Thymidylate Synthase Expression and Outcome of Patients Receiving Pemetrexed for Advanced Nonsquamous Non–Small-Cell Lung Cancer in a Prospective Blinded Assessment Phase II Clinical Trial

Nicolson, Marianne; Fennell, Dean A.; Ferry, David; O’Byrne, Kenneth J.; Shah, Riyaz; Potter, Vanessa; Skailes, G.; Upadhyay, Sunil; Taylor, Paul D.; Andre, Valérie; Nguyen, Tuan S.; Myrand, Scott P.; Visseren‐Grul, Carla; Das, Mayukh; Kerr, Keith M.

doi:10.1097/jto.0b013e318292c500

Cited by 54 publications

(61 citation statements)

References 27 publications

(40 reference statements)

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“…Multiple studies have demonstrated an association between TYMS expression levels and pemetrexed response (37)(38)(39). In these studies, NSCLC tumors and cells with lower expression of TYMS demonstrated enhanced response to pemetrexed.…”

Section: Kras Status Predictsmentioning

confidence: 85%

KRAS Mutation Status Is Associated with Enhanced Dependency on Folate Metabolism Pathways in Non–Small Cell Lung Cancer Cells

Moran

Trusk

Pry

et al. 2014

Molecular Cancer Therapeutics

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KRAS gene mutation is linked to poor prognosis and resistance to therapeutics in non-small cell lung cancer (NSCLC). In this study, we have explored the possibility of exploiting inherent differences in KRAS-mutant cell metabolism for treatment. This study identified a greater dependency on folate metabolism pathways in KRAS mutant compared with KRAS wild-type NSCLC cell lines. Microarray gene expression and biologic pathway analysis identified higher expression of folate metabolism-and purine synthesis-related pathways in KRASmutant NSCLC cells compared with wild-type counterparts. Moreover, pathway analysis and knockdown studies suggest a role for MYC transcriptional activity in the expression of these pathways in KRAS-mutant NSCLC cells. Furthermore, KRAS knockdown and overexpression studies demonstrated the ability of KRAS to regulate expression of genes that comprise folate metabolism pathways. Proliferation studies demonstrated higher responsiveness to methotrexate, pemetrexed, and other antifolates in KRAS-mutant NSCLC cells. Surprisingly, KRAS gene expression is downregulated in KRAS wild-type and KRAS-mutant cells by antifolates, which may also contribute to higher efficacy of antifolates in KRAS-mutant NSCLC cells. In vivo analysis of multiple tumorgraft models in nude mice identified a KRAS-mutant tumor among the pemetrexedresponsive tumors and also demonstrated an association between expression of the folate pathway gene, methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), and antifolate activity. Collectively, we identify altered regulation of folate metabolism in KRAS-mutant NSCLC cells that may account for higher antifolate activity in this subtype of NSCLC. Mol Cancer Ther; 13(6); 1611-24. Ó2014 AACR.

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Section: Kras Status Predictsmentioning

confidence: 85%

KRAS Mutation Status Is Associated with Enhanced Dependency on Folate Metabolism Pathways in Non–Small Cell Lung Cancer Cells

Moran

Trusk

Pry

et al. 2014

Molecular Cancer Therapeutics

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“…Several candidate predictive biomarkers including expression of thymidylate synthase, miR-25, miR-145, miR-210 and serum leptin have been studied but not sufficiently validated for the routine clinical use. [18][19][20][21] In this study, we focused on the association between TTF-1 expression and the efficacy of pemetrexed-based chemotherapy in patients with advancedstage non-squamous NSCLC.…”

Section: Discussionmentioning

confidence: 99%

Thyroid transcription factor 1 expression is associated with outcome of patients with non-squamous non-small cell lung cancer treated with pemetrexed-based chemotherapy

et al. 2017

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Pemetrexed is an antifolate cytostatic agent targeting several folate-dependent enzymatic pathways, widely used in the treatment of locally advanced or metastatic stage non-small cell lung cancer. Aside from the non-squamous histology, there is still no available molecular biomarker predicting treatment efficacy of pemetrexed-based chemotherapy. The aim of our retrospective study was to evaluate the association of thyroid transcription factor 1 expression with outcome of a large cohort of patients with non-squamous non-small cell lung cancer treated with pemetrexed. We retrospectively analysed clinical data of 463 patients with advanced-stage non-small cell lung cancer (IIIB or IV) treated with pemetrexed-based chemotherapy. Thyroid transcription factor 1 expression was assessed using indirect immunohistochemical detection in formalin-fixed paraffin-embedded tumour tissue at the time of diagnosis. Thyroid transcription factor 1 expression was detected in the tumour tissue from 76.0% of patients, and tumours from 24.0% of patients were thyroid transcription factor 1 negative. The median progression-free survival and overall survival for patients with thyroid transcription factor 1 positive tumours were 4.8 and 11.8 months compared to 2.8 and 8.3 months for those with thyroid transcription factor 1 negative tumours (p = 0.001 and p < 0.001). The multivariable Cox proportional hazards model revealed that thyroid transcription factor 1 expression was significantly associated with progression-free survival (hazard ratio = 1.57, p < 0.001) and also with overall survival (hazard ratio = 1.73, p < 0.001). In conclusion, the results of the conducted retrospective study suggest that the thyroid transcription factor 1 expression was independently associated with progression-free survival and overall survival in patients with advanced-stage nonsquamous non-small cell lung cancer treated with pemetrexed-based chemotherapy.

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“…A total of 2280 patients analyzed with TS protein expression were included in the meta-analysis. Eighteen studies were performed in Asia [7,14,18-20, 23,29-39], 4 in Europe [17,21,40,41] and 2 in America [16,42]. OS or PFS were compared according to tumor TS protein expression levels (high/low or positive/negative) (Table 1).…”

Section: Study Characteristicsmentioning

confidence: 99%

Prognostic and predictive significance of thymidylate synthase protein expression in non-small cell lung cancer: A systematic review and meta-analysis

Liu

Xiang

et al. 2015

CBM

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Thymidylate Synthase Expression and Outcome of Patients Receiving Pemetrexed for Advanced Nonsquamous Non–Small-Cell Lung Cancer in a Prospective Blinded Assessment Phase II Clinical Trial

Abstract: The primary endpoint was met; low TS expression was associated with longer PFS. Further randomized studies are needed to explore nuclear TS IHC expression as a potential biomarker of clinical outcomes for pemetrexed treatment in larger patient cohorts.

Cited by 54 publications

References 27 publications

KRAS Mutation Status Is Associated with Enhanced Dependency on Folate Metabolism Pathways in Non–Small Cell Lung Cancer Cells

KRAS Mutation Status Is Associated with Enhanced Dependency on Folate Metabolism Pathways in Non–Small Cell Lung Cancer Cells

Thyroid transcription factor 1 expression is associated with outcome of patients with non-squamous non-small cell lung cancer treated with pemetrexed-based chemotherapy

Prognostic and predictive significance of thymidylate synthase protein expression in non-small cell lung cancer: A systematic review and meta-analysis

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