title: [Prognosis related clinical and molecular factors in malignant pleural mesothelioma].
abstract: OBJECTIVE
  To identify potential prognosis related clinical and molecular factors in malignant pleural mesothelioma (MPM).
  
  
  METHODS
  Seventy-nine patients with MPM treated in Beijing Cancer Hospital from June 1996 to May 2012 were enrolled in this study. Clinical and pathological data were collected, including age, gender, smoking status, treatment, response, and molecular biomarkers such as thymidylate synthetase (TS) expression, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) gene rearrangement. The primary endpoint was overall survival (OS). SPSS 16.0 statistical analysis software was used for univariate analysis. The expression of TS was detected by immunohistochemistry (IHC). Fluorescence in situ hybridization (FISH) was performed to detect EML4-ALK gene rearrangement. Efficacy of the chemotherapy regimen including pemetrexed was analyzed with these molecular biomarkers.
  
  
  RESULTS
  The median survival time (MST) of all patients was 15.5 months (95% CI: 10.6 - 20.4). Univariate survival analysis revealed that treatment factors including receiving operation, systemic chemotherapy, pemetrexed-based chemotherapy and capability of receiving second (or above) line chemotherapy were significantly related with OS. The MST of patients receiving operation was 5.4 months (95% CI: 3.6 - 7.3), significantly shorter than the 17.7months (95% CI: 11.8 - 23.5) in those who didn't receive operation (P = 0.030). Patients receiving systemic chemotherapy had a longer MST of 18.0 months (95% CI: 12.3 - 23.8) as compared to the 7.9 months (95% CI: 1.1 - 14.7) in those who didn't (P = 0.001). The MST of pemetrexed-based chemotherapy was 21.9 months (95% CI: 14.1-29.7) compared with 8.8 months (95% CI: 4.2 - 13.4) of regimens without pemetrexed (P = 0.000). For patients capable of receiving second (or above) line chemotherapy the MST was longer (21.0 months, 95% CI: 12.7 - 29.3) than those who could not (12.1 month, 95% CI: 6.4 - 17.8 month), P = 0.022. For the 42 patients treated with pemetrexed-based chemotherapy, the objective response rate (ORR) was 33.3% (14/42), the disease control rate (DCR) was 78.6% (33/42), the median progression-free survival (PFS) was 4.8 months (95% CI: 3.6 - 6.0) and MST was 21.9 months (95% CI: 14.1 - 29.7). Twenty-nine patients provided adequate specimens for detection of TS expression and 6 cases (20.7%) were positive. EML4-ALK gene rearrangement was studied in 32 patients and 6 (18.8%) were positive. TS expression was found to be inversely related to PFS of pemetrexed-based chemotherapy (P = 0.041). The MST was 19.6 months (95% CI: 6.0 - 7.9) in EML4-ALK-positive patients and 9.57 months (95% CI: 2.7 - 4.3) in negative ones (P = 0.159).
  
  
  CONCLUSIONS
  Systemic chemotherapy especially pemetrexed-based regimen was proved to be a superior option for MPM with a significantly prolonged OS. Correlation between TS expression or EML4-ALK rearrangement and outcome of pemetrexed-based chemotherapy for MPM may contribute to future individualized treatment, which needs further validation from large-scale prospective studies.
authors.affiliation: Department of Thoracic Oncology 1, Beijing Cancer Hospital, Beijing University Oncology College, Beijing 100142, China.
authors.forename: Yu-yan
authors.initials: YY
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Bai
authors.forename: Shu-hang
authors.initials: SH
authors.lastname: Wang
authors.forename: Mei-na
authors.initials: MN
authors.lastname: Wu
authors.forename: Tong-tong
authors.initials: TT
authors.lastname: An
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.forename: Ming-lei
authors.initials: ML
authors.lastname: Zhuo
authors.forename: Jian-chun
authors.initials: JC
authors.lastname: Duan
authors.forename: Zhi-jie
authors.initials: ZJ
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005971:Glutamates / Q000008:administration & dosage*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D000068437:Pemetrexed; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012307:Risk Factors; D013940:Thymidylate Synthase / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C522504:EML4-ALK fusion protein, human; D005971:Glutamates; D015514:Oncogene Proteins, Fusion; D000068437:Pemetrexed; D006147:Guanine; D013940:Thymidylate Synthase; D002945:Cisplatin