Predictive value of thymidylate synthase and folylpoly-glutamate synthetase for clinical benefit from pemetrexed in malignant pleural mesothelioma.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 7024-7024 ◽  
Author(s):  
D. C. Christoph ◽  
C. Mascaux ◽  
M. W. Wynes ◽  
B. Reyna Asuncion ◽  
J. Wohlschlaeger ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Thymidylate Synthase ◽  
Clinical Benefit ◽  
Predictive Value ◽  
Pleural Mesothelioma ◽  
Glutamate Synthetase

scholarly journals Folylpoly-Glutamate Synthetase Expression Is Associated with Tumor Response and Outcome from Pemetrexed-Based Chemotherapy in Malignant Pleural Mesothelioma

2012 ◽  
Vol 7 (9) ◽  
pp. 1440-1448 ◽  
Author(s):  
Daniel C. Christoph ◽  
Bernadette Reyna Asuncion ◽  
Celine Mascaux ◽  
Cindy Tran ◽  
Xian Lu ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Tumor Response ◽  
Pleural Mesothelioma ◽  
Glutamate Synthetase

Pemetrexed in second-line therapy in patients with malignant pleural mesothelioma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18198-18198 ◽  
Author(s):  
M. Serke ◽  
T. Bauer
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Clinical Benefit ◽  
Single Agent ◽  
Sensory Neuropathy ◽  
Patient Characteristics ◽  
Pleural Mesothelioma ◽  
Second Line ◽  
Second Line Therapy ◽  
Mild Renal Impairment ◽  
Line Therapy

18198 Introduction: Based on the study of Vogelzang (2003) standard treatment in patients with malignant pleural mesothelioma (MPM) is pemetrexed cisplatin with a medium survival of 12 months compared to 9 months with cisplatin therapy. As this treatment prolongs survival, but is not a curative treatment, many patients will relapse during the course of their disease. In sensitive relapses (within more than 3 months) our policy was to reintroduce pemetrexed therapy in unselected consecutive patients. Methods: Retrospective analysis of 17 consecutive patients treated in our hospital. Patient characteristics: 17 patients (pat), 14 males, 3 females, with MPM were included between April 2004 and November 2006 with an age between 45 and 82 years, with a median age of 65 years. Histologic subtypes were: 16 epithelial, 1 biphasic MPM. Pretreatment: 8 pat. had undergone palliative debulcing surgery (pleurectomy) 1 pat. underwent EPP. All patients were pretreated with platinum /pemetrexed, 5 pat. were pretreated with platinum/Gemcitabine before the availability of pemetrexed. 2nd line chemotherapy: 9 pat. were treated with carboplatin AUC5 / pemetrexed 500 mg/m2, 1 patient had cisplatinum 75 mg/m2/Pemetrexed 500 mg/m2 and 7 patients had pemetrexed single agent therapy (500 mg/m2 d1, WH d21), repeated on day 22 respectively. Results: Response: 6% (n=1) PR, MR: 12% (n=2 )., NC: 47% (n=8)., PD: 35% (n= 6), clinical benefit (PR, MR, NC) was seen in 65% of ou pat. Toxicity: Pemetrexed/Carboplatin or pemetrexed therapy were well tolerated, toxicity was mild: one patient developed mild sensory neurotoxicity (peripheral sensory neuropathy) (WHO II) under 6 cycles pemetrexed, 35% developed mild fatigue (Who I and II), one patient had mild renal impairment, no alopecia was seen. Survival: Only 3 patients had still died, median survival from start of second-line pemetrexed-therapy was not reached, time to progression was between 25 and 630 days, 4 pat. had not progressed until now. Conclusion: Second line therapy in MPM is not yet standard of care. Nevertheless patients with progressive disease following pemetrexed/platinum therapy may benefit from second line pemetrexed reintroduction therapy. Clinical benefit was seen in 65% with low toxicity. No significant financial relationships to disclose.

Circulating tumor cells (CTCs) and endothelial cells (CECs) in the diagnosis of malignant pleural mesothelioma (MPM): A single institutional prospective study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22107-e22107
Author(s):  
K. Yoneda ◽  
F. Tanaka ◽  
M. Hashimoto ◽  
T. Takuwa ◽  
S. Matsumoto ◽  
...  
Keyword(s):  
Prospective Study ◽  
Malignant Pleural Mesothelioma ◽  
Peripheral Blood ◽  
Predictive Value ◽  
Malignant Tumors ◽  
Promising Result ◽  
Clinical Stage ◽  
Pleural Mesothelioma ◽  
Malignant Diseases ◽  
The Mean

e22107 Background: Circulating tumor cell (CTC), a surrogate of distant metastasis, and circulating endothelia cell (CEC), a surrogate of angiogenesis, are potentially useful in the diagnosis of malignant tumors. Following a promising result of our preliminary study showing the diagnostic value of CTC/CEC in malignant pleural mesothelioma (MPM)(Tanaka F, et al. ASCO 2008), we conducted a prospective study. Methods: Patients (pts), who presented at our institute with suspicion or diagnosis of MPM, were eligible in the study. CTCs and CECs in peripheral blood (7.5mL and 4.0mL, respectively) were captured and quantitatively evaluated with the “CellSearch” system without knowledge of clinical characteristics of patients. Results: A total of 92 pts were enrolled into the study, and the final diagnosis was MPM in 68, other malignant tumors in 7, and non-malignant diseases in 17 pts ( Table ). CTC was positive (CTC-count, 1 or more per 7.5mL of the peripheral blood) in 35%(24/68) of MPM pts (range of CTC-count, 0–27 cells/7.5 mL). Among non-malignant pts, 3 pts (18%) showed a positive-CTC, but no patient showed 2 or more CTCs in 7.5mL of the peripheral blood. The mean CEC-count (/4.0mL) was significantly higher in MPM pts than in non-malignant pts (105.1 versus 40.2; p=0.047). When the cut-off value of CEC-count for the diagnosis of MPM was defined as 50(cells/4.0mL), the sensitivity, specificity, positive predictive value, and negative predictive value for the diagnosis of malignant diseases were 66%, 70%, 93%, and 26%, respectively. There was no correlation between CTC-positivity and clinical stage of MPM pts, but was a trend of increase in the mean CEC-count along with tumor progression (mean CEC-count for stage I, II, III, and IV pts: 63.0, 82.4, 95.6, and 116.7, respectively). Conclusions: CTC and CEC are useful clinical markers in the diagnosis of MPM. [Table: see text] No significant financial relationships to disclose.

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 ◽  
Vol 28 (9) ◽  
pp. 1534-1539 ◽  
Author(s):  
Luisella Righi ◽  
Mauro G. Papotti ◽  
Paolo Ceppi ◽  
Andrea Billè ◽  
Elisa Bacillo ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Thymidylate Synthase ◽  
Excision Repair ◽  
Single Agent ◽  
Complementation Group ◽  
Pleural Mesothelioma ◽  
Mrna Levels ◽  
Lower Tertile ◽  
Protein Levels ◽  
Group 1

PurposeThe relationship between thymidylate synthase (TS) expression and outcome in patients with malignant pleural mesothelioma (MPM) treated with pemetrexed (P) was retrospectively evaluated.Patients and MethodsSixty histologically confirmed patients with MPM previously treated with P and platinum (45 of 60) or as single agent (15 of 60) were retrospectively considered. Eighty-one control patients with MPM not P-treated were also evaluated. TS and excision repair cross-complementation group 1 (ERCC1) gene expression levels were evaluated by real-time polymerase chain reaction and by immunohistochemistry using the H-score.ResultsMedian TS H-score value was 90 (range, 5 to 240). A significant correlation between low TS protein expression and longer time to progression (TTP; 17.9 v 7.9 months; hazard ratio [HR], 2.05, 95% CI, 1.19 to 3.77; P = .02) or overall survival (OS; 30 v 16.7 months; HR, 2.38; 95% CI, 1.15 to 4.91; P = .019) was found when patients were divided according to median H-score. Conversely, TS mRNA levels were not significantly correlated with outcome. In platinum-treated patients (n = 45), no correlation was found with survival according to ERCC1 median H-score, but patients in the lower tertile had a significantly shorter survival (HR, 3.06; 95% CI, 1.08 to 8.69; P = .035). In control MPMs, TS had no prognostic role. At multivariate analysis, TS protein levels were the only independent prognostic factor for both TTP (HR, 2.71; 95% CI, 1.13 to 6.49; P = .02) and OS (HR, 6.91; 95% CI, 1.90 to 25.07; P = .003).ConclusionIn patients with MPM treated with P-based chemotherapy, low TS protein levels are predictive of improved TTP and OS. The role of TS assessment is worth of prospective validation in future studies on MPM.

Relationship of thymidylate synthase levels to outcome of malignant pleural mesothelioma patients treated with pemetrexed-based chemotherapy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7508-7508
Author(s):  
G. Selvaggi ◽  
L. Righi ◽  
P. Ceppi ◽  
E. Bacillo ◽  
A. Billè ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Protein Expression ◽  
Malignant Pleural Mesothelioma ◽  
Thymidylate Synthase ◽  
Mrna Level ◽  
Single Agent ◽  
Outcome Data ◽  
Rank Test ◽  
Pleural Mesothelioma ◽  
Mrna Levels

7508 Background: Pemetrexed has shown activity in malignant pleural mesothelioma (MPM) but scanty data are available on the expression of thymidylate synthase (TS), its most important molecular target. Methods: From a database of 75 non-surgical, chemotherapy-naive MPM patients from our Institution in the period 2004–2008, 50 (male/female: 37/13, median age: 65 years) met the selection criteria i.e. epithelial type, availability of thoracoscopic tissue and outcome data. Pemetrexed was administered as single agent (14/50) or in combination with cisplatin or carboplatin (36/50). Retrospectively TS protein expression levels were evaluated by immunohistochemistry and quantified with H-score method. In addition, mRNA extraction was performed in 23 micro-dissected tissues and TS relative levels quantified by RT-PCR. Survival probability was assessed by Kaplan-Meier method and results compared by log-rank test. Cox multivariate analysis for survival was performed adjusting for clinical-pathological variables. Results: Thirty-two patients had progressive disease and 24 had died at the time of the analysis. Median time to progression (TTP) and median survival time (MST) were 11.6 and 20.9 months, respectively. Median TS H-score value was 90 (5–240). No correlation were found with sex, age, PS, stage and chemotherapy regimen. Patients with high TS H-score (4th quartile) had a significantly shorter MST (13.3 vs 21.1 months, p<0.01) and showed a trend for shorter TTP (8.3 vs 11.9 months, p=0.07). Median TS mRNA level was 1.88 (1–3.7 unit-less ratio) and a significant correlation between mRNA and protein expression (RS=0.67, p<0.0001) was found. Patients with high TS mRNA levels (4th quartile) had significantly shorter TTP (8.7 vs 14.7 months, p=0.019) and MST (11.7 vs 24.7, p=0.018). Multivariate analysis for survival indicated that TS protein levels were an independent prognostic factor (HR=2.17; CI 1.04–4.54; p=0.038). Conclusions: TS (protein and mRNA) levels predict outcome of epithelial MPM patients treated with pemetrexed-based chemotherapy. TS quantification, if confirmed in larger prospective studies, could be used to select those patients more likely to respond to chemotherapy. [Table: see text]

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