Skip to main content

Advertisement

SpringerLink
Log in

Tumor-infiltrating lymphocytes (TILs) in ER+/HER2− breast cancer

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

The prognostic role of tumor-infiltrating lymphocytes (TILs) in ER+/HER2− breast cancer (BC) is debated. We evaluated the association of TILs and clinico-pathological features with distant disease-free survival (DDFS) in patients with ER+/HER2− BC treated at a single institution.

Patients and methods

A mono-institutional case-cohort series of 987 patients with early ER+/HER2− BC was retrospectively analyzed. TILs were considered both as continuous variable, and dichotomized in low (< 5%) vs high (≥ 5%). The main outcome was DDFS. Median follow-up was 7.5 years (0.1–10). Univariate and multivariable Cox proportional hazards regression with inverse sub-cohort sampling probability weighting were used to evaluate the risk across groups.

Results

Median TIL count was 2% (Q1–Q3 1–4%). Higher TILs were positively associated with number of lymph nodes involved (p = 0.003), tumor grade (p < 0.0001), peritumoral vascular invasion (p = 0.003), higher Ki-67 (p = 0.0001), luminal B subtype (p < 0.0001), and chemotherapy use (p < 0.00019). In multivariable regression analysis, only higher Ki-67 expression retained significant association with TILs. At univariate Cox regression analysis, TIL expression (≥ 5% vs. < 5%) was not associated with DDFS (HR 1.08, 95% CI 0.80–1.46, p = 0.62). In patients treated with adjuvant chemotherapy, high TILs were associated with better DDFS (HR 0.52, 95%CI 0.33–0.83, p = 0.006), particularly in the group with Ki-67 ≥ 20% (HR 0.50, 95%CI 0.29–0.86, p = 0.01).

Conclusion

High TILs in ER+/HER2− BC are significantly associated with clinico-pathological features of dismal outcome. TIL prognostic value seems different in patients treated with or without chemotherapy. Our findings suggest that the high-risk subgroup might be more immunogenic, thus deserving the exploration of immunotherapy approaches.

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
Fig. 5

Similar content being viewed by others

References

  1. Prat A, Fan C, Fernandez A et al (2015) Response and survival of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy. BMC Med 13:303

    Article  Google Scholar 

  2. Early Breast Cancer Trialists' Collaborative G, Peto R, Davies C et al (2012) Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 379(9814):432–444

    Article  Google Scholar 

  3. Savas P, Salgado R, Denkert C et al (2016) Clinical relevance of host immunity in breast cancer: from TILs to the clinic. Nat Rev Clin Oncol 13(4):228–241

    Article  CAS  Google Scholar 

  4. Loi S, Sirtaine N, Piette F et al (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(7):860–867

    Article  CAS  Google Scholar 

  5. Loi S, Michiels S, Salgado R et al (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(8):1544–1550

    Article  CAS  Google Scholar 

  6. Ali HR, Provenzano E, Dawson SJ et al (2014) Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol 25(8):1536–1543

    Article  CAS  Google Scholar 

  7. Salgado R, Denkert C, Campbell C et al (2015) 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 1(4):448–454

    Article  Google Scholar 

  8. Adams S, Gray RJ, Demaria S et al (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 32(27):2959–2966

    Article  Google Scholar 

  9. Park JH, Jonas SF, Bataillon G et al (2019) Prognostic value of tumor-infiltrating lymphocytes in patients with early-stage triple-negative breast cancers (TNBC) who did not receive adjuvant chemotherapy. Ann Oncol 30:1941

    Article  CAS  Google Scholar 

  10. Dieci MV, Criscitiello C, Goubar A et al (2015) Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. Ann Oncol 26(7):1518

    Article  CAS  Google Scholar 

  11. Dieci MV, Griguolo G, Miglietta F, Guarneri V (2016) The immune system and hormone-receptor positive breast cancer: is it really a dead end? Cancer Treat Rev 46:9–19

    Article  CAS  Google Scholar 

  12. Denkert C, von Minckwitz G, Darb-Esfahani S et al (2018) Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol 19(1):40–50

    Article  Google Scholar 

  13. Maisonneuve P, Disalvatore D, Rotmensz N et al (2014) Proposed new clinicopathological surrogate definitions of luminal A and luminal B (HER2-negative) intrinsic breast cancer subtypes. Breast Cancer Res 16(3):R65

    Article  Google Scholar 

  14. Salgado R, Denkert C, Demaria S et al (2015) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26(2):259–271

    Article  CAS  Google Scholar 

  15. Denkert C, Wienert S, Poterie A et al (2016) Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer: results of the ring studies of the international immuno-oncology biomarker working group. Mod Pathol 29(10):1155–1164

    Article  CAS  Google Scholar 

  16. Stanton SE, Disis ML (2016) Clinical significance of tumor-infiltrating lymphocytes in breast cancer. J Immunother Cancer 4:59

    Article  Google Scholar 

  17. Mostafa AA, Codner D, Hirasawa K et al (2014) Activation of ERalpha signaling differentially modulates IFN-gamma induced HLA-class II expression in breast cancer cells. PLoS ONE 9(1):e87377

    Article  Google Scholar 

  18. Fujimoto Y, Watanabe T, Hida AI et al (2019) Prognostic significance of tumor-infiltrating lymphocytes may differ depending on Ki67 expression levels in estrogen receptor-positive/HER2-negative operated breast cancers. Breast Cancer (Tokyo, Japan) 26:738

    Article  Google Scholar 

  19. Bates GJ, Fox SB, Han C et al (2006) Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24(34):5373–5380

    Article  Google Scholar 

  20. Sobral-Leite M, Salomon I, Opdam M et al (2019) Cancer-immune interactions in ER-positive breast cancers: PI3K pathway alterations and tumor-infiltrating lymphocytes. Breast Cancer Res 21(1):90

    Article  Google Scholar 

  21. Dunbier AK, Ghazoui Z, Anderson H et al (2013) Molecular profiling of aromatase inhibitor-treated postmenopausal breast tumors identifies immune-related correlates of resistance. Clin Cancer Res 19(10):2775–2786

    Article  CAS  Google Scholar 

  22. Gao Q, Patani N, Dunbier AK et al (2014) Effect of aromatase inhibition on functional gene modules in estrogen receptor-positive breast cancer and their relationship with antiproliferative response. Clin Cancer Res 20(9):2485–2494

    Article  CAS  Google Scholar 

Download references

Funding

None.

Author information

Author notes

  1. C. Criscitiello and A. Vingiani have contributed equally to this work.

Authors and Affiliations

  1. Division of Early Drug Development for Innovative Therapies, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, Italy

    C. Criscitiello, G. Viale & G. Curigliano

  2. Pathology Department, IEO, European Institute of Oncology IRCCS, Milan, Italy

    A. Vingiani & G. Viale

  3. Division of Epidemiology and Biostatistics, IEO, European Institute of Oncology IRCCS, Milan, Italy

    P. Maisonneuve

  4. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

    G. Viale & G. Curigliano

Authors
  1. C. Criscitiello
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Vingiani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. Maisonneuve
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Viale
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. Viale
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. Curigliano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Criscitiello.

Ethics declarations

Conflict of interest

CC: honoraria for speakers' bureau or consultancy from Roche, Pfizer, Novartis, Lilly. AV, PM, CV: no competing interests to disclose. GV: personal honoraria from MSD Oncology, Pfizer; Consulting or Advisory Role from Dako, Roche/Genentech, Astellas Pharma, Novartis, Bayer, Daiichi Sankyo; Speakers' Bureau from Roche/Genentech; Institutional research Funding from Roche/Genentech, Ventana Medical Systems, Dako/Agilent Technologies. GC: honoraria for speaker, consultancy, or advisory role from Roche, Pfizer, Novartis, Seattle Genetics, Lilly, Ellipsis.

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.

Electronic supplementary material 1 (DOCX 236 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Criscitiello, C., Vingiani, A., Maisonneuve, P. et al. Tumor-infiltrating lymphocytes (TILs) in ER+/HER2− breast cancer. Breast Cancer Res Treat 183, 347–354 (2020). https://doi.org/10.1007/s10549-020-05771-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-020-05771-7

Keywords

Search

Navigation