İleri Evre Mide Kanseri Hastalarında ERCC1 Ekspresyonunun Sağkalım ve Tedavi Yanıtı Üzerindeki Etkisinin Değerlendirilmesi

Öz

Amaç: Mide kanseri, dünyada kansere bağlı ölümlerin önde gelen nedenlerinden biridir ve genellikle ileri evrede tanı aldığı için prognozu kötüdür.Bu nedenle sağkalımı ve tedavi cevabını etkileyen faktörler önem kazanmaktadır. Mide kanseri tedavisinde yaygın olarak kullanılan platinlerin oluşturduğu DNA hasarının onarımında nükleotid eksizyon onarımı (NER ) önemli bir yoldur ve bu yolda ERCC1 anahtar rol oynamaktadır. ERCC1 gen ekspesyonunun ise ileri evre mide kanserinde platin-temelli tedavi alan hastalarda uzun dönem sağkalımı etkilediği ve prognostik bir faktör olabileceği düşünülmektedir Bu çalışmada ileri evre mide adenokarsinomlu hastalarda ERCC1 ekspresyonunun prognostik ve prediktif değeri araştırılmıştır. Materyal ve Metod: Ekim 2007–Mayıs 2012 arasında Onkoloji Kliniğinde takip edilen, Her-2 negatif metastatik mide adenokarsinomu tanısı almış 45 hasta retrospektif olarak değerlendirildi. Tümör örneklerinde immünohistokimyasal yöntemle ERCC1 ekspresyonu incelendi. Klinikopatolojik veriler, tedavi rejimleri, progresyonsuz sağkalım (PFS) ve genel sağkalım (OS) Kaplan-Meier ve çok değişkenli analizlerle hesaplandı. Bulgular: Hastaların ortanca yaşı 63 olup %64’ü erkekti. Olguların %76’sı platin bazlı tedavi aldı. ERCC1 pozitiflik oranı %38 idi. ERCC1 pozitif ve negatif gruplar arasında PFS açısından fark yoktu (her iki grup 5 ay). OS ise ERCC1 negatif grupta 11 ay, pozitif grupta 7 ay olarak bulundu; aradaki 4 aylık fark istatistiksel olarak anlamlı değildi (p>0.05). Çok değişkenli analizde yalnızca tedavi cevabı ile sağkalım arasında anlamlı ilişki görüldü (p=0.0001). Sonuç: ERCC1 ekspresyonu ile sağkalım veya tedavi yanıtı arasında anlamlı ilişki gösterilemedi. Bununla birlikte, OS’deki 4 aylık fark klinik açıdan dikkate değer olabilir. Bu nedenle ERCC1’in prognostik ve prediktif değerini doğrulamak için daha geniş, prospektif çalışmalara ihtiyaç vardır.

Anahtar Kelimeler

• ERCC1 ekspresyonu
• gastrik kanser
• platin bazlı kemoterapi

Evaluation of the Effect of ERCC1 Expression on Survival and Treatment Response in Patients with Advanced Gastric Cancer

Öz

Purpose: Gastric cancer is one of the leading causes of cancer-related deaths worldwide and is usually diagnosed at an advanced stage, resulting in poor prognosis. Therefore, identifying factors that influence survival and treatment response is important. Platinum-based chemotherapies are widely used in the treatment of gastric cancer, and nucleotide excision repair (NER) plays a key role in repairing platinum-induced DNA damage, with ERCC1 being a critical component of this pathway. ERCC1 expression has been suggested to affect treatment response and long-term survival in advanced gastric cancer patients receiving platinum-based therapy. This study aimed to evaluate the prognostic and predictive value of ERCC1 expression in advanced gastric adenocarcinoma. Patients and Methods: Forty-five patients diagnosed with HER-2 negative metastatic gastric adenocarcinoma and followed in the Oncology Clinic between October 2007 and May 2012 were retrospectively analyzed. ERCC1 expression was assessed by immunohistochemistry in tumor samples. Clinicopathological data, treatment regimens, progression-free survival (PFS), and overall survival (OS) were evaluated using Kaplan-Meier and multivariate analyses. Results: The median age was 63 years, and 64% of patients were male. Seventy-six percent received platinum-based therapy. The ERCC1 positivity rate was 38%. No significant difference in PFS was observed between ERCC1 positive and negative groups (both 5 months). OS was 11 months in the ERCC1-negative group and 7 months in the positive group; the 4-month difference was not statistically significant (p>0.05). In multivariate analysis, only treatment response was significantly associated with survival (p=0.0001). Conclusion: ERCC1 expression was not significantly associated with survival or treatment response. However, the 4-month OS difference may be clinically relevant. Larger prospective studies are needed to clarify the prognostic and predictive value of ERCC1 in gastric cancer.

Anahtar Kelimeler

• ERCC1 expression
• gastric cancer
• platinum-based chemotherapy

Kaynakça

1. Bray F, Laversanne M, Sung, H, Ferlay J, Siegel R. L, Soerjomataram, I, & Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 74(3), (2024), 229–263. https://doi.org/10.3322/caac.21834.
2. World Health Organization. International Agency for Research on Cancer. GLOBOCAN 2022: stomach cancer fact sheet. (2024). Available at: https://gco.iarc.who.int/media/globocan/factsheets/cancers/7-stomachfact-sheet.pdf. (Accessed May 8, 2024).
3. Sitarz R, Skierucha M, Mielko J, Offerhaus GJA, Maciejewski R, Polkowski WP. Gastric cancer: epidemiology, prevention, classification, and treatment. Cancer Management and Research, 10, (2018), 239–248. https://doi.org/10.2147/CMAR.S149619
4. Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends—an update. Cancer Epidemiology, Biomarkers & Prevention, 25(1),(2016) 16–27. https://doi.org/10.1158/1055-9965.EPI-15-0578
5. Etemadi A, Safiri S, Sepanlou SG, Ikuta KS, Bisignano C, Merat S, et al. The global, regional, and national burden of stomach cancer in 195 countries, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017. Lancet Gastroenterology & Hepatology, 5(1), (2020) 42–54. https://doi.org/10.1016/S2468-1253(19)30339-4.
6. Zhao JK, Wu M, Kim CH, Zhang Y, Xiang YB, Zheng W, et al. Jiangsu Four Cancers Study: a large case-control study of lung, liver, stomach, and esophageal cancers in Jiangsu Province, China. European Journal of Cancer Prevention, 26(4), (2017), 357–364. https://doi.org/10.1097/CEJ.0000000000000272
7. T.C. Sağlık Bakanlığı Halk Sağlığı Genel Müdürlüğü. (2020). Türkiye kanser istatistikleri. hsgm.saglik.com.tr. Istatistikler. Turkiye_Kanser_ Istatistikleri. 2020.
8. Basaran H, Koca T, Cerkesli AK, Arslan D, Karaca S. Treatment outcomes and survival study of gastric cancer patients: a retrospective analysis in an endemic region. Asian Pacific Journal of Cancer Prevention. 16(5), (2015), 2055–2060. https://doi.org/10.7314/APJCP.2015.16.5. 2055.

9. Yamada Y, Boku N, Nishina T, Denda T, Kawano T, Sugimoto N, et al. Impact of excision repair cross-complementing gene 1 (ERCC1) on the outcomes of patients with advanced gastric cancer: correlative study in Japan clinical oncology group trial JCOG9912. Annals of Oncology, 24(10), (2013), 2560–2565. https://doi.org/10.1093/annonc/mdt290
10. Liu YP, Ling Y, Qi QF, Zhang YP, Zhang CS, Zhu CT, et al. The effects of ERCC1 expression levels on the chemosensitivity of gastric cancer cells to platinum agents and survival in gastric cancer patients treated with oxaliplatin-based adjuvant chemotherapy. Oncology Letters, 5(3), (2013), 935–942. https://doi.org/10.3892/ol.2013.1131.
11. Reardon JT, Sancar A. Nucleotide excision repair. Progress in Nucleic Acid Research and Molecular Biology, 79, (2005),183–235. https://doi.org/10.1016/S0079-6603(05)79006-2
12. Cobo M, Isla D, Massuti B, Provencio M, Paz-Ares L, Rosell R, et al. Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: A phase III trial in non-small-cell lung cancer. Journal of Clinical Oncology, 25(19), (2007), 2747–2754. https://doi.org/10.1200/JCO.2006.07.4790.
13. Lee SM, Falzon M, Blackhall F, Han JY, Park K, Kim DW, et al. Randomized prospective biomarker trial of ERCC1 for comparing platinum and nonplatinum therapy in advanced non–small-cell lung cancer: ERCC1 trial (ET). Journal of Clinical Oncology, 35(4),(2017) 402–411. https://doi.org/10.1200/JCO.2016.69.7369.
14. Metzger R, Leichman CG, Danenberg KD, Danenberg PV, Lenz HJ, Schwartz GK, et al. ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. Journal of Clinical Oncology, 16(1), (1998), 309–316. https://doi.org/10.1200/JCO.1998.16.1.309.
15. Kwon HC, Roh MS, Oh SY, Kim KH, Kim JS, Kim HJ, et al. Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-fluorouracil/oxaliplatin chemotherapy in advanced gastric cancer. Annals of Oncology, 18(3),(2007), 504–509. https://doi.org/10.1093/annonc/mdl444.
16. Wei J, Zou Z, Qian X, Zhang H, Zhao Z, Liu Q, et al. ERCC1 mRNA levels and survival of advanced gastric cancer patients treated with a modified FOLFOX regimen. British Journal of Cancer, 98(9), (2008),1398–1402. https://doi.org/10.1038/sj.bjc.6604303.
17. Matsubara J, Nishina T, Yamada Y, Boku N, Kawano T, Sugimoto N, et al. Impacts of excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase, and epidermal growth factor receptor on the outcomes of patients with advanced gastric cancer. British Journal of Cancer, 98(5), (2008), 832–839. https://doi.org/10.1038/sj.bjc.6604235.
18. Amin, M. B., Edge, S. B., & Greene, F. L. (Eds.). (2017). AJCC cancer staging manual (8th ed.). Springer. https://doi.org/10.1007/978-3-319-40617-6.
19. Lee KH, Min HS, Han SW, Oh DY, Lee SH, Kim DW, et al. ERCC1 expression by immunohistochemistry and EGFR mutations in resected non-small cell lung cancer. Lung Cancer, 60(3), 401–407. (2008). https://doi.org/10.1016/j.lungcan.2007.10.014.
20. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European Journal of Cancer, 45(2), (2009), 228–247. https://doi.org/10.1016/j.ejca.2008.10.026.
21. Fareed KR, Al-Attar A, Soomro IN, Bury J, Gouda I, Pritchard SA, et al. Tumour regression and ERCC1 nuclear protein expression predict clinical outcome in patients with gastro-oesophageal cancer treated with neoadjuvant chemotherapy. British Journal of Cancer, 102(11),(2010), 1600–1607. https://doi.org/10.1038/sj.bjc.6605666.
22. Li Q, Dang C, Liu Z, Wang Y, Zhang Q, Li J, et al. ERCC1 expression is a predictor of survival in gastric cancer patients treated with surgery and adjuvant chemotherapy. Chinese-German Journal of Clinical Oncology, 10(2), 92–95. (2011).
23. Nouspikel, T. (2009). Nucleotide excision repair: variations on versatility. Cellular and Molecular Life Sciences, 66(6), 994–1009. https://doi.org/10.1007/s00018-009-8740-4.
24. McNeil, E. M., & Melton, D. W. DNA repair endonuclease ERCC1–XPF as a novel therapeutic target to overcome chemoresistance in cancer therapy. Nucleic Acids Research, 40(20), (2012), 9990–10004. https://doi.org/10.1093/nar/gks710.
25. Altaha, R., Liang, X., Yu, J. J., & Reed, E. Excision repair cross-complementing group 1: gene expression and platinum resistance. International Journal of Molecular Medicine, 14(6), (2004), 959–970. https://doi.org/10.3892/ijmm.14.6.959.
26. Lee KB, Parker RJ, Bohr VA, Cornelius J, Tarone RE, Grossman L, et al. Cisplatin sensitivity/resistance in UV-repair deficient Chinese hamster ovary cells of complementation groups 1 and 3. Carcinogenesis, 14(10), (1993), 2177–2180. https://doi.org/10.1093/carcin/14.10. 2177.
27. Li Q, Yu JJ, Mu C, Slavsky D, Sugrue MM, Yagi T, et al. Association between the level of ERCC1 expression and the repair of cisplatin-induced DNA damage in human ovarian cancer cells. Anticancer Research, 20(2A), (2000), 645–652. https://pubmed.ncbi.nlm.nih.gov/ 10810375/.
28. Li Q, Gardner K, Zhang L, Tsai MM, Wang H, Reed E, et al. Cisplatin induction of ERCC-1 mRNA expression in A2780/CP70 human ovarian cancer cells. Journal of Biological Chemistry, 273(37), (1998), 23419–23425. https://doi.org/10.1074/jbc.273.37.23419.
29. Simon GR, Sharma S, Cantor A, Smith P, Bepler G, Antonia S, et al. ERCC1 expression is a predictor of survival in resected patients with non-small cell lung cancer. Chest, 127(3), (2005),978–983. https://doi.org/10.1378/chest.127.3.978.
30. Olaussen KA, Dunant A, Fouret P, Brambilla E, André F, Haddad V, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. New England Journal of Medicine, 355(10), (2006), 983–991. https://doi.org/10.1056/NEJMoa060570.
31. Pierceall WE, Olaussen KA, Rousseau V, Brambilla E, Sprott KM, Andre F, et al. Cisplatin benefit is predicted by immunohistochemical analysis of DNA repair proteins in squamous cell carcinoma but not adenocarcinoma: theranostic modeling by NSCLC constituent histological subclasses. Annals of Oncology, 23(9), (2012), 2245–2252. https://doi.org/10.1093/annonc/mdr624.
32. Bellmunt J, Paz-Ares L, Cuello M, Cecere F, Albiol S, Guillem V, et al. Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy. Annals of Oncology, 18(3), (2007), 522–528. https://doi.org/10.1093/annonc/mdl428.
33. Kim MK, Cho KJ, Kwon GY, Park SI, Kim HJ, Lee CH, et al. ERCC1 predicting chemoradiation resistance and poor outcome in oesophageal cancer. European Journal of Cancer, 44(1), (2008), 54–60. https://doi.org/10.1016/j.ejca.2007.09.019.
34. Huang ZH, Hua D, Du X, Wang Q, Yuan Y, Liu Z, et al. ERCC1 polymorphism, expression and clinical outcome of oxaliplatin-based adjuvant chemotherapy in gastric cancer. World Journal of Gastroenterology, 14(41), (2008), 6401–6407. https://doi.org/10.3748/wjg.14.6401.
35. Deng Q, Yang H, Lin Y, Qiu Y, Gu X, He P, et al. Prognostic value of ERCC1 mRNA expression in non-small cell lung cancer, breast cancer, and gastric cancer in patients from Southern China. International Journal of Clinical and Experimental Pathology, 7(12), (2014), 8312–8321. http://www.ijcep.com/files/ijcep0003198.pdf
36. Wang J, Zhou XQ, Li JY, Cheng JF, Zeng XN, Li X, et al. Prognostic significance of ERCC1 expression in postoperative patients with gastric cancer. Chinese Journal of Cancer Research, 26(3),(2014), 323–330. https://doi.org/10.3978/j.issn.1000-9604.2014.06.07.
37. Yun J, Kim KM, Kim ST, Lee J, Park SH, Park JO, et al. Predictive value of the ERCC1 expression for treatment response and survival in advanced gastric cancer patients receiving cisplatin-based first-line chemotherapy. Cancer Research and Treatment, 42(2), (2010), 101–106. https://doi.org/10.4143/crt.2010.42.2.101.
38. Iqbal S, McDonough S, Lenz HJ, Ilson D, Burtness B, Nangia CS, et al. Randomized, phase II study prospectively evaluating treatment of metastatic esophageal, gastric, or gastroesophageal cancer by gene expression of ERCC1: SWOG S1201. Journal of Clinical Oncology, 38(5),(2020), 472–479. https://doi.org/10.1200/JCO.19.00925.
39. Yin M, Yan J, Martinez-Balibrea E, Graziano F, Lenz HJ, Zhang W, et al. ERCC1 and ERCC2 polymorphisms predict clinical outcomes of oxaliplatin-based chemotherapies in gastric and colorectal cancer: a systemic review and meta-analysis. Clinical Cancer Research, 17(6),(2011), 1632–1640. https://doi.org/10.1158/1078-0432.CCR-10-2070.
40. Wang Z, Chen J, Liu J, Qin X, & Huang Y. Polymorphisms in ERCC1, GSTs, TS and MTHFR predict clinical outcomes of gastric cancer patients treated with platinum/5-Fu-based chemotherapy: A systematic review. Asian Pacific Journal of Cancer Prevention, 13(9), (2012),4425–4430. https://doi.org/10.7314/APJCP.2012. 13.9.4425.
41. Li Y, Liu Z, Liu H, Wang L‑E, Tan D, Ajani JA, et al. ERCC1 and ERCC2 variants predict survival in gastric cancer patients. PLOS ONE, 8(9),(2013), e71994. https://doi.org/10.1371/journal.pone.0071994.
42. Mo J, Luo M, Cui J, & Zhou S. Prognostic value of ERCC1 and ERCC2 gene polymorphisms in patients with gastric cancer receiving platinum-based chemotherapy. International Journal of Clinical and Experimental Pathology, 8(11),(2015), 15065–15071. http://www.ijcep.com/files/ijcep0015110.pdf.
43. Lu Z‑m, Luo T‑h, Nie M‑m, Fang G‑e, Ma L‑y, Xue X‑c, et al. Influence of ERCC1 and ERCC4 polymorphisms on response to prognosis in gastric cancer treated with FOLFOX-based chemotherapy. Tumour Biology, 37(7), (2016), 8877–8885. https://doi.org/10.1007/s13277-016-4918-8.
44. Özkan, M., Akbudak, İ. H., Deniz, K., Dikilitaş, M., Doğu, G. G., & Berk, V. Prognostic value of excision repair cross-complementing gene 1 expression for cisplatin-based chemotherapy in advanced gastric cancer. Asian Pacific Journal of Cancer Prevention, 11(1), (2010),181–185.
45. Oishi T, Sasaki Y, Tong Y, Chen L, Onodera T, Iwasa S, et al. A newly established monoclonal antibody against ERCC1 detects major isoforms of ERCC1 in gastric cancer. Gastric Cancer, 16(1),(2013), 99–107. https://doi.org/10.1007/s10120-012-0153-9.