INTRODUCTION: Platinum-based chemotherapy is besides the standard antifolate therapy with pemetrexed, the cornerstone for treatment of patients with malignant pleural mesothelioma (MPM), and its efficacy depends on several DNA repair enzymes. Therefore, these enzymes could be biomarkers for "tailoring" chemotherapy. This study evaluated enzymes involved in repair of platinum-caused DNA damage, potentially resulting in a biomarker panel associated with patient response and outcome to platinum-based chemotherapy. MATERIAL AND METHODS: Pre- or posttreatment specimens from a total of 103 patients with MPM who were undergoing first-line chemotherapy were tested separately. Immunohistochemistry for ERCC1 (endonuclease excision repair cross-complementing 1), MLH1 (MutL homologue 1), MutS homologue (MSH) 2, MSH6, and βIII-tubulin protein expression, and pyrosequencing for ERCC1 codon 118 and C8092A polymorphisms were performed, and their results were correlated to clinicopathologic data. RESULTS: ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin were expressed in human MPM specimens at different intensities. When considering only pretreatment specimens, MSH6 protein levels were correlated to progression during chemotherapy (P = .0281). MLH1 protein levels (P = .0205), and ERCC1 codon 118 polymorphisms (P ≤ .0001) were significantly associated with progression-free survival. A significant association between ERCC1 protein levels and overall survival was noted (P = .032). Analyses of posttreatment specimens revealed significant associations between βIII-tubulin protein levels and progression-free survival (P = .0066). ERCC1 C8092A polymorphisms were significantly associated with progression-free survival and overall survival (P = .0463 and P = .0080, respectively) in this group. CONCLUSIONS: Enzymes involved in DNA repair mechanisms are associated with patient response and outcome to platinum-based chemotherapy. Their assessment may be a helpful tool to tailor platinum-based chemotherapy of MPM patients who might expect the largest clinical benefit. Prospective validation of this biomarker panel is warranted.
INTRODUCTION:Platinum-based chemotherapy is besides the standard antifolate therapy with pemetrexed, the cornerstone for treatment of patients with malignant pleural mesothelioma (MPM), and its efficacy depends on several DNA repair enzymes. Therefore, these enzymes could be biomarkers for "tailoring" chemotherapy. This study evaluated enzymes involved in repair of platinum-caused DNA damage, potentially resulting in a biomarker panel associated with patient response and outcome to platinum-based chemotherapy. MATERIAL AND METHODS: Pre- or posttreatment specimens from a total of 103 patients with MPM who were undergoing first-line chemotherapy were tested separately. Immunohistochemistry for ERCC1 (endonuclease excision repair cross-complementing 1), MLH1 (MutL homologue 1), MutS homologue (MSH) 2, MSH6, and βIII-tubulin protein expression, and pyrosequencing for ERCC1 codon 118 and C8092A polymorphisms were performed, and their results were correlated to clinicopathologic data. RESULTS:ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin were expressed in human MPM specimens at different intensities. When considering only pretreatment specimens, MSH6 protein levels were correlated to progression during chemotherapy (P = .0281). MLH1 protein levels (P = .0205), and ERCC1 codon 118 polymorphisms (P ≤ .0001) were significantly associated with progression-free survival. A significant association between ERCC1 protein levels and overall survival was noted (P = .032). Analyses of posttreatment specimens revealed significant associations between βIII-tubulin protein levels and progression-free survival (P = .0066). ERCC1C8092A polymorphisms were significantly associated with progression-free survival and overall survival (P = .0463 and P = .0080, respectively) in this group. CONCLUSIONS: Enzymes involved in DNA repair mechanisms are associated with patient response and outcome to platinum-based chemotherapy. Their assessment may be a helpful tool to tailor platinum-based chemotherapy of MPM patients who might expect the largest clinical benefit. Prospective validation of this biomarker panel is warranted.
Authors: Fabian Dominik Mairinger; Robert Werner; Elena Flom; Jan Schmeller; Sabrina Borchert; Michael Wessolly; Jeremias Wohlschlaeger; Thomas Hager; Thomas Mairinger; Jens Kollmeier; Daniel Christian Christoph; Kurt Werner Schmid; Robert Fred Henry Walter Journal: Virchows Arch Date: 2017-05-02 Impact factor: 4.064
Authors: R F H Walter; F D Mairinger; S Ting; C Vollbrecht; T Mairinger; D Theegarten; D C Christoph; K W Schmid; J Wohlschlaeger Journal: Br J Cancer Date: 2015-02-10 Impact factor: 7.640
Authors: Adam Szulkin; Rita Otvös; Carl-Olof Hillerdal; Aytekin Celep; Eviane Yousef-Fadhel; Henriette Skribek; Anders Hjerpe; László Székely; Katalin Dobra Journal: BMC Cancer Date: 2014-09-24 Impact factor: 4.430
Authors: Robert Fred Henry Walter; Fabian Dominik Mairinger; Robert Werner; Claudia Vollbrecht; Thomas Hager; Kurt Werner Schmid; Jeremias Wohlschlaeger; Daniel Christian Christoph Journal: Oncotarget Date: 2016-04-12