Treated with Pemetrexed / Carboplatin PatientsGroup-1 as Predictors of Responsiveness in Mesothelioma Thymidylate Synthase and Excision Repair Cross-Complementing

Purpose: The pemetrexed/platinum agent combination represents the standard of care in first-line treatment for malignant pleural mesothelioma (MPM). However, there are no established indicators of responsiveness that can be used to optimize the treatment. This retrospective study aimed to assess the role of excision repair cross-complementing group-1 (ERCC1) and thymidylate synthase (TS) in tumors, and correlate expression levels and polymorphisms of these key determinants of drug activity with the outcome of MPM patients treated with carboplatin/pemetrexed in first-line setting. Experimental design: Analysis of TS and ERCC1 polymorphisms, mRNA and protein expression was done by PCR and immunohistochemistry [with the H-score (histologic score)] in tumor specimens from 126 MPM patients, including 99 carboplatin-/pemetrexed-treated patients. Results: A significant correlation between low TS protein expression and disease control (DC) to carboplatin/pemetrexed therapy (P1⁄4 0.027), longer progression-free survival (PFS; P1⁄4 0.017), and longer overall survival (OS; P 1⁄4 0.022) was found when patients were categorized according to median H-score. However, patients with the higher tertile of TSmRNA expression correlated with higher risk of developing progressive disease (P 1⁄4 0.022), shorter PFS (P < 0.001), and shorter OS (P < 0.001). At multivariate analysis, the higher tertile of TS mRNA level and TS H-score confirmed their independent prognostic role for DC, PFS, and OS. No significant associations were found among ERCC1 protein expression, TS and ERCC1 polymorphisms, and clinical outcome. Conclusions: In our series of carboplatin-/pemetrexed-treatedMPM patients, low TS protein andmRNA levels were significantly associated to DC, improved PFS, andOS. Prospective trials for the validation of the prognostic/predictive role of TS in MPM patients treated with pemetrexed-based regimens are warranted. Clin Cancer Res; 17(8); 2581–90. 2011 AACR.

[1]  Yi Shi,et al.  Predictive value of ERCC1 and XPD polymorphism in patients with advanced non-small cell lung cancer receiving platinum-based chemotherapy: a systematic review and meta-analysis , 2011, Medical oncology.

[2]  G. Scagliotti,et al.  Thymidylate synthase but not excision repair cross-complementation group 1 tumor expression predicts outcome in patients with malignant pleural mesothelioma treated with pemetrexed-based chemotherapy. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  E. Giovannetti,et al.  Polymorphisms in the enhancer region of the thymidylate synthase gene are associated with thymidylate synthase levels in normal tissues but not in malignant tissues of patients with colorectal cancer. , 2009, Clinical colorectal cancer.

[4]  E. Giovannetti,et al.  Pharmacogenomics in non-small-cell lung cancer chemotherapy. , 2009, Advanced drug delivery reviews.

[5]  R. Lucito,et al.  Genomic events associated with progression of pleural malignant mesothelioma , 2009, International journal of cancer.

[6]  C. Obasaju,et al.  Clinical Efficacy and Predictive Molecular Markers of Neoadjuvant Gemcitabine and Pemetrexed in Resectable Non-small Cell Lung Cancer , 2008, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[7]  E. Giovannetti,et al.  Role of cMET expression in non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[8]  M. Ahn,et al.  ERCC1 expression as a predictive marker of squamous cell carcinoma of the head and neck treated with cisplatin-based concurrent chemoradiation , 2008, British Journal of Cancer.

[9]  G. Bepler,et al.  Thymidylate synthase in situ protein expression and survival in stage I nonsmall‐cell lung cancer , 2008, Cancer.

[10]  V. Torri,et al.  Pemetrexed plus carboplatin in elderly patients with malignant pleural mesothelioma: combined analysis of two phase II trials , 2008, British Journal of Cancer.

[11]  E. Giovannetti,et al.  Molecular Mechanisms Underlying the Synergistic Interaction of Erlotinib, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, with the Multitargeted Antifolate Pemetrexed in Non-Small-Cell Lung Cancer Cells , 2008, Molecular Pharmacology.

[12]  G. Scagliotti,et al.  Thymidylate Synthase Expression in Gastroenteropancreatic and Pulmonary Neuroendocrine Tumors , 2008, Clinical Cancer Research.

[13]  D. Katsaros,et al.  ERCC1 genotype and phenotype in epithelial ovarian cancer identify patients likely to benefit from paclitaxel treatment in addition to platinum-based therapy. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  L. Lesko,et al.  Personalized Medicine: Elusive Dream or Imminent Reality? , 2007, Clinical pharmacology and therapeutics.

[15]  H. Pospisil,et al.  In vitro chemosensitivity of freshly explanted tumor cells to pemetrexed is correlated with target gene expression , 2007, Investigational New Drugs.

[16]  E. Reed,et al.  A Gynecologic Oncology Group study of platinum-DNA adducts and excision repair cross-complementation group 1 expression in optimal, stage III epithelial ovarian cancer treated with platinum-taxane chemotherapy. , 2007, Cancer research.

[17]  V. Catalano,et al.  Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  E. Giovannetti,et al.  Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels , 2007, British Journal of Cancer.

[19]  Zhong Zheng,et al.  DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. , 2007, The New England journal of medicine.

[20]  D. Goldman,et al.  Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications , 2007, Molecular Cancer Therapeutics.

[21]  Y. Ozeki,et al.  Significance of thymidylate synthase gene expression level in patients with adenocarcinoma of the lung , 2006, Cancer.

[22]  A. Ceribelli,et al.  Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  R. Peters.  Pharmacogenetics of Colon Cancer and Potential Implications for 5- Fluorouracil-Based Chemotherapy , 2006 .

[24]  Y. Bang,et al.  Cytotoxic effects of pemetrexed in gastric cancer cells , 2005, Cancer science.

[25]  Youngchul Kim,et al.  Association between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy. , 2004, Lung cancer.

[26]  新谷 康.  New prognostic indicator for non-small-cell lung cancer, quantitation of thymidylate synthase by real-time reverse transcription polymerase chain reaction , 2004 .

[27]  M. Byrne,et al.  Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[28]  David B. Goldstein,et al.  Pharmacogenetics goes genomic , 2003, Nature Reviews Genetics.

[29]  G. Peters,et al.  Induction of resistance to the multitargeted antifolate Pemetrexed (ALIMTA) in WiDr human colon cancer cells is associated with thymidylate synthase overexpression. , 2003, Biochemical pharmacology.

[30]  Claude Denham,et al.  Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  G. Scagliotti,et al.  Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  M. Paesmans,et al.  Activity of chemotherapy and immunotherapy on malignant mesothelioma: a systematic review of the literature with meta-analysis. , 2002, Lung cancer.

[33]  B. Iacopetta,et al.  A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil , 2001, British Journal of Cancer.

[34]  J. García-Foncillas,et al.  Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  H. Kindler,et al.  Malignant pleural mesothelioma , 2000, Current treatment options in oncology.

[36]  F Levi,et al.  The European mesothelioma epidemic , 1999, British Journal of Cancer.

[37]  J. Herndon,et al.  Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B. , 1998, Chest.

[38]  R M Schultz,et al.  LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. , 1997, Cancer research.

[39]  V. Rusch,et al.  A proposed new international TNM staging system for malignant pleural mesothelioma from the International Mesothelioma Interest Group. , 1996, Lung cancer.

[40]  P C Elwood,et al.  Autoregulation of human thymidylate synthase messenger RNA translation by thymidylate synthase. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Wang Yang.  DNA Repair by ERCC1 in Non-Small-Cell Lung Cancer and Cisplatin-Based Adjuvant Chemotherapy , 2010 .

[42]  S. Lundgren,et al.  pleural mesothelioma : Genome-wide expression patterns reflecting eneral resistance mechanisms and a proposal of novel targets luf , 2009 .

[43]  A. Durandy,et al.  Repair of U/G and U/A in DNA by UNG2-associated repair complexes takes place predominantly by short-patch repair both in proliferating and growth-arrested cells. , 2004, Nucleic acids research.

[44]  D. Goldstein,et al.  Pharmacogenetics goes genomic (vol 4, pg 937, 2003) , 2004 .

[45]  S. Groshen,et al.  Thymidylate synthase gene polymorphism predicts response to capecitabine in advanced colorectal cancer , 2002, International Journal of Colorectal Disease.

[46]  G. Giaccone,et al.  Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer experience. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[47]  A. Sancar.  DNA repair in humans. , 1995, Annual review of genetics.