INTRODUCTION: Increased expression of thymidylate synthase (TS) is thought to be associated with resistance to TS-targeting drugs, e.g., pemetrexed. METHODS: TS protein expression (PE) and gene copy number (GCN) were assayed using immunohistochemistry and silver in situ hybridization, respectively, on primary tumors of 189 resected non-small cell lung patients. Associations with pathological and clinical features and prognosis were explored. RESULTS: Median immunohistochemistry H-score was 220 (range, 10-380) on a 0 to 400 scale; 17% of the patients had a TS expression of 300 or more. TS PE expression did not significantly differ by histology and did not significantly associate with disease-free survival (DFS) or overall survival (OS). However, there was a tendency for increased DFS (p = 0.12) and OS (p = 0.12) in PE positive (>median) squamous-cell carcinoma (SCC) patients. Median GCN was 2.5 genes/nucleus (range, 1.4-9.6); 29% of patients had GCN of 3 or more, 7% of 4 or more and 0.8% amplification. GCN differed by histology (p = 0.015); 50% of SCCs having GCN more than 2.5 versus 32% of adenocarcinomas. There was no significant relationship between TS GCN and DFS or OS; however, a trend toward better DFS (p = 0.18) and OS (p = 0.10) with increased GCN in SCCs was observed. TS GCN was significantly correlated with PE (r = 0.30, p = 0.0009). CONCLUSIONS: TS PE and GCN vary widely in non-small cell lung and correlate significantly with each other. TS GCN is higher in SCCs, whereas TS PE does not associate with histological subtypes, clinical features, or survival. Variability of TS PE and GCN may indicate potential benefit from pemetrexed therapy in selected SCC patients.
INTRODUCTION: Increased expression of thymidylate synthase (TS) is thought to be associated with resistance to TS-targeting drugs, e.g., pemetrexed. METHODS:TS protein expression (PE) and gene copy number (GCN) were assayed using immunohistochemistry and silver in situ hybridization, respectively, on primary tumors of 189 resected non-small cell lung patients. Associations with pathological and clinical features and prognosis were explored. RESULTS: Median immunohistochemistry H-score was 220 (range, 10-380) on a 0 to 400 scale; 17% of the patients had a TS expression of 300 or more. TSPE expression did not significantly differ by histology and did not significantly associate with disease-free survival (DFS) or overall survival (OS). However, there was a tendency for increased DFS (p = 0.12) and OS (p = 0.12) in PE positive (>median) squamous-cell carcinoma (SCC) patients. Median GCN was 2.5 genes/nucleus (range, 1.4-9.6); 29% of patients had GCN of 3 or more, 7% of 4 or more and 0.8% amplification. GCN differed by histology (p = 0.015); 50% of SCCs having GCN more than 2.5 versus 32% of adenocarcinomas. There was no significant relationship between TS GCN and DFS or OS; however, a trend toward better DFS (p = 0.18) and OS (p = 0.10) with increased GCN in SCCs was observed. TS GCN was significantly correlated with PE (r = 0.30, p = 0.0009). CONCLUSIONS:TSPE and GCN vary widely in non-small cell lung and correlate significantly with each other. TS GCN is higher in SCCs, whereas TSPE does not associate with histological subtypes, clinical features, or survival. Variability of TSPE and GCN may indicate potential benefit from pemetrexed therapy in selected SCCpatients.
Authors: Rafal Dziadziuszko; Daniel T Merrick; Samir E Witta; Adelita D Mendoza; Barbara Szostakiewicz; Amelia Szymanowska; Witold Rzyman; Katarzyna Dziadziuszko; Jacek Jassem; Paul A Bunn; Marileila Varella-Garcia; Fred R Hirsch Journal: J Clin Oncol Date: 2010-03-29 Impact factor: 44.544
Authors: Andrzej Badzio; Murry W Wynes; Rafal Dziadziuszko; Daniel T Merrick; Marta Pardo; Witold Rzyman; Anna Kowalczyk; Shalini Singh; James Ranger-Moore; Guadalupe Manriquez; Fabien Gaire; Jacek Jassem; Fred R Hirsch Journal: J Thorac Oncol Date: 2010-12 Impact factor: 15.609
Authors: Bettina G Papouchado; Jonathan Myles; Ricardo V Lloyd; Mark Stoler; Andre M Oliveira; Erinn Downs-Kelly; Adrienne Morey; Michael Bilous; Ray Nagle; Nichole Prescott; Lin Wang; Lidija Dragovich; Abigail McElhinny; Carole Ferrell Garcia; Jim Ranger-Moore; Heather Free; William Powell; Margaret Loftus; James Pettay; Fabien Gaire; Christopher Roberts; Manfred Dietel; Patrick Roche; Thomas Grogan; Raymond Tubbs Journal: Am J Surg Pathol Date: 2010-06 Impact factor: 6.394
Authors: Gerold Bepler; K Eric Sommers; Alan Cantor; Xueli Li; Anupama Sharma; Charles Williams; Alberto Chiappori; Eric Haura; Scott Antonia; Tawee Tanvetyanon; George Simon; Coleman Obasaju; Lary A Robinson Journal: J Thorac Oncol Date: 2008-10 Impact factor: 15.609
Authors: Tudor Ciuleanu; Thomas Brodowicz; Christoph Zielinski; Joo Hang Kim; Maciej Krzakowski; Eckart Laack; Yi-Long Wu; Isabel Bover; Stephen Begbie; Valentina Tzekova; Branka Cucevic; Jose Rodrigues Pereira; Sung Hyun Yang; Jayaprakash Madhavan; Katherine P Sugarman; Patrick Peterson; William J John; Kurt Krejcy; Chandra P Belani Journal: Lancet Date: 2009-09-18 Impact factor: 79.321
Authors: Oukseub Lee; Katherine Page; David Ivancic; Irene Helenowski; Vamsi Parini; Megan E Sullivan; Julie A Margenthaler; Robert T Chatterton; Borko Jovanovic; Barbara K Dunn; Brandy M Heckman-Stoddard; Kathleen Foster; Miguel Muzzio; Julia Shklovskaya; Silvia Skripkauskas; Piotr Kulesza; David Green; Nora M Hansen; Kevin P Bethke; Jacqueline S Jeruss; Raymond Bergan; Seema A Khan Journal: Clin Cancer Res Date: 2014-07-15 Impact factor: 12.531
Authors: Christopher I McHugh; Monica R Thipparthi; Jawana M Lawhorn-Crews; Lisa Polin; Shirish Gadgeel; Janice Akoury; Thomas J Mangner; Kirk A Douglas; Jing Li; Manohar Ratnam; Anthony F Shields Journal: J Nucl Med Date: 2018-04-19 Impact factor: 10.057
Authors: Daniel C Christoph; Bernadette Reyna Asuncion; Biftu Hassan; Cindy Tran; Julia D Maltzman; Daniel J O'Shannessy; Murry W Wynes; Thomas C Gauler; Jeremias Wohlschlaeger; Mathias Hoiczyk; Martin Schuler; Wilfried E Eberhardt; Fred R Hirsch Journal: J Thorac Oncol Date: 2013-01 Impact factor: 15.609