Abstract
Amaç: Hücre büyümesinde folat taşınmasında rol oynayan folat reseptörü-1'in (FOLR1) histopatolojik aşırı ekspresyonu çeşitli kanserlerde bildirilmiştir. Artmış serum FOLR1(sFOLR1) epitelyal yumurtalık kanserinde de rapor edilmiştir. Amaç, küçük hücreli dışı akciğer kanseri (KHDAK) hastalarında sFOLR1 düzeylerini ve folik asit metabolizmasını hedefleyen standart kemoterapinin tahminini yanıtını araştırmaktı.
Gereç ve Yöntem: Bu prospektif çalışmada, standart kemoterapi öncesi ve sonrası evre4 malign metastatik KHDAK'li 60 hasta ve 30 sağlıklı bireyde sFOLR1 düzeyleri araştırıldı. Ticari immünolojik test (ELISA) kiti sFOLR1'in analizi için kullanıldı. Serum karsinoembriyonik antijen (CEA), vitamin B12 ve folat düzeyleri de araştırıldı.
Bulgular: KHDAK hastalarında sFOLR1 seviyeleri sağlıklı bireylere göre anlamlı derecede yüksekti(p<0,001). 3 aylık standart tedaviden sonra hastalarda sFOLR1 anlamlı olarak daha düşüktü (p<0,001). KHDAK hastalarının sağlıklı bireylerden ayırt edilmesinde tanısal doğruluk güçlüydü (AUC= 0.966). Tanısal doğruluk sFOLR1 seviyesi 82.45 pg/ml kesme noktasında %95 duyarlılık ve %99 özgüllük gerçekleştirmiştir. Standart kemoterapiye yanıt veren hastalarda tedavi öncesi sFOLR1 düzeyleri anlamlı olarak daha düşüktü(p<0.01). En iyi tahmin değeri 393.80 pg/ml olarak belirlendi. 401 günün sonunda sFOLR1 tahmin değeri yüksek olan hastalarda anlamlı fark bulundu. Medyan genel sağkalım (OS) süresi tüm hastalar için 288 gündü (%95 GA 198.13-377.87). Medyan progresyonsuz sağkalım (PFS) 321 gündü (%95 GA 211.90-430.10).
Sonuç: Folik asit metabolizmasını hedefleyen ilaçlarla standart kemoterapiyi izlemek için sFOLR-1 seviyeleri önemli bir biyobelirteç olabilir.
Keywords
Folat Reseptörü 1 (FOLR1) Karsinoembriyonik Antijen (CEA) Küçük Hücreli Olmayan Akciğer Kanseri (KHDAK) Kemoterapi Biyobelirteç
Supporting Institution
yok
Project Number
2018.110.08.01
Thanks
Tıbbi ve laboratuvar ekiplerimize teşekkürler.
References
- 1. Dong Y, Zheng X, Yang Z, Sun M, Zhang G, An X, et al. Serum carcinoembryonic antigen, neuron-specific enolase as biomarkers for diagnosis of nonsmall cell lung cancer. J Cancer Res Ther. 2016;12(5):C34–6.
- 2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Vol. 68, CA: A Cancer Journal for Clinicians. 2018. p. 394–424.
- 3. Nunez MI, Behrens C, Woods DM, Lin H, Suraokar M, Kadara H, et al. High expression of folate receptor alpha in lung cancer correlates with adenocarcinoma histology and mutation. Journal of Thoracic Oncology Lippincott Williams and Wilkins; 2012 p. 833–40.
- 4. Ji W, Weng X, Xu D, Cai S, Lou H, Ding L. Non-small cell lung cancer cells with deficiencies in homologous recombination genes are sensitive to PARP inhibitors. Biochem Biophys Res Commun. 2020;522(1):121–6.
- 5. Kelemen LE. The role of folate receptor α in cancer development, progression and treatment: Cause, consequence or innocent bystander? International Journal of Cancer. John Wiley & Sons, Ltd; 2006. 119: 243–50.
- 6. Kurosaki A, Hasegawa K, Kato T, Abe K, Hanaoka T, Miyara A, et al. Serum folate receptor alpha as a biomarker for ovarian cancer: Implications for diagnosis, prognosis and predicting its local tumor expression. Int J Cancer. 2016;138(8):1994–2002.
- 7. Driver BR, Barrios R, Ge Y, Haque A, Tacha D, Cagle PT. Folate receptor a expression level correlates with histologic grade in lung adenocarcinoma. Arch Pathol Lab Med. 2016;140(7):682–5.
- 8. Hartmann LC, Keeney GL, Lingle WL, Christianson TJH, Varghese B, Hillman D, et al. Folate receptor overexpression is associated with poor outcome in breast cancer. Int J Cancer. 2007;121(5):938–42.
- 9. Shia J, Klimstra DS, Nitzkorski JR, Low PS, Gonen M, Landmann R, et al. Immunohistochemical expression of folate receptor α in colorectal carcinoma: patterns and biological significance. Hum Pathol. 2008;39(4):498–505.
- 10. Senol S, Ceyran AB, Aydin A, Zemheri E, Ozkanli S, Kösemetin D, et al. Folate receptor α expression and significance in endometrioid endometrium carcinoma and endometrial hyperplasia. Int J Clin Exp Pathol. 2015;8(5):5633–41.
- 11. Omote S, Takata K, Tanaka T, Miyata-Takata T, Ayada Y, Noujima-Harada M, et al. Overexpression of folate receptor alpha is an independent prognostic factor for outcomes of pancreatic cancer patients. Med Mol Morphol. 2018;51(4):237–43.
- 12. Leung F, Dimitromanolakis A, Kobayashi H, Diamandis EP, Kulasingam V. Folate-receptor 1 (FOLR1) protein is elevated in the serum of ovarian cancer patients. Clin Biochem. 2013;46(15):1462–8.
- 13. O’Shannessy DJ, Somers EB, Palmer LM, Thiel RP, Oberoi P, Heath R, et al. Serum folate receptor alpha, mesothelin and megakaryocyte potentiating factor in ovarian cancer: Association to disease stage and grade and comparison to CA125 and HE4. J Ovarian Res. 2013;6(1):29.
- 14. Chenhon ZQ, Huang LS, Zhu B. Assessment of seven clinical tumor markers in diagnosis of non-small-cell lung cancer. Dis Markers. 2018; 2018;9845123.
- 15. Altman DG, McShane LM, Sauerbrei W, Taube SE. Reporting recommendations for tumor marker prognostic studies (REMARK): Explanation and elaboration. PLoS Med. 2012;9(5).
- 16. Sauerbrei W, Taube SE, McShane LM, Cavenagh MM, Altman DG. Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): An abridged explanation and elaboration. Journal of the National Cancer Institute. 201;110,803–11.
- 17. Non-small Cell Lung Cancer Chemotherapy | Chemo Side Effects. [cited 2022 May 29]. Available from: https://www.cancer.org/cancer/lung-cancer/treating-non-small-cell/chemotherapy.html.
- 18. Nishino M, Jackman DM, Hatabu H, Yeap BY, Cioffredi LA, Yap JT, et al. New Response Evaluation Criteria in Solid Tumors (RECIST) guidelines for advanced non - small cell lung cancer: Comparison with original RECIST and Impact on Assessment of Tumor Response to Targeted Therapy. Am J Roentgenol. 2010;195(3).
- 19. Wei Z, Ye X, Yang X, Zheng A, Huang G, Li W, et al. Microwave Ablation in Combination with Chemotherapy for the Treatment of Advanced Non-Small Cell Lung Cancer. Cardiovasc Intervent Radiol. 2015;38(1):135–42.
- 20. Christoph DC, Asuncion BR, Hassan B, Tran C, Maltzman JD, O’Shannessy DJ, et al. Folate receptor in adenocarcinoma and squamous cell carcinoma of the lung: Potential target for folate-linked therapeutic agents. Arch Pathol Lab Med. 2013;137(2):241–4.
- 21. Iwakiri S, Sonobe M, Nagai S, Hirata T, Wada H, Miyahara R. Expression status of folate receptor α is significantly correlated with prognosis in non-small-cell lung cancers. Ann Surg Oncol. 2008;15(3):889–99.
- 22. Basal E, Eghbali-Fatourechi GZ, Kalli KR, Hartmann LC, Goodman KM, Goode EL, et al. Functional folate receptor alpha is elevated in the blood of ovarian cancer patients. PLoS One. 2009;4(7): e6292.
- 23. Huang MJ, Zhang W, Wang Q, Yang ZJ, Liao S Bin, Li L. FOLR1 increases sensitivity to cisplatin treatment in ovarian cancer cells. J Ovarian Res. 2018;11(1).
- 24. Han X, Chen L, Hu Z, Chen L, Sun P, Wang Y, et al. Identification of proteins related with pemetrexed resistance by iTRAQ and PRM-based comparative proteomic analysis and exploration of IGF2BP2 and FOLR1 functions in non-small cell lung cancer cells. J Proteomics. 2021; 237:104122.
- 25. O’Shannessy DJ, Yu G, Smale R, Fu YS, Singhal S, Thiel RP, et al. Folate receptor alpha expression in lung cancer: Diagnostic and prognostic significance. Oncotarget. 2012;3(4):414–25.
Abstract
Objective: Histopathological overexpression of folate receptor-1 (FOLR1) involved in folate transport in cell growth has been reported in various cancers. Increased serum FOLR1(sFOLR1) has also been reported in epithelial ovarian cancer. The aim was to investigate sFOLR1 levels in non-small cell lung cancer (NSCLC) patients and the response prediction of the standard chemotherapy targeting folic acid metabolism.
Method: In this prospective study, sFOLR1 levels were investigated in 30 healthy individuals and 60 patients with stage4 malign metastatic NSCLC before and after standard chemotherapy. The commercial immunoassay (ELISA) kit used for analysis of sFOLR1. Serum carcinoembryonic antigen (CEA), vitamin B12, and folate levels were also investigated.
Result: In NSCLC patients sFOLR1 levels were significantly higher(p<0.001) than the healthy individuals. After 3 months of standard treatment, sFOLR1 was significantly lower in patients(p<0.001). Diagnostic accuracy was strong in the differentiation of NSCLC patients from healthy individuals (AUC= 0.966). with the cut-off point of 82.45 pg/ml, the sFOLR1 level was performed with 95% sensitivity and 99% specificity. Pretreatment sFOLR1 levels were significantly lower in patients with-response to standard chemotherapy(p<0.01). The best predictive value was determined as 393.80 pg/ml. At the end of the 401 days, a significant difference found in patients with high the sFOLR1 predictive value. The median overall survival (OS) duration was 288 days for all patients (95% GA 198.13-377.87). Median progression-free survival (PFS) was 321 days (95% GA 211.90-430.10).
Conclusion: For monitoring standard chemotherapy with drugs targeting folic acid metabolism, sFOLR-1 levels may be important biomarker.
Keywords
Folate receptor 1 biomarker Nonsmall cell lung cancer chemotherapy carcinoembryonic antigen
Project Number
2018.110.08.01
References
- 1. Dong Y, Zheng X, Yang Z, Sun M, Zhang G, An X, et al. Serum carcinoembryonic antigen, neuron-specific enolase as biomarkers for diagnosis of nonsmall cell lung cancer. J Cancer Res Ther. 2016;12(5):C34–6.
- 2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Vol. 68, CA: A Cancer Journal for Clinicians. 2018. p. 394–424.
- 3. Nunez MI, Behrens C, Woods DM, Lin H, Suraokar M, Kadara H, et al. High expression of folate receptor alpha in lung cancer correlates with adenocarcinoma histology and mutation. Journal of Thoracic Oncology Lippincott Williams and Wilkins; 2012 p. 833–40.
- 4. Ji W, Weng X, Xu D, Cai S, Lou H, Ding L. Non-small cell lung cancer cells with deficiencies in homologous recombination genes are sensitive to PARP inhibitors. Biochem Biophys Res Commun. 2020;522(1):121–6.
- 5. Kelemen LE. The role of folate receptor α in cancer development, progression and treatment: Cause, consequence or innocent bystander? International Journal of Cancer. John Wiley & Sons, Ltd; 2006. 119: 243–50.
- 6. Kurosaki A, Hasegawa K, Kato T, Abe K, Hanaoka T, Miyara A, et al. Serum folate receptor alpha as a biomarker for ovarian cancer: Implications for diagnosis, prognosis and predicting its local tumor expression. Int J Cancer. 2016;138(8):1994–2002.
- 7. Driver BR, Barrios R, Ge Y, Haque A, Tacha D, Cagle PT. Folate receptor a expression level correlates with histologic grade in lung adenocarcinoma. Arch Pathol Lab Med. 2016;140(7):682–5.
- 8. Hartmann LC, Keeney GL, Lingle WL, Christianson TJH, Varghese B, Hillman D, et al. Folate receptor overexpression is associated with poor outcome in breast cancer. Int J Cancer. 2007;121(5):938–42.
- 9. Shia J, Klimstra DS, Nitzkorski JR, Low PS, Gonen M, Landmann R, et al. Immunohistochemical expression of folate receptor α in colorectal carcinoma: patterns and biological significance. Hum Pathol. 2008;39(4):498–505.
- 10. Senol S, Ceyran AB, Aydin A, Zemheri E, Ozkanli S, Kösemetin D, et al. Folate receptor α expression and significance in endometrioid endometrium carcinoma and endometrial hyperplasia. Int J Clin Exp Pathol. 2015;8(5):5633–41.
- 11. Omote S, Takata K, Tanaka T, Miyata-Takata T, Ayada Y, Noujima-Harada M, et al. Overexpression of folate receptor alpha is an independent prognostic factor for outcomes of pancreatic cancer patients. Med Mol Morphol. 2018;51(4):237–43.
- 12. Leung F, Dimitromanolakis A, Kobayashi H, Diamandis EP, Kulasingam V. Folate-receptor 1 (FOLR1) protein is elevated in the serum of ovarian cancer patients. Clin Biochem. 2013;46(15):1462–8.
- 13. O’Shannessy DJ, Somers EB, Palmer LM, Thiel RP, Oberoi P, Heath R, et al. Serum folate receptor alpha, mesothelin and megakaryocyte potentiating factor in ovarian cancer: Association to disease stage and grade and comparison to CA125 and HE4. J Ovarian Res. 2013;6(1):29.
- 14. Chenhon ZQ, Huang LS, Zhu B. Assessment of seven clinical tumor markers in diagnosis of non-small-cell lung cancer. Dis Markers. 2018; 2018;9845123.
- 15. Altman DG, McShane LM, Sauerbrei W, Taube SE. Reporting recommendations for tumor marker prognostic studies (REMARK): Explanation and elaboration. PLoS Med. 2012;9(5).
- 16. Sauerbrei W, Taube SE, McShane LM, Cavenagh MM, Altman DG. Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): An abridged explanation and elaboration. Journal of the National Cancer Institute. 201;110,803–11.
- 17. Non-small Cell Lung Cancer Chemotherapy | Chemo Side Effects. [cited 2022 May 29]. Available from: https://www.cancer.org/cancer/lung-cancer/treating-non-small-cell/chemotherapy.html.
- 18. Nishino M, Jackman DM, Hatabu H, Yeap BY, Cioffredi LA, Yap JT, et al. New Response Evaluation Criteria in Solid Tumors (RECIST) guidelines for advanced non - small cell lung cancer: Comparison with original RECIST and Impact on Assessment of Tumor Response to Targeted Therapy. Am J Roentgenol. 2010;195(3).
- 19. Wei Z, Ye X, Yang X, Zheng A, Huang G, Li W, et al. Microwave Ablation in Combination with Chemotherapy for the Treatment of Advanced Non-Small Cell Lung Cancer. Cardiovasc Intervent Radiol. 2015;38(1):135–42.
- 20. Christoph DC, Asuncion BR, Hassan B, Tran C, Maltzman JD, O’Shannessy DJ, et al. Folate receptor in adenocarcinoma and squamous cell carcinoma of the lung: Potential target for folate-linked therapeutic agents. Arch Pathol Lab Med. 2013;137(2):241–4.
- 21. Iwakiri S, Sonobe M, Nagai S, Hirata T, Wada H, Miyahara R. Expression status of folate receptor α is significantly correlated with prognosis in non-small-cell lung cancers. Ann Surg Oncol. 2008;15(3):889–99.
- 22. Basal E, Eghbali-Fatourechi GZ, Kalli KR, Hartmann LC, Goodman KM, Goode EL, et al. Functional folate receptor alpha is elevated in the blood of ovarian cancer patients. PLoS One. 2009;4(7): e6292.
- 23. Huang MJ, Zhang W, Wang Q, Yang ZJ, Liao S Bin, Li L. FOLR1 increases sensitivity to cisplatin treatment in ovarian cancer cells. J Ovarian Res. 2018;11(1).
- 24. Han X, Chen L, Hu Z, Chen L, Sun P, Wang Y, et al. Identification of proteins related with pemetrexed resistance by iTRAQ and PRM-based comparative proteomic analysis and exploration of IGF2BP2 and FOLR1 functions in non-small cell lung cancer cells. J Proteomics. 2021; 237:104122.
- 25. O’Shannessy DJ, Yu G, Smale R, Fu YS, Singhal S, Thiel RP, et al. Folate receptor alpha expression in lung cancer: Diagnostic and prognostic significance. Oncotarget. 2012;3(4):414–25.
Details
| Primary Language | English |
|---|---|
| Subjects | Health Care Administration |
| Journal Section | Articles |
| Authors | |
| Project Number | 2018.110.08.01 |
| Publication Date | October 20, 2022 |
| Acceptance Date | October 6, 2022 |
| Published in Issue | Year 2022 Volume: 14 Issue: 3 |
