ERCC1, MLH1, MSH2, MSH6, and beta III-Tubulin: Resistance Proteins Associated With Response and Outcome to Platinum-based Chemotherapy in Malignant Pleural Mesothelioma

作者：Ting Saskia^*; Mairinger Fabian D; Hager Thomas; Welter Stefan; Eberhardt Wilfried E; Wohlschlaeger Jeremias; Schmid Kurt W; Christoph Daniel C

来源：Clinical Lung Cancer, 2013, 14(5): 558-U150.

DOI：10.1016/j.cllc.2013.04.013

• Biomarker
• DNA repair
• Immunohistochemistry
• Pyrosequencing
• Tailored therapy

Outcome of patients with malignant pleural mesothelioma after platinum-based chemotherapy depends on DNA repair enzymes. In 79 patients with pretreatment specimens, MSH (MutS homologue) 6 expression was correlated to progression, MLH1 (MutL homologue 1) expression was associated with progression-free survival, and ERCC1 (endonuclease excision repair cross-complementing 1) expression was associated with overall survival. In 41 patients with posttreatment specimens, beta III-tubulin expression was associated with progression-free survival. Associations between ERCC1 polymorphisms and survival were noted in both groups. 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 %26quot;tailoring%26quot; 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 beta III-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 beta III-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%26lt;.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 beta III-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.

• 出版日期2013-9