Tumor-infiltrating Lymphocytes in HER2-positive Breast Cancer: Potential Impact and Challenges

Overview

Journal ESMO Open

Publisher Elsevier

Date 2025 Jan 18

PMID 39826475

Authors

I Schlam

S Loi

R Salgado

S M Swain

Affiliations

Soon will be listed here.

Abstract

Introduction: In this review, we evaluate the role of stromal tumor-infiltrating lymphocytes (sTILs) as a biomarker in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, exploring the prognostic and predictive potential in various treatment settings.

Methods: Data from multiple clinical trials in the early and metastatic settings, focusing on TILs' correlation with pathologic complete response (pCR), progression-free survival (PFS), and overall survival across early and metastatic HER2-positive breast cancer were summarized. This review also discusses TILs' assessment methods, interobserver variability, and emerging technologies to assess TILs.

Results: TILs have been identified as a highly reproducible biomarker that predicts pCR in patients receiving neoadjuvant therapy and serves as a prognostic indicator for long-term outcomes in several breast cancer subtypes, including HER2-positive. Studies indicate that higher TIL levels correlate with better recurrence-free survival rates. Despite these findings, there is no consensus on the optimal TIL threshold for clinical decision making, and further research is required on how to incorporate TILs into routine clinical practice.

Conclusions: TILs represent a promising biomarker in HER2-positive breast cancer, particularly in early disease settings. This assessment could guide treatment de-escalation or intensification, tailoring therapies to individual patient profiles. Due to their prognostic importance, TILs can be added to pathology reports. However, further validation in clinical trials is essential for the widespread adoption of TILs in clinical practice.

References

Savas P, Virassamy B, Ye C, Salim A, Mintoff C, Caramia F . Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat Med. 2018; 24(7):986-993. DOI: 10.1038/s41591-018-0078-7. View

Villacampa G, Pascual T, Braso-Maristany F, Pare L, Martinez-Saez O, Cortes J . Prognostic value of HER2DX in early-stage HER2-positive breast cancer: a comprehensive analysis of 757 patients in the Sweden Cancerome Analysis Network-Breast dataset (SCAN-B). ESMO Open. 2024; 9(3):102388. PMC: 10925926. DOI: 10.1016/j.esmoop.2024.102388. View

Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D . 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):1544-50. DOI: 10.1093/annonc/mdu112. View

DHondt V, Canon J, Roca L, Levy C, Pierga J, Le Du F . UCBG 2-04: Long-term results of the PACS 04 trial evaluating adjuvant epirubicin plus docetaxel in node-positive breast cancer and trastuzumab in the human epidermal growth factor receptor 2-positive subgroup. Eur J Cancer. 2019; 122:91-100. DOI: 10.1016/j.ejca.2019.09.014. View

Cortes J, Rugo H, Cescon D, Im S, Yusof M, Gallardo C . Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2022; 387(3):217-226. DOI: 10.1056/NEJMoa2202809. View

Hammerl D, Martens J, Timmermans M, Smid M, Trapman-Jansen A, Foekens R . Spatial immunophenotypes predict response to anti-PD1 treatment and capture distinct paths of T cell evasion in triple negative breast cancer. Nat Commun. 2021; 12(1):5668. PMC: 8476574. DOI: 10.1038/s41467-021-25962-0. View

von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G . Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. N Engl J Med. 2017; 377(2):122-131. PMC: 5538020. DOI: 10.1056/NEJMoa1703643. View

Li S, Zhang Y, Zhang P, Xue S, Chen Y, Sun L . Predictive and prognostic values of tumor infiltrating lymphocytes in breast cancers treated with neoadjuvant chemotherapy: A meta-analysis. Breast. 2022; 66:97-109. PMC: 9550538. DOI: 10.1016/j.breast.2022.10.001. View

van Ramshorst M, van der Voort A, van Werkhoven E, Mandjes I, Kemper I, Dezentje V . Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018; 19(12):1630-1640. DOI: 10.1016/S1470-2045(18)30570-9. View

10.

Prat A, Guarneri V, Pascual T, Braso-Maristany F, Sanfeliu E, Pare L . Development and validation of the new HER2DX assay for predicting pathological response and survival outcome in early-stage HER2-positive breast cancer. EBioMedicine. 2022; 75:103801. PMC: 8741424. DOI: 10.1016/j.ebiom.2021.103801. View

11.

Swain S, Baselga J, Kim S, Ro J, Semiglazov V, Campone M . Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015; 372(8):724-34. PMC: 5584549. DOI: 10.1056/NEJMoa1413513. View

12.

Swain S, Shastry M, Hamilton E . Targeting HER2-positive breast cancer: advances and future directions. Nat Rev Drug Discov. 2022; 22(2):101-126. PMC: 9640784. DOI: 10.1038/s41573-022-00579-0. View

13.

Schettini F, Prat A . Dissecting the biological heterogeneity of HER2-positive breast cancer. Breast. 2021; 59:339-350. PMC: 8374722. DOI: 10.1016/j.breast.2021.07.019. View

14.

Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G . The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2014; 26(2):259-71. PMC: 6267863. DOI: 10.1093/annonc/mdu450. View

15.

Emens L, Esteva F, Beresford M, Saura C, De Laurentiis M, Kim S . Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial. Lancet Oncol. 2020; 21(10):1283-1295. DOI: 10.1016/S1470-2045(20)30465-4. View

16.

Hurvitz S, Martin M, Fraser Symmans W, Jung K, Huang C, Thompson A . Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2017; 19(1):115-126. DOI: 10.1016/S1470-2045(17)30716-7. View

17.

Loi S, Giobbie-Hurder A, Gombos A, Bachelot T, Hui R, Curigliano G . Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. Lancet Oncol. 2019; 20(3):371-382. DOI: 10.1016/S1470-2045(18)30812-X. View

18.

Tarantino P, Tayob N, Villacampa G, Dang C, Yardley D, Isakoff S . Adjuvant Trastuzumab Emtansine Versus Paclitaxel Plus Trastuzumab for Stage I Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: 5-Year Results and Correlative Analyses From ATEMPT. J Clin Oncol. 2024; 42(31):3652-3665. PMC: 11527383. DOI: 10.1200/JCO.23.02170. View

19.

Bergstrom E, Abbasi A, Diaz-Gay M, Galland L, Ladoire S, Lippman S . Deep Learning Artificial Intelligence Predicts Homologous Recombination Deficiency and Platinum Response From Histologic Slides. J Clin Oncol. 2024; 42(30):3550-3560. PMC: 11469627. DOI: 10.1200/JCO.23.02641. View

20.

Heppner B, Untch M, Denkert C, Pfitzner B, Lederer B, Schmitt W . Tumor-Infiltrating Lymphocytes: A Predictive and Prognostic Biomarker in Neoadjuvant-Treated HER2-Positive Breast Cancer. Clin Cancer Res. 2016; 22(23):5747-5754. DOI: 10.1158/1078-0432.CCR-15-2338. View