56 MPM specimens from patients treated with pemetrexed were used for qPCR analysis. Phenotypes and risk groups were defined by their expression levels of members of the folic acid metabolism and correlated to survival and objective response. Conclusion: Our results indicate that the balance between folic acid uptake, activation and metabolism plays a crucial role in response to pemetrexed-based chemotherapy and the prognosis of MPM patients. Implementing this marker profile in MPM stratification may help to individualize MPM-therapy more efficiently.