Skip to main content

Advertisement

SpringerLink
Log in

The influence of PD-L1 genetic variation on the prognosis of R0 resection colorectal cancer patients received capecitabine-based adjuvant chemotherapy: a long-term follow-up, real-world retrospective study

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

This study investigated the influence of PD-L1 genetic variation on the prognosis of R0 resection colorectal cancer (CRC) patients who received capecitabine-based adjuvant chemotherapy in real world.

Methods

A total of 315 CRC patients underwent R0 surgical resection and received capecitabine-based adjuvant chemotherapy were included. Clinical characteristics were collected from the hospital record system, prognosis was obtained by telephone follow-up. Peripheral blood and peripheral blood mononuclear cell (PBMC) specimen of CRC patients were performed for the genotyping of polymorphism and mRNA expression of PD-L1, respectively. Analysis on the association between genotypes and prognosis was conducted.

Results

The median disease-free survival (DFS) of the 315 CRC patients was 5.1 years, the median overall survival (OS) was 6.0 years. Regarding the PD-L1 gene polymorphism analysis, the prevalence of 901T>C among the CRC patients was as follows: TT genotype 221 cases (70.16%), TC genotype 86 cases (27.30%), CC genotype 8 cases (2.54%), the minor allele frequency was 0.16, the distribution of three genotypes was in accordance with Hardy–Weinberg equilibrium (P = 0.915). Moreover, the prognosis analysis indicated that the median DFS of patients with TT and TC/CC genotype was 5.4 and 4.0 years, respectively (P = 0.008). The median OS of patients with the two genotypes was 6.4 and 5.0 years (P = 0.007). The multivariate Cox regression analysis showed that the TC/CC genotypes were an independent factor for DFS (odds ratio = 1.56, P = 0.018). Furthermore, the mRNA expression results indicated that the mRNA expression of PD-L1 in PBMC of the patients with TC/CC genotype was significantly higher than patients with TT genotype (P < 0.001).

Conclusion

The prognosis of R0 resection CRC patients received capecitabine-based adjuvant chemotherapy in real world may be influenced by PD-L1 901T>C polymorphism through mediation of the mRNA expression of PD-L1.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424. https://doi.org/10.3322/caac.21492

    Article  PubMed  Google Scholar 

  2. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66(2):115–132. https://doi.org/10.3322/caac.21338

    Article  PubMed  Google Scholar 

  3. Abakushina EV, Gelm YV, Pasova IA, Bazhin AV (2019) Immunotherapeutic approaches for the treatment of colorectal cancer. Biochemistry (Mosc) 84(7):720–728. https://doi.org/10.1134/s0006297919070046

    Article  CAS  Google Scholar 

  4. Emambux S, Tachon G, Junca A, Tougeron D (2018) Results and challenges of immune checkpoint inhibitors in colorectal cancer. Expert Opin Biol Ther 18(5):561–573. https://doi.org/10.1080/14712598.2018.1445222

    Article  CAS  PubMed  Google Scholar 

  5. Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T (2018) Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med 378(13):1177–1188. https://doi.org/10.1056/NEJMoa1713709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. McQuade RM, Stojanovska V, Bornstein JC, Nurgali K (2017) Colorectal cancer chemotherapy: the evolution of treatment and new approaches. Curr Med Chem 24(15):1537–1557. https://doi.org/10.2174/0929867324666170111152436

    Article  CAS  PubMed  Google Scholar 

  7. Cassidy J, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Saltz L (2008) Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 26(12):2006–2012. https://doi.org/10.1200/jco.2007.14.9898

    Article  CAS  PubMed  Google Scholar 

  8. Reck M, Brahmer J, Bennett B, Taylor F, Penrod JR, DeRosa M, Dastani H, Spigel DR, Gralla RJ (2018) Evaluation of health-related quality of life and symptoms in patients with advanced non-squamous non-small cell lung cancer treated with nivolumab or docetaxel in CheckMate 057. Eur J Cancer 102:23–30. https://doi.org/10.1016/j.ejca.2018.05.005

    Article  CAS  PubMed  Google Scholar 

  9. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J, Hermes B, Cay Senler F, Csoszi T, Fulop A, Rodriguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM (2018) Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 379(21):2040–2051. https://doi.org/10.1056/NEJMoa1810865

    Article  CAS  PubMed  Google Scholar 

  10. Wu Y, Chen W, Xu ZP, Gu W (2019) PD-L1 distribution and perspective for cancer immunotherapy-blockade, knockdown, or inhibition. Front Immunol 10:2022. https://doi.org/10.3389/fimmu.2019.02022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kim J, Cho J, Lee MH, Lim JH (2018) Relative efficacy of checkpoint inhibitors for advanced NSCLC according to programmed death-ligand-1 expression: a systematic review and network meta-analysis. Sci Rep 8(1):11738. https://doi.org/10.1038/s41598-018-30277-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ma LJ, Feng FL, Dong LQ, Zhang Z, Duan M, Liu LZ, Shi JY, Yang LX, Wang ZC, Zhang S, Ding ZB, Ke AW, Cao Y, Zhang XM, Zhou J, Fan J, Wang XY, Gao Q (2018) Clinical significance of PD-1/PD-Ls gene amplification and overexpression in patients with hepatocellular carcinoma. Theranostics 8(20):5690–5702. https://doi.org/10.7150/thno.28742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Han K, Zhang Y (2019) mRNA expression of programmed cell death ligand 1 and components of the phosphatidylinositol 3-kinase/AKT/phosphatase and tensin homolog pathway in epidermal growth factor receptor mutation-positive lung adenocarcinoma. J Cancer Res Ther 15(4):914–920. https://doi.org/10.4103/jcrt.JCRT_636_18

    Article  PubMed  Google Scholar 

  14. Xie Q, Chen Z, Xia L, Zhao Q, Yu H, Yang Z (2018) Correlations of PD-L1 gene polymorphisms with susceptibility and prognosis in hepatocellular carcinoma in a Chinese Han population. Gene 674:188–194. https://doi.org/10.1016/j.gene.2018.06.069

    Article  CAS  PubMed  Google Scholar 

  15. Krawczyk P, Grenda A, Wojas-Krawczyk K, Nicos M, Kucharczyk T, Jarosz B, Reszka K, Pankowski J, Krukowska K, Bozyk A, Szumilo J, Sawicki M, Trojanowski T, Milanowski J (2019) PD-L1 gene copy number and promoter polymorphisms regulate PD-L1 expression in tumor cells of non-small cell lung cancer patients. Cancer Genet 237:10–18. https://doi.org/10.1016/j.cancergen.2019.06.001

    Article  CAS  PubMed  Google Scholar 

  16. Ntavatzikos A, Spathis A, Patapis P, Machairas N, Vourli G, Peros G, Papadopoulos I, Panayiotides I, Koumarianou A (2019) TYMS/KRAS/BRAF molecular profiling predicts survival following adjuvant chemotherapy in colorectal cancer. World J Gastrointest Oncol 11(7):551–566. https://doi.org/10.4251/wjgo.v11.i7.551

    Article  PubMed  PubMed Central  Google Scholar 

  17. Mizushima T, Ikeda M, Kato T, Ikeda A, Nishimura J, Hata T, Matsuda C, Satoh T, Mori M, Doki Y (2019) Postoperative XELOX therapy for patients with curatively resected high-risk stage II and stage III rectal cancer without preoperative chemoradiation: a prospective, multicenter, open-label, single-arm phase II study. BMC Cancer 19(1):929. https://doi.org/10.1186/s12885-019-6122-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ma F, Ouyang Q, Li W, Jiang Z, Tong Z, Liu Y, Li H, Yu S, Feng J, Wang S, Hu X, Zou J, Zhu X, Xu B (2019) Pyrotinib or lapatinib combined with capecitabine in HER2-positive metastatic breast cancer with prior taxanes, anthracyclines, and/or trastuzumab: a randomized phase II study. J Clin Oncol. https://doi.org/10.1200/jco.19.00108

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sasaki M, Miyoshi N, Fujino S, Ishikawa S, Saso K, Takahashi H, Haraguchi N, Hata T, Matsuda C, Mizushima T, Doki Y, Mori M (2019) Development of novel prognostic prediction models including the prognostic nutritional index for patients with colorectal cancer after curative resection. J Anus Rectum Colon 3(3):106–115. https://doi.org/10.23922/jarc.2018-041

    Article  PubMed  PubMed Central  Google Scholar 

  20. Vacante M, Borzi AM, Basile F, Biondi A (2018) Biomarkers in colorectal cancer: current clinical utility and future perspectives. World J Clin Cases 6(15):869–881. https://doi.org/10.12998/wjcc.v6.i15.869

    Article  PubMed  PubMed Central  Google Scholar 

  21. Yousef AM, Zawiah M, Al-Yacoub S, Kadi T, Tantawi DA, Al-Ramadhani H (2018) The association of polymorphisms in folate-metabolizing genes with response to adjuvant chemotherapy of colorectal cancer. Cancer Chemother Pharmacol 82(2):237–243. https://doi.org/10.1007/s00280-018-3608-6

    Article  CAS  PubMed  Google Scholar 

  22. Castro-Rojas CA, Esparza-Mota AR, Hernandez-Cabrera F, Romero-Diaz VJ, Gonzalez-Guerrero JF, Maldonado-Garza H, Garcia-Gonzalez IS, Buenaventura-Cisneros S, Sanchez-Lopez JY, Ortiz-Lopez R, Camacho-Morales A, Barboza-Quintana O, Rojas-Martinez A (2017) Thymidylate synthase gene variants as predictors of clinical response and toxicity to fluoropyrimidine-based chemotherapy for colorectal cancer. Drug Metab Pers Ther 32(4):209–218. https://doi.org/10.1515/dmpt-2017-0028

    Article  CAS  PubMed  Google Scholar 

  23. Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Hoersch S, Rittweger K, Haller DG (2015) Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results of the NO16968 randomized controlled phase III trial. J Clin Oncol 33(32):3733–3740. https://doi.org/10.1200/jco.2015.60.9107

    Article  CAS  PubMed  Google Scholar 

  24. Li S, Zhu L, Cheng X, Wang Q, Feng J, Zhou J (2019) The significance of CO2 combining power in predicting prognosis of patients with stage II and III colorectal cancer. Biomark Med 13(13):1071–1080. https://doi.org/10.2217/bmm-2018-0321

    Article  CAS  PubMed  Google Scholar 

  25. Sun DC, Shi Y, Wang YR, Lv Y, Yan H, Mao H, Wang ZK, Wu ZY, Shi WW, Dai GH (2017) KRAS mutation and primary tumor location do not affect efficacy of bevacizumab-containing chemotherapy in stagae IV colorectal cancer patients. Sci Rep 7(1):14368. https://doi.org/10.1038/s41598-017-14669-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kim SK, Kim SY, Kim CW, Roh SA, Ha YJ, Lee JL, Heo H, Cho DH, Lee JS, Kim YS, Kim JC (2019) A prognostic index based on an eleven gene signature to predict systemic recurrences in colorectal cancer. Exp Mol Med 51(10):115. https://doi.org/10.1038/s12276-019-0319-y

    Article  CAS  PubMed Central  Google Scholar 

  27. Ji D, Qiao M, Yao Y, Li M, Chen H, Dong Q, Jia J, Cui X, Li Z, Xia J, Gu J (2018) Serum-based microRNA signature predicts relapse and therapeutic outcome of adjuvant chemotherapy in colorectal cancer patients. EBioMedicine 35:189–197. https://doi.org/10.1016/j.ebiom.2018.08.042

    Article  PubMed  PubMed Central  Google Scholar 

  28. Tao Y, Ding L, Yang GG, Qiu JM, Wang D, Wang H, Fu C (2018) Predictive impact of the inflammation-based indices in colorectal cancer patients with adjuvant chemotherapy. Cancer Med. https://doi.org/10.1002/cam4.1542

    Article  PubMed  PubMed Central  Google Scholar 

  29. Catalano C, da Silva Filho MI, Frank C, Jiraskova K, Vymetalkova V, Levy M, Liska V, Vycital O, Naccarati A, Vodickova L, Hemminki K, Vodicka P, Weber ANR, Forsti A (2018) Investigation of single and synergic effects of NLRC5 and PD-L1 variants on the risk of colorectal cancer. PLoS ONE 13(2):e0192385. https://doi.org/10.1371/journal.pone.0192385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wu Y, Zhao T, Jia Z, Cao D, Cao X, Pan Y, Zhao D, Zhang B, Jiang J (2019) Polymorphism of the programmed death-ligand 1 gene is associated with its protein expression and prognosis in gastric cancer. J Gastroenterol Hepatol 34(7):1201–1207. https://doi.org/10.1111/jgh.14520

    Article  CAS  PubMed  Google Scholar 

  31. Du W, Zhu J, Chen Y, Zeng Y, Shen D, Zhang N, Ning W, Liu Z, Huang JA (2017) Variant SNPs at the microRNA complementary site in the B7H1 3'untranslated region increase the risk of nonsmall cell lung cancer. Mol Med Rep 16(3):2682–2690. https://doi.org/10.3892/mmr.2017.6902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E (2008) Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol 26(21):3523–3529. https://doi.org/10.1200/jco.2007.15.4138

    Article  CAS  PubMed  Google Scholar 

  33. Yang Q, Xu Z, Zheng L, Zhang L, You Q, Sun J (2018) Multimodal detection of PD-L1: reasonable biomarkers for immune checkpoint inhibitor. Am J Cancer Res 8(9):1689–1696

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Xu Y, Wan B, Chen X, Zhan P, Zhao Y, Zhang T, Liu H, Afzal MZ, Dermime S, Hochwald SN, Hofman P, Borghaei H, Lin D, Lv T, Song Y (2019) The association of PD-L1 expression with the efficacy of anti-PD-1/PD-L1 immunotherapy and survival of non-small cell lung cancer patients: a meta-analysis of randomized controlled trials. Transl Lung Cancer Res 8(4):413–428. https://doi.org/10.21037/tlcr.2019.08.09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Enkhbat T, Nishi M, Takasu C, Yoshikawa K, Jun H, Tokunaga T, Kashihara H, Ishikawa D, Shimada M (2018) Programmed cell death ligand 1 expression is an independent prognostic factor in colorectal cancer. Anticancer Res 38(6):3367–3373. https://doi.org/10.21873/anticanres.12603

    Article  CAS  PubMed  Google Scholar 

  36. Zhou C, Che G, Zheng X, Qiu J, Xie Z, Cong Y, Pei X, Zhang H, Sun H, Ma H (2019) Expression and clinical significance of PD-L1 and c-Myc in non-small cell lung cancer. J Cancer Res Clin Oncol. https://doi.org/10.1007/s00432-019-03025-8

    Article  PubMed  Google Scholar 

  37. Shan T, Chen S, Wu T, Yang Y, Li S, Chen X (2019) PD-L1 expression in colon cancer and its relationship with clinical prognosis. Int J Clin Exp Pathol 12(5):1764–1769

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Zippelius A, Schreiner J, Herzig P, Muller P (2015) Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment. Cancer Immunol Res 3(3):236–244. https://doi.org/10.1158/2326-6066.cir-14-0226

    Article  CAS  PubMed  Google Scholar 

  39. Christofi T, Baritaki S, Falzone L, Libra M, Zaravinos A (2019) Current perspectives in cancer immunotherapy. Cancers (Basel). https://doi.org/10.3390/cancers11101472

    Article  Google Scholar 

  40. Berntsson J, Eberhard J, Nodin B, Leandersson K, Larsson AH, Jirstrom K (2018) Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: relationship with sidedness and prognosis. Oncoimmunology 7(8):e1465165. https://doi.org/10.1080/2162402x.2018.1465165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study received funding from the Youth fund of the National Natural Science Foundation of China (81902992).

Author information

Authors and Affiliations

  1. Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, Henan, China

    Jinsong Su, Weitang Yuan, Guixian Wang, Zhiyong Zhang, Zhen Li, Jinbo Liu & Junmin Song

  2. Department of Pathology, School of Medicine, Hangzhou Normal University, Hangzhou, China

    Baiyun Dai

Authors
  1. Jinsong Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Baiyun Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Weitang Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guixian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhiyong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jinbo Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Junmin Song
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Junmin Song.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the ethics committee of the First Affiliated Hospital of Zhengzhou University (registration number: Scientific research-2015-LW-025) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants or their family members included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1143 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Su, J., Dai, B., Yuan, W. et al. The influence of PD-L1 genetic variation on the prognosis of R0 resection colorectal cancer patients received capecitabine-based adjuvant chemotherapy: a long-term follow-up, real-world retrospective study. Cancer Chemother Pharmacol 85, 969–978 (2020). https://doi.org/10.1007/s00280-020-04069-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-020-04069-1

Keywords

Search

Navigation