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The prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancer: a meta-analysis

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Abstract

In a recent meta-analysis, we demonstrated that rich tumor-infiltrating lymphocytes (TILs) were significantly correlated to a favorable breast cancer (BC) outcome largely in estrogen receptor-negative tumors. It is known that TILs predominate in triple-negative (TN) BC, and to the best of our knowledge, there is no published meta-analysis that examined their prognostic value exclusively in that subtype. Therefore, we planned this meta-analysis to explore the clinical utility of rich TILs in TN-BC. According to predefined selection criteria, literature search identified eight eligible studies. The meta-analysis included data on 2,987 patients with early stage BC. The median percentage of lymph node positivity was 47 % (95 % confidence interval [CI] 23–82 %). Over a median follow-up of 113 months (95 % CI 80–144 months), it was found that rich TILs were associated with 30 % (hazard ratio [HR] = 0.70; 95 % CI 0.56–0.87; P = 0.001), 22 % (HR = 0.78; 95 % CI 0.68–0.90; P = 0.0008), and 34 % (HR = 0.66; 95 % CI 0.53–0.83; P = 0.0003), reduction in the risk of recurrence, distant recurrence, and death, respectively. In addition, for every 10 % increments in rich TILs, there was an approximate 15–20 % reduction in any recurrence, distant recurrence, or mortality. Moreover, rich TILs predicted superior overall survival (OS) benefit irrespective of the disease phenotype (TN-BC or core-basal phenotype), TILs location (intratumoral or stromal), or TILs qualification as either TILs-non-specified, cytotoxic (CD8+) or regulatory (forkhead box protein 3, FOXP3+) T cells. Data on 5-negative phenotype population were limited, and rich TILs failed to demonstrate a prognostic significance in this phenotype. To investigate the heterogeneity that was shown in the analyses of disease-free survival and OS, a set of meta-analyses showed that the method used in TILs detection (hematoxylin and eosin stains vs. immunohistochemistry) could explain most of the variability in the pooled estimates. Rich TILs were significantly associated with better survival outcome in early TN-BC and should be considered as a strong prognostic factor in this subtype. The results from the current meta-analysis support integrating immunotherapy with conventional therapy in future BC research.

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References

  1. Zitvogel L, Kepp O, Kroemer G (2011) Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol 8:151–160. doi:10.1038/nrclinonc.2010.223

    Article  CAS  PubMed  Google Scholar 

  2. Zitvogel L, Apetoh L, Ghiringhelli F, Andre F, Tesniere A, Kroemer G (2008) The anticancer immune response: indispensable for therapeutic success? J Clin Investig 118:1991–2001. doi:10.1172/JCI35180

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Demaria S, Volm MD, Shapiro RL, Yee HT, Oratz R, Formenti SC, Muggia F, Symmans WF (2001) Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res 7:3025–3030

    CAS  PubMed  Google Scholar 

  4. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:203–213. doi:10.1056/NEJMoa020177

    Article  CAS  PubMed  Google Scholar 

  5. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964. doi:10.1126/science.1129139

    Article  CAS  PubMed  Google Scholar 

  6. Pages F, Galon J, Dieu-Nosjean MC, Tartour E, Sautes-Fridman C, Fridman WH (2010) Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene 29:1093–1102. doi:10.1038/onc.2009.416

    Article  CAS  PubMed  Google Scholar 

  7. Whitford P, Mallon EA, George WD, Campbell AM (1990) Flow cytometric analysis of tumour infiltrating lymphocytes in breast cancer. Br J Cancer 62:971–975

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Nixon AJ, Schnitt SJ, Gelman R, Gage I, Bornstein B, Hetelekidis S, Recht A, Silver B, Harris JR, Connolly JL (1996) Relationship of tumor grade to other pathologic features and to treatment outcome of patients with early stage breast carcinoma treated with breast-conserving therapy. Cancer 78:1426–1431. doi:10.1002/(SICI)1097-0142(19961001)78:7<1426::AID-CNCR8>3.0.CO;2-I

    Article  CAS  PubMed  Google Scholar 

  9. Droeser R, Zlobec I, Kilic E, Guth U, Heberer M, Spagnoli G, Oertli D, Tapia C (2012) Differential pattern and prognostic significance of CD4+, FOXP3+ and IL-17+ tumor infiltrating lymphocytes in ductal and lobular breast cancers. BMC Cancer 12:134. doi:10.1186/1471-2407-12-134

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, Perou CM (2006) Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol 19:264–271. doi:10.1038/modpathol.3800528

    Article  CAS  PubMed  Google Scholar 

  11. Lakhani SR (1999) The pathology of familial breast cancer: morphological aspects. Breast Cancer Res 1:31–35

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Tamiolakis D, Simopoulos C, Cheva A, Lambropoulou M, Kotini A, Jivannakis T, Papadopoulos N (2002) Immunophenotypic profile of tumor infiltrating lymphocytes in medullary carcinoma of the breast. Eur J Gynaecol Oncol 23:433–436

    CAS  PubMed  Google Scholar 

  13. Baker K, Lachapelle J, Zlobec I, Bismar TA, Terracciano L, Foulkes WD (2011) Prognostic significance of CD8+ T lymphocytes in breast cancer depends upon both oestrogen receptor status and histological grade. Histopathology 58:1107–1116. doi:10.1111/j.1365-2559.2011.03846.x

    PubMed  Google Scholar 

  14. Ibrahim EM, Al-Foheidi M, Al-Mansour MM, Kazkaz GA, Yunus TE (2014) The prognostic and predicting roles of tumor-Infiltrating lymphocytes in breast cancer: a meta-analysis. The Open Breast Cancer J 6:9–19

    Article  Google Scholar 

  15. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR (2007) Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8:16. doi:10.1186/1745-6215-8-16

    Article  PubMed Central  PubMed  Google Scholar 

  16. Parmar MK, Torri V, Stewart L (1998) Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 17:2815–2834

    Article  CAS  PubMed  Google Scholar 

  17. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558. doi:10.1002/sim.1186

    Article  PubMed  Google Scholar 

  18. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560. doi:10.1136/bmj.327.7414.557

    Article  PubMed Central  PubMed  Google Scholar 

  19. Dersimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    Article  CAS  PubMed  Google Scholar 

  20. Donders AR, Van Der Heijden GJ, Stijnen T, Moons KG (2006) Review: a gentle introduction to imputation of missing values. J Clin Epidemiol 59:1087–1091. doi:10.1016/j.jclinepi.2006.01.014

    Article  PubMed  Google Scholar 

  21. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101

    Article  CAS  PubMed  Google Scholar 

  23. Kreike B, Van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H, Van De Vijver MJ (2007) Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res 9:R65. doi:10.1186/bcr1771

    Article  PubMed Central  PubMed  Google Scholar 

  24. Liu S, Lachapelle J, Leung S, Gao D, Foulkes WD, Nielsen TO (2012) CD8 + lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res 14:R48. doi:10.1186/bcr3148

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, Rouas G, Francis P, Crown JP, Hitre E, De Azambuja E, Quinaux E, Di Leo A, Michiels S, Piccart MJ, Sotiriou C (2013) Prognostic and Predictive Value of Tumor-Infiltrating Lymphocytes in a Phase III Randomized Adjuvant Breast Cancer Trial in Node-Positive Breast Cancer Comparing the Addition of Docetaxel to Doxorubicin With Doxorubicin-Based Chemotherapy: bIG 02-98. J Clin Oncol 31:860–867. doi:10.1200/JCO.2011.41.0902

    Article  CAS  PubMed  Google Scholar 

  26. West NR, Kost SE, Martin SD, Milne K, Deleeuw RJ, Nelson BH, Watson PH (2013) Tumour-infiltrating FOXP3(+) lymphocytes are associated with cytotoxic immune responses and good clinical outcome in oestrogen receptor-negative breast cancer. Br J Cancer 108:155–162. doi:10.1038/bjc.2012.524

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, Martino S, Wang M, Jones VE, Saphner TJ, Wolff AC, Wood WC, Davidson NE, Sledge GW, Sparano JA, Badve SS (2014) Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199. J Clin Oncol. doi:10.1200/JCO.2013.55.0491

    Google Scholar 

  28. Ali HR, Provenzano E, Dawson SJ, Blows FM, Liu B, Shah M, Earl HM, Poole CJ, Hiller L, Dunn JA, Bowden SJ, Twelves C, Bartlett JM, Mahmoud SM, Rakha E, Ellis IO, Liu S, Gao D, Nielsen TO, Pharoah PD, Caldas C (2014) Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol 25:1536–1543. doi:10.1093/annonc/mdu191

    Article  CAS  PubMed  Google Scholar 

  29. Chen Z, Chen X, Zhou E, Chen G, Qian K, Wu X, Miao X, Tang Z (2014) Intratumoral CD8(+) cytotoxic lymphocyte is a favorable prognostic marker in node-negative breast cancer. PLoS One 9:e95475. doi:10.1371/journal.pone.0095475

    Article  PubMed Central  PubMed  Google Scholar 

  30. Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, Kellokumpu-Lehtinen PL, Bono P, Kataja V, Desmedt C, Piccart MJ, Loibl S, Denkert C, Smyth MJ, Joensuu H, Sotiriou C (2014) Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol 25:1544–1550. doi:10.1093/annonc/mdu112

    Article  CAS  PubMed  Google Scholar 

  31. Rubbert A, Manger B, Lang N, Kalden JR, Platzer E (1991) Functional characterization of tumor-infiltrating lymphocytes, lymph-node lymphocytes and peripheral-blood lymphocytes from patients with breast cancer. Int J Cancer 49:25–31

    Article  CAS  PubMed  Google Scholar 

  32. Bertucci F, Finetti P, Cervera N, Maraninchi D, Viens P, Birnbaum D (2006) Gene expression profiling and clinical outcome in breast cancer. OMICS 10:429–443. doi:10.1089/omi.2006.10.429

    Article  CAS  PubMed  Google Scholar 

  33. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Investig 121:2750–2767. doi:10.1172/JCI45014

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Verbrugge I, Johnstone RW (2012) Regulating the TRAIL of destruction: how A20 protects glioblastomas from TRAIL-mediated death. Cancer Discov 2:112–114. doi:10.1158/2159-8290.CD-11-0350

    Article  CAS  PubMed  Google Scholar 

  35. John LB, Kershaw MH, Darcy PK (2013) Blockade of PD-1 immunosuppression boosts CAR T-cell therapy. Oncoimmunology 2:e26286. doi:10.4161/onci.26286

    Article  PubMed Central  PubMed  Google Scholar 

  36. Kershaw MH, Devaud C, John LB, Westwood JA, Darcy PK (2013) Enhancing immunotherapy using chemotherapy and radiation to modify the tumor microenvironment. Oncoimmunology 2:e25962. doi:10.4161/onci.25962

    Article  PubMed Central  PubMed  Google Scholar 

  37. Disis ML, Coveler AL, Higgins D, Fintak P, Waisman JR, Reichow J, Slota M, Childs J, Dang Y, Salazar LG (2014) A phase I trial of the safety and immunogenicity of a DNA-based vaccine encoding the HER2/neu (HER2) intracellular domain in subjects with HER2+ breast cancer. ASCO Meet Abstr 32:616

    Google Scholar 

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Acknowledgments

Conflict of Interest: None

Funding Information: None

Ethical Standards: The meta-analysis complies with the current laws of Saudi Arabia

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Authors and Affiliations

  1. Oncology Center of Excellence, International Medical Center, PO Box 2172, Jeddah, 21451, Kingdom of Saudi Arabia

    Ezzeldin M. Ibrahim & Ghieth A. Kazkaz

  2. Princess Noorah Oncology Center, King Abdulaziz Medical City, PO Box 9515, Jeddah, 21423, Kingdom of Saudi Arabia

    Meteb E. Al-Foheidi & Mubarak M. Al-Mansour

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  1. Ezzeldin M. Ibrahim
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  2. Meteb E. Al-Foheidi
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Correspondence to Ezzeldin M. Ibrahim.

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Ibrahim, E.M., Al-Foheidi, M.E., Al-Mansour, M.M. et al. The prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancer: a meta-analysis. Breast Cancer Res Treat 148, 467–476 (2014). https://doi.org/10.1007/s10549-014-3185-2

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