The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014

Salgado, Roberto; Denkert, Carsten; Demaria, Sandra; Sirtaine, Nicolas; Klauschen, Frederick; Pruneri, Giancarlo; Wienert, Stephan; Eynden, Gert Van den; Baehner, Frederick L.; Penault‐Llorca, Frédérique; Perez, Edith A.; Thompson, E. Aubrey; Symmans, W. Fraser; Richardson, Andrea L.; Brock, Jane E.; Criscitiello, Carmen; Bailey, Helen; Ignatiadis, M.; Floris, Giuseppe; Sparano, Joseph A.; Kos, Zuzana; Nielsen, Torsten O.; Rimm, David L.; Allison, Kimberly H.; Reis‐Filho, Jorge S.; Loibl, Sibylle; Sotiriou, Christos; Viale, Giuseppe; Badve, Sunil; Adams, Sylvia; Willard-Gallo, Karen; Loi, Sherene

doi:10.1093/annonc/mdu450

Cited by 2,437 publications

(2,575 citation statements)

References 45 publications

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“…Overall stromal TILs were scored on H&E-scanned images of the TMA cores using the assessment recommendations of the International TILs Working Group 48 , whereby stromal TILs are scored as the percentage of intertumoral stromal surface area (i.e. excluding areas occupied by carcinoma cells) containing mononuclear lymphocytic infiltrates.…”

Section: Methodsmentioning

confidence: 99%

TIM-3 expression in breast cancer

et al. 2018

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Tumor-infiltrating lymphocytes (TILs) are predominantly present in breast cancer patients with estrogen receptor negative tumors, among whom increasing levels correlate with favorable outcomes. Nevertheless, currently available immune checkpoint inhibitors appear to benefit only a small number of women with breast cancer. Upregulation of additional immune checkpoint markers is one mechanism of resistance to current inhibitors that might be amenable to targeting with newer agents. T-cell Immunoglobulin and Mucin domain-containing molecule 3 (TIM-3) is an immune checkpoint receptor that is an emerging target for cancer immunotherapy. We investigated TIM-3 immunohistochemical expression in 3,992 breast cancer specimens assembled into tissue microarrays, linked to detailed outcome, clinico-pathological parameters and biomarkers including CD8, PD-1, PD-L1 and LAG-3. We scored and reported absolute counts for TIM-3+ intra-epithelial and stromal TILs (iTILs and sTILs), and find that breast cancer patients with TIM-3+ iTILs (≥ 1) represent a minority of cases (11%), with a predilection for basal-like breast cancers (among which 28% had TIM-3+ iTILs). TIM-3+ sTILs (≥ 2) represented 20% of cases and included more non-basal cases. The presence of TIM-3+ iTILs highly correlates with hematoxylin and eosin-stained stromal TILs and with other immune checkpoint markers (PD-1+ iTILs, LAG-3+ iTILs and PD-L1+ tumors). In prognostic analyses, early breast cancer patients with TIM-3+ iTILs have significantly improved breast cancer-specific survival whereas TIM-3+ sTILs did not reach statistical significance. In multivariate analyses, the presence of TIM-3+ iTILs is an independent favorable prognostic factor in the whole cohort as well as among ER negative patients. Our study supports TIM-3 as a target for breast cancer immunotherapy.

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Section: Methodsmentioning

confidence: 99%

TIM-3 expression in breast cancer

et al. 2018

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“…The TIL score was classified as low (<10%), intermediate (10-50%) and high (>50%) as described previously. 27 , 28 The estimation of the number of positive cells with immune reactivity for FOXP3 and CD163 within the tumor and adjacent stroma area was scored as follows low (<10%), intermediate (10-30%) and high (>30%). 29 The TIL, FOXP3 and CD163 score was assessed by two different observers blinded to the clinical data.…”

Section: Methodsmentioning

confidence: 99%

Dynamic evaluation of the immune infiltrate and immune function genes as predictive markers for neoadjuvant chemotherapy in hormone receptor positive, HER2 negative breast cancer

et al. 2018

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Gene expression (GE) signatures and Tumor Infiltrating Lymphocytes (TIL) enumeration are predictive for response to neoadjuvant chemotherapy in HR- and in HER2+ breast cancer, but data are conflicting in HR+/HER2- disease. This study aimed to explore their predictive value in this subset, measured both at baseline and after short exposure to chemotherapy. Specifically, the PROMIX phase 2 trial enrolled patients with locally advanced HER2- BC to receive six cycles of epirubicin and docetaxel, plus bevacizumab during cycles 3–6. Patients underwent tumor biopsies at baseline and after cycle 2 for GE profiling and enumeration of TIL, FOXP3+ T-cells and CD163+ macrophages. An immune related gene module and the quantification of the immune infiltrate were analyzed for association with pathologic complete response (pCR), decrease in tumor size and disease-free survival (DFS). Of the 150 patients enrolled in PROMIX, 113 were HR+/HER2-. Baseline GE and immune cell enumeration data were available from 71 patients, while data after 2 cycles of chemotherapy were available from 41. At baseline, only GE was statistically significantly associated with higher pCR rates (OR 2.29, 95% CI 1.05 – 5.38, p = 0.037) and decrease in tumor size (r = 0.25, p = 0.047). In contrast, longitudinal data indicate that both GE (r = 0.54, p<0.001) and TIL abundance (p = 0.009) are stronger predictors for the reduction of tumor size, while low FOXP3+ was statistically significantly associated with an improved DFS (p = 0.027). In conclusion, GE analysis, TIL and FOXP3+ enumeration after short-term exposure to chemotherapy carry important predictive information in HR+/HER2- breast cancer at the neoadjuvant setting.

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“…Two distinct subsets of lymphocytes were usually assessed: stromal TILs (sTILs; mononuclear cells within the tumor stroma but not in direct contact with invasive carcinoma cells) and intratumoral TILs (iTILs; mononuclear cells that were directly associated with the tumor cells) [11].…”

Section: Introductionmentioning

confidence: 99%

“…Analysis of TILs as a noncontinuous parameter, such as lymphocyte-predominant BC (LPBC; iTILs and/or sTILs $50% or 60%) can also be considered a secondary option. Other TILs assays, such as immunohistochemistry to detect lymphocyte subtypes or molecular techniques, are not recommended for clinical practice [11].…”

Section: Introductionmentioning

confidence: 99%

Predictive and Prognostic Role of Tumor-Infiltrating Lymphocytes for Early Breast Cancer According to Disease Subtypes: Sensitivity Analysis of Randomized Trials in Adjuvant and Neoadjuvant Setting

et al. 2016

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Background. The role of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is still an issue for clinical research.Toward this end, a sensitivity analysis of neoadjuvant and adjuvant randomized clinical trials was performed according to disease subtypes. Methods. Pathological complete responses (pCRs) after neoadjuvant treatment according to the presence or absence of lymphocyte-predominant BC (LPBC) were extracted and cumulated as odds ratios (ORs) by adopting a random-effects model by subtype. Overall survival hazard ratios as a function of 10% incremental values of stromal TILs (sTILs) in adjuvant trials were extracted. The interaction test was adopted to determine the differential effect according to the subtype. Results. Eight trials (5,514 patients) were identified. With regard to neoadjuvant setting (4 studies), a significant interaction (p , .0001) according to LPBC was found. The

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The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014

Abstract: The methodology provided is sufficiently detailed to offer a uniformly applied, pragmatic starting point and improve consistency and reproducibility in the measurement of TILs for future studies.

Cited by 2,437 publications

References 45 publications

TIM-3 expression in breast cancer

TIM-3 expression in breast cancer

Dynamic evaluation of the immune infiltrate and immune function genes as predictive markers for neoadjuvant chemotherapy in hormone receptor positive, HER2 negative breast cancer

Predictive and Prognostic Role of Tumor-Infiltrating Lymphocytes for Early Breast Cancer According to Disease Subtypes: Sensitivity Analysis of Randomized Trials in Adjuvant and Neoadjuvant Setting

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