Prognostic and predictive value of tumor-infiltrating lymphocytes in breast cancer (literature review)


  • M.O. Bilych Bogomolets National Medical University, Kyiv, Ukraine, Ukraine



breast cancer, tumor infiltrating lymphocytes, predictive factor, prognostic factor, review


Background. Breast cancer is the leading cancer type in women. Improvement in its management requires a continuous investigation of new tools for diagnosis and treatment. Biomarkers for breast cancer remain a field of great interest, despite existing knowledge. Extensive research recognizes the critical role played by tumor-infiltrating lymphocytes (TILs) in terms of prognosis and prediction, but much uncertainty still exists about the application of this biomarker in clinical practice. Thus, the purpose of this paper is to review recent researches about the role of TILs as a prognostic and predictive factor in the clinical management of breast cancer subtypes. Materials and methods. Eligible studies from Medline, Pubmed, Google Scholar (2010–2020) databases were analyzed and retrieved. Results. For primary tumors, a positive correlation was found between TILs and survival prognosis for HER2+ and TNBC subtypes, while for luminal subtypes it was a negative correlation. The predictive value of TILs in the neoadjuvant setting is established for HER2+, TNBC subtypes. In the case of using TILs as a predictive factor for HER2-targeted therapy, it remains a concern due to controversial data. For residual tumor, it is growing body of evidence about the positive correlation of TILs and prognosis for all subtypes, but data are limited. Conclusions. TILs were found to have prognostic and predictive value. However, due to the heterogeneity of breast cancer subtypes, TILs as a biomarker should be interpreted with caution. Further studies need to be carried out to determine the validity of making a clinical decision based on TILs count.


Annaratone L., Cascardi E., Vissio E. et al. The Multifaceted Nature of Tumor Microenvironment in Breast Carcinomas. Pathobio­logy. 2020. № 87(suppl. 2). Р. 125-42. DOI: 10.1159/000507055.

Salgado R., Denkert C., Demaria S. et al. The evaluation of tumor-infiltrating lymphocytes (TILS) in breast cancer: Recommendations by an International TILS Working Group 2014. Ann. Oncol. 2015. № 26(2). Р. 259-71. DOI: 10.1001/jamaoncol.2015.0830.

Dannenfelser R., Nome M., Tahiri A. et al. Data-driven analysis of immune infiltrate in a large cohort of breast cancer and its association with disease progression, ER activity, and genomic complexity. Oncotarget. 2017. № 8(34). Р. 57121-33. DOI: 10.18632/oncotarget.19078.

Dieci M.V., Griguolo G., Miglietta F., Guarneri V. The immune system and hormone-receptor positive breast cancer: Is it really a dead end? Cancer Treat. Rev. [Internet]. 2016. № 46. Р. 9-19.

Millar E., Browne L., Slapetova I. et al. Tils immunophenotype in breast cancer predicts local failure and overall survival: Analysis in a large radiotherapy trial with long-term follow-up. Cancers (Basel). 2020. № 12(9). Р. 1-15. DOI: 10.3390/cancers12092365.

Sobral-Leite M., Salomon I., Opdam M. et al. Cancer-immune interactions in ER-positive breast cancers: PI3K pathway alte­rations and tumor-infiltrating lymphocytes. Breast Cancer Res. 2019. № 21(1). Р. 1-12. DOI: 10.1186/s13058-019-1176-2.

Gao Z., Li C., Liu M., Jiang J. Predictive and Prognostic Role of Tumor Infiltrating Lymphocytes in Breast Cancer Patients With Different Molecular Subtypes: a Meta-Analysis. 2020. Р. 1-14. DOI: 10.21203/

Tsang J.Y.S., Hui S.W., Ni Y.B. et al. Lymphocytic infiltrate is associated with favorable biomarkers profile in HER2-overexpressing breast cancers and adverse biomarker profile in ER-positive breast cancers. Breast Cancer Res. Treat. 2014. № 143(1). Р. 1-9. DOI: 10.1007/s10549-013-2781-x

Denkert C., von Minckwitz G., Darb-Esfahani S. et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 2018. № 19(1). Р. 40-50. DOI: 10.1016/S1470-2045(17)30904-X.

Pruneri G., Vingiani A., Bagnardi V. et al. Clinical validity of tumor-infiltrating lymphocytes analysis in patients with triple-negative breast cancer. Ann. Oncol. 2016. № 27(2). Р. 249-56. Available from:

Park J.H., Jonas S.F., Bataillon G. et al. Prognostic value of tumor-infiltrating lymphocytes in patients with early-stage triple-negative breast cancers (TNBC) who did not receive adjuvant chemotherapy. Ann. Oncol. 2019. № 30(12). Р. 1941-9. DOI: 10.1093/annonc/mdz395.

De Jong V.M.T., Wang Y., Opdam M. et al. Breast cancer, early stage 1590. Prognostic value of tumour infiltrating lymphocytes in young triple negative breast cancer patients who did not receive adjuvant systemic treatment; by the PARADIGM study group. 2020 [cited 2020 Dec 7].

van Rossum A.G.J., Hoogstraat M., Opdam M. et al. Tumor infiltrating lymphocytes predict benefit from TAC but not from ddAC in triple negative breast cancer in the randomized MATADOR trial (BOOG 2004-04). Ann. Oncol. 2018. № 29(October). viii60.

He L., Wang Y., Wu Q. et al. Association between levels of tumor-infiltrating lymphocytes in different subtypes of primary breast tumors and prognostic outcomes: A meta-analysis. BMC Womens Health. 2020. № 20(1). Р. 1-11. DOI: 10.1186/s12905-020-01038-x.

Solinas C., Ceppi M., Lambertini M. et al. Tumor-infiltrating lymphocytes in patients with HER2-positive breast cancer treated with neoadjuvant chemotherapy plus trastuzumab, lapatinib or their combination: A meta-analysis of randomized controlled trials. Cancer Treat Rev. 2017. № 57. Р. 8-15.

Salgado R., Denkert C., Campbell C. et al. Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: A secondary analysis of the NeoALTTO trial. JAMA Oncol. 2015. № 1(4). Р. 448-55. DOI: 10.1093/annonc/mdu450.

Liu S., Mou E., Zeng S. et al. Therapeutic effect of trastuzumab in neoadjuvant-treated her2-positive breast cancer with low infiltrating level of tumor-infiltrating lymphocytes. Cancer Manag. Res. 2020. № 12. Р. 3145-53. DOI: 10.2147/CMAR.S248071.

Ignatiadis M., Van Den Eynden G., Roberto S. et al.Tumor-infiltrating lymphocytes in patients receiving trastuzumab/pertuzumab-based chemotherapy: A TRYPHAENA Substudy. J. Natl. Cancer Inst. 2019. № 111(1). Р. 69-77. DOI: 10.1093/jnci/djy076.

Nuciforo P., Pascual T., Cortés J. et al. A predictive model of pathologic response based on tumor cellularity and tumor-infiltrating lymphocytes (CelTIL) in HER2-positive breast cancer treated with chemo-free dual HER2 blockade. Ann. Oncol. 2018 Jan 1. № 29(1). Р. 170-7. DOI:10.1093/annonc/mdx647.

Griguolo G., Pascual T., Dieci M.V., Guarneri V., Prat A. Interaction of host immunity with HER2-targeted treatment and tumor heterogeneity in HER2-positive breast cancer. J. Immunother. Cancer. 2019. № 7(1). Р. 1-14. DOI: 10.1186/s40425-019-0548-6.

Loi S., Michiels S., Salgado R. et al. 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. 2014. № 25(8). Р. 1544-50. DOI: 10.1093/annonc/mdu112.

Dieci M.V., Conte P., Bisagni G. et al. Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer. Ann. Oncol. 2019. № 30(3). Р. 418-23.

Asano Y., Kashiwagi S., Goto W. et al. Prediction of survival after neoadjuvant chemotherapy for breast cancer by evaluation of tumor-infiltrating lymphocytes and residual cancer burden. BMC Cancer. 2017. № 17(1). Р. 1-10. DOI: 10.1186/s12885-017-3927-8.

Hamy A.S., Pierga J.Y., Sabaila A. et al. Stromal lymphocyte infiltration after neoadjuvant chemotherapy is associated with aggressive residual disease and lower disease-free survival in HER2-positive breast cancer. Ann. Oncol. 2017. № 28(9). Р. 2233-40. DOI: 10.1093/annonc/mdx309.

Dieci M.V., Criscitiello C., Goubar A. et al. Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: A retrospective multicenter study. Ann. Oncol. 2014. № 25(3). Р. 611-8.

Dieci M.V., Radosevic-Robin N., Fineberg S. et al. Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: A report of the International Immuno-Oncology Biomarker Working Group on Bre. Semin. Cancer Biol. 2018. № 52(October). Р. 16-25.

Luen S.J., Salgado R., Dieci M.V. et al. Prognostic implications of residual disease tumor-infiltrating lymphocytes and residual cancer burden in triple-negative breast cancer patients after neoadjuvant chemotherapy. Ann. Oncol. 2019. № 30(2). Р. 236-42.

Balic M., Thomssen C., Würstlein R., Gnant M., Harbeck N. St. Gallen/Vienna 2019: A brief summary of the consensus discussion on the optimal primary breast cancer treatment. Breast Care. 2019. № 14(2). Р. 103-10. DOI: 10.1159/000499931.

Glajcar A., Szpor J., Hodorowicz-Zaniewska D., Tyrak K.E., Okoń K. The composition of T cell infiltrates varies in primary invasive breast cancer of different molecular subtypes as well as according to tumor size and nodal status. Virchows Arch. 2019. № 475(1). Р. 13-23. DOI: 10.1007/s00428-019-02568-y.

Bates J.P., Derakhshandeh R., Jones L., Webb T.J. Mecha­nisms of immune evasion in breast cancer. BMC Cancer. 2018. № 18(1). Р. 1-14. DOI: 10.1186/s12885-018-4441-3.

Glajcar A., Szpor J., Pacek A., Tyrak K.E., Chan F., Streb J., Hodorowicz-Zaniewska D., Okoń K. The relationship between breast cancer molecular subtypes and mast cell populations in tumor microenvironment. Virchows Arch. 2017. № 470(5). Р. 505-15. DOI: 10.1007/s00428-017-2103-5.

Shen M., Wang J., Ren X. New insights into tumor-infiltra­ting B lymphocytes in breast cancer: Clinical impacts and regulatory mechanisms. Front. Immunol. 2018. № 9(Mar). Р. 1-8.

Song P.N., Mansur A., Dugger K.J., Davis T.R., Howard G., Yankeelov T.E., Sorace A.G. CD4 T-cell immune stimulation of HER2 + breast cancer cells alters response to trastuzumab in vitro. Cancer Cell. Int. 2020. № 20(1). Р. 1-11.

Ahn S., Chung Y.R., Seo A.N., Kim M., Woo J.W., Park S.Y. Changes and prognostic values of tumor-infiltrating lymphocyte subsets after primary systemic therapy in breast cancer. PLoS One. 2020. № 15(5). Р. 1-14.

Kaewkangsadan V., Verma C., Eremin J.M., Cowley G., Ilyas M., Eremin O. Crucial Contributions by T Lymphocytes (Effector, Regulatory, and Checkpoint Inhibitor) and Cytokines (TH1, TH2, and TH17) to a Pathological Complete Response Induced by Neoadjuvant Chemotherapy in Women with Breast Cancer. J. Immunol. Res. 2016. № 2016. Р. 4-7. DOI: 10.1155/2016/4757405

Kim R., Kawai A., Wakisaka M. et al. Immune factors associated with the pathological and therapeutic effects of preope­rative chemotherapy in patients with breast cancer. Transl. Oncol. 2021. № 14(1). Р. 100927.

Miyashita M., Sasano H., Tamaki K. et al. Prognostic significance of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in residual tumors and alterations in these parameters after neoadjuvant chemotherapy in triple-negative breast cancer: A retrospective multicenter study. Breast Cancer Res. 2015. № 17(1). Р. 1-13.

Goto W., Kashiwagi S., Asano Y. et al. Predictive value of improvement in the immune tumour microenvironment in patients with breast cancer treated with neoadjuvant chemotherapy. ESMO Open. 2018. № 3(6). Р. 1-10. DOI: 10.1136/esmoopen-2017-000305.