Предиктивные молекулярные факторы в оценке эффективности химиотерапии при протоковой аденокарциноме головки поджелудочной железы: обзор литературы

1. Jemal A, Bray F, Center MM et al. Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90.
2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013 CA. Cancer J Clin 2013; 63: 11–3.
3. López Serrano A. Risk factors and early diagnosis of pancreatic cancer. Gastroenterol Hepatol 2010; 33: 382–90.
4. Oettle H, Post S, Neuhaus P et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007; 297: 267–77.
5. Neoptolemos JP, Stocken DD, Friess H et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350: 1200–10. 
6. Lamarca A, Feliu J. Pancreatic biomarkers: Сould they be the answer? World J Gastroenterol 2014; 20 (24): 7819–29.
7. Jones S, Zhang X, Parsons DW et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321: 1801–6.
8. Biankin AV, Waddell N, Kassahn KS et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012; 491: 399–405.
9. Hidalgo M. New insights into pancreatic cancer biology. Ann Oncol 2012; 23 (Suppl. 10): x135-x138.
10. Whatcott CJ, Posner RG, Von Hoff DD, Han H. Desmoplasia and chemoresistance in pancreatic cancer. In: Grippo PJ, Munshi HG, editors. Pancreatic Cancer and Tumor Microenvironment. Trivandrum (India): Transworld Research Network, 2012: Chapter 8.
11. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001; 69: 89–95. 
12. Kruger S, Haas M, Ormanns S et al. Translational research in pancreatic ductal adenocarcinoma: current evidence and future concepts. World J Gastroenterol 2014; 20 (31): 10769–77.
13. Bilici A. Prognostic factors related with survival in patients with pancreatic adenocarcinoma. World J Gastroenterol 2014; 20 (31): 10802–12. 
14. Nordh S, Ansari D, Andersson R. hENT1 expression is predictive of gemcitabine outcome in pancreatic cancer: A systematic review. World J Gastroenterol 2014; 20 (26): 8482–90. 
15. Spratlin J, Sangha R, Glubrecht D et al. The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin Cancer Res 2004; 10: 6956–61.
16. Giovannetti E, Del Tacca M, Mey V et al. Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res 2006; 66: 3928–35.
17. Maréchal R, Mackey JR, Lai R et al. Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma. Clin Cancer Res 2009; 15: 2913–19.
18. Fujita H, Ohuchida K, Mizumoto K et al. Gene expression levels as predictive markers of outcome in pancreatic cancer after gemcitabine-based adjuvant chemotherapy. Neoplasia 2010; 12: 807–17. 
19. Nakagawa N, Murakami Y, Uemura K et al. Combined analysis of intratumoral human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase regulatory subunit M1 (RRM1) expression is a powerful predictor of survival in patients with pancreatic carcinoma treated with adjuvant gemcitabine-based chemotherapy after operative resection. Surgery 2013; 153: 565–75.
20. Greenhalf W, Ghaneh P, Neoptolemos JP et al. Pancreatic Cancer hENT1 Expression and Survival From Gemcitabine in Patients From the ESPAC-3 Trial. JNCI J Natl Cancer Inst 2014; 106 (1).
21. Murata Y, Hamada T, Kishiwada M et al. Human equilibrative nucleoside transporter 1 expression is a strong independent prognostic factor in UICC T3-T4 pancreatic cancer patients treated with preoperative gemcitabine-based chemoradiotherapy. J Hepatobiliary Pancreat Sci 2012; 19: 413–25.
22. Kawada N, Uehara H, Katayama K. Human equilibrative nucleoside transporter 1 level does not predict prognosis in pancreatic cancer patients treated with neoadjuvant chemoradiation including gemcitabine. J Hepatobiliary Pancreat Sci 2012; 19: 717–22.
23. Costantino CL, Witkiewicz AK, Kuwano Y. The role of HuR in gemcitabine efficacy in pancreatic cancer: HuR Up-regulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase. Cancer Res 2009; 69: 4567–72. 
24. Richards NG, Rittenhouse DW, Freydin B et al. HuR status is a powerful marker for prognosis and response to gemcitabine-based chemotherapy for resected pancreatic ductal adenocarcinoma patients. Ann Surg 2010; 252: 499–505; discussion 505–6. 
25. Jakstaite A, Maziukiene A, Silkuniene G et al. HuR mediated post-transcriptional regulation as a new potential adjuvant therapeutic target in chemotherapy for pancreatic cancer. World J Gastroenterol 2015; 21 (46): 13004–19. 
26. Xie H, Jiang W, Jiang J et al. Predictive and prognostic roles of ribonucleotide reductase M1 in resectable pancreatic adenocarcinoma. Cancer 2013; 119: 173–81. 
27. Preis M. MicroRNA-10b Expression Correlates with Response to Neoadjuvant Therapy and Survival in Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 2011; 17 (17): 5812–21.
28. Hwang J, Voortman J, Giovannetti E et al. Identification of MicroRNA-21 as a Biomarker for Chemoresistance and Clinical Outcome Following Adjuvant Therapy in Resectable Pancreatic Cancer. PLoS One 2010; 5 (5): e10630.
29. Ohuchida K, Mizumoto K, Kayashima T. MicroRNA expression as a predictive marker for gemcitabine response after surgical resection of pancreatic cancer. Ann Surg Oncol 2011; 18 (8): 2381–7. 
30. Bachet JB, Maréchal R, Demetter P et al. S100A2 is a predictive biomarker of adjuvant therapy benefit in pancreatic adenocarcinoma. Eur J Cancer 2013; 49 (12): 2643–53.
31. Eguchi H, Ishikawa O, Ohigashi H et al. Serum REG4 level is a predictive biomarker for the response to preoperative chemoradiotherapy in patients with pancreatic cancer. Pancreas 2009; 38 (7): 791–8.
32. Tascilar M, Skinner HG, Rosty C et al. The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin Cancer Res 2001; 7 (12): 4115–21. 
33. Blackford A, Serrano OK, Wolfgang CL et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res 2009; 15: 4674–79.
34. Infante JR, Matsubayashi H, Sato N et al. Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. J Clin Oncol 2007; 25: 319–25.
35. Bachet JB, Maréchal R, Demetter P et al. Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma. Ann Oncol 2012; 23 (9): 2327–35.
36. Neesse A, Michl P, Tuveson DA et al. nab-Paclitaxel: novel clinical and experimental evidence in pancreatic cancer. Z Gastroenterol 2014; 52 (4): 360–6. 
37. Tabernero J, Chiorean EG, Infante JR et al. Prognostic factors of survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer. Oncologist 2015; 20 (2): 143–50. 
38. Infante JR, Matsubayashi H, Sato N et al. Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. J Clin Oncol 2007; 25: 319–25. 
39. Sinn M, Sinn BV, Striefler JK et al. SPARC expression in resected pancreatic cancer patients treated with gemcitabine: results from the CONKO-001 study. Ann Oncol 2014; 25 (5): 1025–32.
40. Von Hoff DD, Stephenson JJ, Rosen P et al. Pilot study using molecular profiling of patients’ tumors to find potential targets and sel ect treatments for their refractory cancers. J Clin Oncol 2010; 28: 4877–83. 
41. Boeck S, Jung A, Laubender RP et al. EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104. Br J Cancer 2013; 108 (2): 469–76. 
42. Lambrechts D, Claes B, Delmar P et al. VEGF pathway genetic variants as biomarkers of treatment outcome with bevacizumab: an analysis of data fr om the AViTA and AVOREN randomised trials. Lancet Oncol 2012; 13 (7): 724–33.

________________________________________________

1. Jemal A, Bray F, Center MM et al. Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90.
2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013 CA. Cancer J Clin 2013; 63: 11–3.
3. López Serrano A. Risk factors and early diagnosis of pancreatic cancer. Gastroenterol Hepatol 2010; 33: 382–90.
4. Oettle H, Post S, Neuhaus P et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007; 297: 267–77.
5. Neoptolemos JP, Stocken DD, Friess H et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350: 1200–10. 
6. Lamarca A, Feliu J. Pancreatic biomarkers: Сould they be the answer? World J Gastroenterol 2014; 20 (24): 7819–29.
7. Jones S, Zhang X, Parsons DW et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321: 1801–6.
8. Biankin AV, Waddell N, Kassahn KS et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012; 491: 399–405.
9. Hidalgo M. New insights into pancreatic cancer biology. Ann Oncol 2012; 23 (Suppl. 10): x135-x138.
10. Whatcott CJ, Posner RG, Von Hoff DD, Han H. Desmoplasia and chemoresistance in pancreatic cancer. In: Grippo PJ, Munshi HG, editors. Pancreatic Cancer and Tumor Microenvironment. Trivandrum (India): Transworld Research Network, 2012: Chapter 8.
11. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001; 69: 89–95. 
12. Kruger S, Haas M, Ormanns S et al. Translational research in pancreatic ductal adenocarcinoma: current evidence and future concepts. World J Gastroenterol 2014; 20 (31): 10769–77.
13. Bilici A. Prognostic factors related with survival in patients with pancreatic adenocarcinoma. World J Gastroenterol 2014; 20 (31): 10802–12. 
14. Nordh S, Ansari D, Andersson R. hENT1 expression is predictive of gemcitabine outcome in pancreatic cancer: A systematic review. World J Gastroenterol 2014; 20 (26): 8482–90. 
15. Spratlin J, Sangha R, Glubrecht D et al. The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin Cancer Res 2004; 10: 6956–61.
16. Giovannetti E, Del Tacca M, Mey V et al. Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res 2006; 66: 3928–35.
17. Maréchal R, Mackey JR, Lai R et al. Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma. Clin Cancer Res 2009; 15: 2913–19.
18. Fujita H, Ohuchida K, Mizumoto K et al. Gene expression levels as predictive markers of outcome in pancreatic cancer after gemcitabine-based adjuvant chemotherapy. Neoplasia 2010; 12: 807–17. 
19. Nakagawa N, Murakami Y, Uemura K et al. Combined analysis of intratumoral human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase regulatory subunit M1 (RRM1) expression is a powerful predictor of survival in patients with pancreatic carcinoma treated with adjuvant gemcitabine-based chemotherapy after operative resection. Surgery 2013; 153: 565–75.
20. Greenhalf W, Ghaneh P, Neoptolemos JP et al. Pancreatic Cancer hENT1 Expression and Survival From Gemcitabine in Patients From the ESPAC-3 Trial. JNCI J Natl Cancer Inst 2014; 106 (1).
21. Murata Y, Hamada T, Kishiwada M et al. Human equilibrative nucleoside transporter 1 expression is a strong independent prognostic factor in UICC T3-T4 pancreatic cancer patients treated with preoperative gemcitabine-based chemoradiotherapy. J Hepatobiliary Pancreat Sci 2012; 19: 413–25.
22. Kawada N, Uehara H, Katayama K. Human equilibrative nucleoside transporter 1 level does not predict prognosis in pancreatic cancer patients treated with neoadjuvant chemoradiation including gemcitabine. J Hepatobiliary Pancreat Sci 2012; 19: 717–22.
23. Costantino CL, Witkiewicz AK, Kuwano Y. The role of HuR in gemcitabine efficacy in pancreatic cancer: HuR Up-regulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase. Cancer Res 2009; 69: 4567–72. 
24. Richards NG, Rittenhouse DW, Freydin B et al. HuR status is a powerful marker for prognosis and response to gemcitabine-based chemotherapy for resected pancreatic ductal adenocarcinoma patients. Ann Surg 2010; 252: 499–505; discussion 505–6. 
25. Jakstaite A, Maziukiene A, Silkuniene G et al. HuR mediated post-transcriptional regulation as a new potential adjuvant therapeutic target in chemotherapy for pancreatic cancer. World J Gastroenterol 2015; 21 (46): 13004–19. 
26. Xie H, Jiang W, Jiang J et al. Predictive and prognostic roles of ribonucleotide reductase M1 in resectable pancreatic adenocarcinoma. Cancer 2013; 119: 173–81. 
27. Preis M. MicroRNA-10b Expression Correlates with Response to Neoadjuvant Therapy and Survival in Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 2011; 17 (17): 5812–21.
28. Hwang J, Voortman J, Giovannetti E et al. Identification of MicroRNA-21 as a Biomarker for Chemoresistance and Clinical Outcome Following Adjuvant Therapy in Resectable Pancreatic Cancer. PLoS One 2010; 5 (5): e10630.
29. Ohuchida K, Mizumoto K, Kayashima T. MicroRNA expression as a predictive marker for gemcitabine response after surgical resection of pancreatic cancer. Ann Surg Oncol 2011; 18 (8): 2381–7. 
30. Bachet JB, Maréchal R, Demetter P et al. S100A2 is a predictive biomarker of adjuvant therapy benefit in pancreatic adenocarcinoma. Eur J Cancer 2013; 49 (12): 2643–53.
31. Eguchi H, Ishikawa O, Ohigashi H et al. Serum REG4 level is a predictive biomarker for the response to preoperative chemoradiotherapy in patients with pancreatic cancer. Pancreas 2009; 38 (7): 791–8.
32. Tascilar M, Skinner HG, Rosty C et al. The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin Cancer Res 2001; 7 (12): 4115–21. 
33. Blackford A, Serrano OK, Wolfgang CL et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res 2009; 15: 4674–79.
34. Infante JR, Matsubayashi H, Sato N et al. Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. J Clin Oncol 2007; 25: 319–25.
35. Bachet JB, Maréchal R, Demetter P et al. Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma. Ann Oncol 2012; 23 (9): 2327–35.
36. Neesse A, Michl P, Tuveson DA et al. nab-Paclitaxel: novel clinical and experimental evidence in pancreatic cancer. Z Gastroenterol 2014; 52 (4): 360–6. 
37. Tabernero J, Chiorean EG, Infante JR et al. Prognostic factors of survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer. Oncologist 2015; 20 (2): 143–50. 
38. Infante JR, Matsubayashi H, Sato N et al. Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. J Clin Oncol 2007; 25: 319–25. 
39. Sinn M, Sinn BV, Striefler JK et al. SPARC expression in resected pancreatic cancer patients treated with gemcitabine: results from the CONKO-001 study. Ann Oncol 2014; 25 (5): 1025–32.
40. Von Hoff DD, Stephenson JJ, Rosen P et al. Pilot study using molecular profiling of patients’ tumors to find potential targets and sel ect treatments for their refractory cancers. J Clin Oncol 2010; 28: 4877–83. 
41. Boeck S, Jung A, Laubender RP et al. EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104. Br J Cancer 2013; 108 (2): 469–76. 
42. Lambrechts D, Claes B, Delmar P et al. VEGF pathway genetic variants as biomarkers of treatment outcome with bevacizumab: an analysis of data fr om the AViTA and AVOREN randomised trials. Lancet Oncol 2012; 13 (7): 724–33.

З.А.Коваленко*1, Т.В.Кекеева1, В.К.Лядов1,2

1 ФГАУ Лечебно-реабилитационный центр Минздрава России. 125367, Россия, Москва, Иваньковское шоссе, д. 3;
2 ГБОУ ДПО Российская медицинская академия последипломного образования Минздрава России. 125993, Россия, Москва, ул. Баррикадная, д. 2/1 
*zahar_kovalenko_@mail.ru

________________________________________________

Z.A.Kovalenko*1, T.V.Kekeeva1, V.K.Lyadov1,2

1 Federal Medical and Rehabilitation Center. 125367, Russian Federation, Moscow, Ivan'kovskoe shosse, d. 3;
2 Russian Medical Academy of Postgraduate Education of the Ministry of Health of the Russian Federation. 125993, Russian Federation, Moscow, ul. Barrikadnaia, d. 2/1
*zahar_kovalenko_@mail.ru