Clinical Utility of Tumor-infiltrating Lymphocyte Evaluation by Two Different Methods in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy

Overview

Journal Breast Cancer

Date 2025 Jan 14

PMID 39808396

Authors

Masayuki Nagahashi

Eri Ishikawa

Takahiro Nagai

Haruka Kanaoka

Aoi Oshiro

Yusa Togashi

Akira Hattori

Junko Tsuchida

Tomoko Higuchi

Arisa Nishimukai

Keiko Murase

Yuichi Takatsuka

Takako Kihara

Yiwei Ling

Shujiro Okuda

Seiichi Hirota

Yasuo Miyoshi

Affiliations

Soon will be listed here.

Abstract

Purpose: The aim of this study was to examine the clinical utility of tumor-infiltrating lymphocytes (TILs) evaluated by "average" and "hot-spot" methods in breast cancer patients.

Methods: We examined 367 breast cancer patients without neoadjuvant chemotherapy (NAC) by average and hot-spot methods to determine the consistency of TIL scores between biopsy and surgical specimens. TIL scores before NAC were also compared with the pathological complete response (pCR) rate and clinical outcomes in 144 breast cancer patients that received NAC. TIL scores evaluated by the two methods were predicted from clinicopathological data using random forest regression.

Results: Surgical specimens showed higher TIL scores than biopsy specimens using the hot-spot method (p < 0.001), while biopsy and surgical specimens showed similar TIL scores using the average method. There was a linear relationship between the pCR rate and TIL scores determined using hot-spot (p < 0.001) and average methods (p = 0.001). Patients without pCR and low TILs by the average method had significantly worse overall survival compared to other patients (p = 0.02). The root mean squared errors of the predicted TIL score for the test set were 19.662 (hot-spot) and 10.955 (average).

Conclusion: The average method may have an advantage for breast cancer patients receiving NAC, since the TIL score using this method is more consistent between biopsy and surgical specimens, and it associates better with clinical outcomes. Our exploratory study showed that machine learning from clinicopathological data may better predict TIL scores assessed by the average, rather than hot-spot, method.

References

Adams S, Gray R, Demaria S, Goldstein L, Perez E, Shulman L . 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. 2014; 32(27):2959-66. PMC: 4162494. DOI: 10.1200/JCO.2013.55.0491. View

Fukui R, Watanabe T, Morimoto K, Fujimoto Y, Nagahashi M, Ishikawa E . An increase in tumor-infiltrating lymphocytes after treatment is significantly associated with a poor response to neoadjuvant endocrine therapy for estrogen receptor-positive/HER2-negative breast cancers. Breast Cancer. 2023; 30(5):703-713. PMC: 10404203. DOI: 10.1007/s12282-023-01462-5. View

Fukui R, Fujimoto Y, Watanabe T, Inoue N, Bun A, Higuchi T . Association Between FOXP3/CD8 Lymphocyte Ratios and Tumor Infiltrating Lymphocyte Levels in Different Breast Cancer Subtypes. Anticancer Res. 2020; 40(4):2141-2150. DOI: 10.21873/anticanres.14173. View

Faur I, Dobrescu A, Clim A, Pasca P, Prodan-Barbulescu C, Gherle B . The Value of Tumor Infiltrating Lymphocytes (TIL) for Predicting the Response to Neoadjuvant Chemotherapy (NAC) in Breast Cancer according to the Molecular Subtypes. Biomedicines. 2023; 11(11). PMC: 10669335. DOI: 10.3390/biomedicines11113037. View

Frankowska K, Zarobkiewicz M, Dabrowska I, Bojarska-Junak A . Tumor infiltrating lymphocytes and radiological picture of the tumor. Med Oncol. 2023; 40(6):176. PMC: 10182948. DOI: 10.1007/s12032-023-02036-3. View

Wu R, Horimoto Y, Oshi M, Benesch M, Khoury T, Takabe K . Emerging measurements for tumor-infiltrating lymphocytes in breast cancer. Jpn J Clin Oncol. 2024; 54(6):620-629. PMC: 11144297. DOI: 10.1093/jjco/hyae033. View

Hida A, Sagara Y, Yotsumoto D, Kanemitsu S, Kawano J, Baba S . Prognostic and predictive impacts of tumor-infiltrating lymphocytes differ between Triple-negative and HER2-positive breast cancers treated with standard systemic therapies. Breast Cancer Res Treat. 2016; 158(1):1-9. PMC: 4937092. DOI: 10.1007/s10549-016-3848-2. View

Lotfinejad P, Jafarabadi M, Shadbad M, Kazemi T, Pashazadeh F, Sandoghchian Shotorbani S . Prognostic Role and Clinical Significance of Tumor-Infiltrating Lymphocyte (TIL) and Programmed Death Ligand 1 (PD-L1) Expression in Triple-Negative Breast Cancer (TNBC): A Systematic Review and Meta-Analysis Study. Diagnostics (Basel). 2020; 10(9). PMC: 7554852. DOI: 10.3390/diagnostics10090704. View

Hamy A, Bonsang-Kitzis H, de Croze D, Laas E, Darrigues L, Topciu L . Interaction between Molecular Subtypes and Stromal Immune Infiltration before and after Treatment in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy. Clin Cancer Res. 2019; 25(22):6731-6741. DOI: 10.1158/1078-0432.CCR-18-3017. View

10.

Erol V, Goktas Aydin S, Bilici A, Cakir A, Acikgoz O, Olmez O . Relationship between the change in tumour-infiltrating lymphocyte level and residual tumour after neoadjuvant chemotherapy in patients with locally advanced breast cancer. J Chemother. 2023; 35(7):662-670. DOI: 10.1080/1120009X.2023.2247207. View

11.

von Minckwitz G, Huang C, Mano M, Loibl S, Mamounas E, Untch M . Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2018; 380(7):617-628. DOI: 10.1056/NEJMoa1814017. View

12.

Lee H, Lee M, Seo J, Gong G, Lee H . Changes in Tumor-infiltrating Lymphocytes After Neoadjuvant Chemotherapy and Clinical Significance in Triple Negative Breast Cancer. Anticancer Res. 2020; 40(4):1883-1890. DOI: 10.21873/anticanres.14142. View

13.

Asano Y, Kashiwagi S, Goto W, Takada K, Takahashi K, Hatano T . Prediction of survival after neoadjuvant chemotherapy for breast cancer by evaluation of tumor-infiltrating lymphocytes and residual cancer burden. BMC Cancer. 2017; 17(1):888. PMC: 5745786. DOI: 10.1186/s12885-017-3927-8. View

14.

Bun A, Fujimoto Y, Higuchi T, Sata A, Fukui R, Ozawa H . Prognostic Significance of Neutrophil-to-lymphocyte Ratio in Luminal Breast Cancers With Low Levels of Tumour-infiltrating Lymphocytes. Anticancer Res. 2020; 40(5):2871-2880. DOI: 10.21873/anticanres.14263. View

15.

Watanabe T, Hida A, Inoue N, Imamura M, Fujimoto Y, Akazawa K . Abundant tumor infiltrating lymphocytes after primary systemic chemotherapy predicts poor prognosis in estrogen receptor-positive/HER2-negative breast cancers. Breast Cancer Res Treat. 2017; 168(1):135-145. DOI: 10.1007/s10549-017-4575-z. View

16.

Liu S, Lachapelle J, Leung S, Gao D, Foulkes W, Nielsen T . CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res. 2012; 14(2):R48. PMC: 3446382. DOI: 10.1186/bcr3148. View

17.

Stover D, Salgado R, Savenkov O, Ballman K, Mayer E, Magbanua M . Association between tumor-infiltrating lymphocytes and survival in patients with metastatic breast cancer receiving first-line chemotherapy: analysis of CALGB 40502. NPJ Breast Cancer. 2024; 10(1):75. PMC: 11339397. DOI: 10.1038/s41523-024-00683-x. View

18.

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

19.

Hida A, Ohi Y . Evaluation of tumor-infiltrating lymphocytes in breast cancer; proposal of a simpler method. Ann Oncol. 2015; 26(11):2351. DOI: 10.1093/annonc/mdv363. 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