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Reduced folate carrier (RFC) as a predictive marker for response to pemetrexed in advanced non-small cell lung cancer (NSCLC)

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Summary

Introduction RFC is the major transport system in mammalian cells for folate cofactors and antifolate therapeutics. The aim of this study was to assess the predictive value of RFC expression in patients receiving pemetrexed for advanced NSCLC. Methods The study was carried out in a population of 48 patients with advanced NSCLC which have received pemetrexed monotherapy in second and third line. RFC expression was assessed using a two-step model of immunohistochemical staining in paraffin-embedded tissue samples. Results RFC expression was detected in 16 (33 %) patients. In the global population, the median progression free survival (PFS) and the median overall survival (OS) were 3.3 and 6.5 months respectively. The subgroup of patients with expression of RFC had a tendency to better median PFS (4.5 vs 2.8 months; p = 0.926) and median OS (11.7 vs 4.8; p = 0.150). In patients with adenocarcinoma histology and RFC expression median OS after treatment with pemetrexed was 14.4 months versus 5.0 in those with adenocarcinoma but without RFC expression (p = 0.039). Conclusions These results suggest the possible relation between RFC expression and response to treatment with antifolates (pemetrexed) independently of the tumor histology. Further studies are required to confirm these results.

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References

  1. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108

    Article  PubMed  Google Scholar 

  2. D’Addario G, Fruh M, Reck M, Baumann P, Klepetko W, Felip E (2010) Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 21(Suppl 5):v116–v119

    Article  PubMed  Google Scholar 

  3. Azzoli CG, Temin S, Aliff T, Baker S Jr, Brahmer J, Johnson DH, Laskin JL, Masters G, Milton D, Nordquist L, Pao W, Pfister DG, Piantadosi S, Schiller JH, Smith R, Smith TJ, Strawn JR, Trent D, Giaccone G (2011) 2011 focused update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 29(28):3825–3831

    Article  PubMed Central  PubMed  Google Scholar 

  4. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26(21):3543–3551

    Article  CAS  PubMed  Google Scholar 

  5. Scagliotti G, Hanna N, Fossella F, Sugarman K, Blatter J, Peterson P, Simms L, Shepherd FA (2009) The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist 14(3):253–263

    Article  CAS  PubMed  Google Scholar 

  6. Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Pereira JR, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP (2009) Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 374(9699):1432–1440

    Article  CAS  PubMed  Google Scholar 

  7. Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C (2012) Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol 13(3):247–255

    Article  CAS  PubMed  Google Scholar 

  8. Gridelli C, Maione P, Rossi A, Bareschino MA, Schettino C, Sacco PC, Zeppa R (2011) Pemetrexed in advanced non-small cell lung cancer. Expert Opin Drug Saf 10(2):311–317

    Article  CAS  PubMed  Google Scholar 

  9. Esteban E, Casillas M, Cassinello A (2009) Pemetrexed in first-line treatment of non-small cell lung cancer. Cancer Treat Rev 35(4):364–373

    Article  CAS  PubMed  Google Scholar 

  10. Sun JM, Han J, Ahn JS, Park K, Ahn MJ (2011) Significance of thymidylate synthase and thyroid transcription factor 1 expression in patients with nonsquamous non-small cell lung cancer treated with pemetrexed-based chemotherapy. J Thorac Oncol 6(8):1392–1399

    Article  PubMed  Google Scholar 

  11. Takezawa K, Okamoto I, Okamoto W, Takeda M, Sakai K, Tsukioka S, Kuwata K, Yamaguchi H, Nishio K, Nakagawa K (2011) Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer. Br J Cancer 104(10):1594–1601

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Assaraf YG (2007) Molecular basis of antifolate resistance. Cancer Metastasis Rev 26(1):153–181

    Article  CAS  PubMed  Google Scholar 

  13. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr (2004) Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22(9):1589–1597

    Article  CAS  PubMed  Google Scholar 

  14. Ceppi P, Volante M, Saviozzi S, Rapa I, Novello S, Cambieri A, Lo Iacono M, Cappia S, Papotti M, Scagliotti GV (2006) Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer 107(7):1589–1596

    Article  CAS  PubMed  Google Scholar 

  15. Matherly LH, Hou Z, Deng Y (2007) Human reduced folate carrier: translation of basic biology to cancer etiology and therapy. Cancer Metastasis Rev 26(1):111–128

    Article  CAS  PubMed  Google Scholar 

  16. Wettergren Y, Odin E, Nilsson S, Willen R, Carlsson G, Gustavsson B (2005) Low expression of reduced folate carrier-1 and folylpolyglutamate synthase correlates with lack of a deleted in colorectal carcinoma mRNA splice variant in normal-appearing mucosa of colorectal carcinoma patients. Cancer Detect Prev 29(4):348–355

    Article  CAS  PubMed  Google Scholar 

  17. Ferreri AJ, Dell’Oro S, Capello D, Ponzoni M, Iuzzolino P, Rossi D, Pasini F, Ambrosetti A, Orvieto E, Ferrarese F, Arrigoni G, Foppoli M, Reni M, Gaidano G (2004) Aberrant methylation in the promoter region of the reduced folate carrier gene is a potential mechanism of resistance to methotrexate in primary central nervous system lymphomas. Br J Haematol 126(5):657–664

    Article  CAS  PubMed  Google Scholar 

  18. Adjei AA, Salavaggione OE, Mandrekar SJ, Dy GK, Ziegler KL, Endo C, Molina JR, Schild SE (2010) Correlation between polymorphisms of the reduced folate carrier gene (SLC19A1) and survival after pemetrexed-based therapy in non-small cell lung cancer: a North Central Cancer Treatment Group-based exploratory study. J Thorac Oncol 5(9):1346–1353

    Article  PubMed  Google Scholar 

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Medical Oncology, Hospital Universitario Central de Asturias, Celestino Villamil s/n. 33006, Oviedo, Asturias, Spain

    Carlos Alvarez-Fernandez, Quionia Perez-Arnillas, Lucrecia Ruiz-Echeverria, David Rodriguez-Rubi, Luisa Sanchez-Lorenzo, Walter Li-Torres, Marta Izquierdo-Manuel, Jose P. Berros, Maria Luque-Cabal, Paula Jimenez-Fonseca, Noemi Villanueva-Palicio & Emilio Esteban-Gonzalez

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  1. Carlos Alvarez-Fernandez
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  2. Quionia Perez-Arnillas
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  3. Lucrecia Ruiz-Echeverria
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  4. David Rodriguez-Rubi
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  5. Luisa Sanchez-Lorenzo
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  11. Noemi Villanueva-Palicio
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  12. Emilio Esteban-Gonzalez
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Correspondence to Carlos Alvarez-Fernandez.

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Alvarez-Fernandez, C., Perez-Arnillas, Q., Ruiz-Echeverria, L. et al. Reduced folate carrier (RFC) as a predictive marker for response to pemetrexed in advanced non-small cell lung cancer (NSCLC). Invest New Drugs 32, 377–381 (2014). https://doi.org/10.1007/s10637-013-9992-1

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  • DOI: https://doi.org/10.1007/s10637-013-9992-1

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