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- Tzoras, Evangelos, et al.
(author)
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Dissecting Tumor-Immune Microenvironment in Breast Cancer at a Spatial and Multiplex Resolution
- 2022
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In: Cancers. - : MDPI AG. - 2072-6694. ; 14:8
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Research review (peer-reviewed)abstract
- The evaluation of breast cancer immune microenvironment has been increasingly used in clinical practice, either by counting tumor infiltrating lymphocytes or assessing programmed death ligand 1 expression. However, the spatiotemporal organization of anti-breast cancer immune response has yet to be fully explored. Multiplex in situ methods with spectral imaging have emerged to deconvolute the different elements of tumor immune microenvironment. In this narrative review, we provide an overview of the impact that those methods have, to characterize spatiotemporal heterogeneity of breast cancer microenvironment at neoadjuvant, adjuvant and metastatic setting. Multiplexing in situ can then be useful for new classifications of tumor microenvironment and discovery of immune-related biomarkers within their spatial niche. The tumor immune microenvironment (TIME) is an important player in breast cancer pathophysiology. Surrogates for antitumor immune response have been explored as predictive biomarkers to immunotherapy, though with several limitations. Immunohistochemistry for programmed death ligand 1 suffers from analytical problems, immune signatures are devoid of spatial information and histopathological evaluation of tumor infiltrating lymphocytes exhibits interobserver variability. Towards improved understanding of the complex interactions in TIME, several emerging multiplex in situ methods are being developed and gaining much attention for protein detection. They enable the simultaneous evaluation of multiple targets in situ, detection of cell densities/subpopulations as well as estimations of functional states of immune infiltrate. Furthermore, they can characterize spatial organization of TIME-by cell-to-cell interaction analyses and the evaluation of distribution within different regions of interest and tissue compartments-while digital imaging and image analysis software allow for reproducibility of the various assays. In this review, we aim to provide an overview of the different multiplex in situ methods used in cancer research with special focus on breast cancer TIME at the neoadjuvant, adjuvant and metastatic setting. Spatial heterogeneity of TIME and importance of longitudinal evaluation of TIME changes under the pressure of therapy and metastatic progression are also addressed.
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| 2. |
- Zerdes, Ioannis, et al.
(author)
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Tumor-infiltrating lymphocytes (TILs) dynamics in breast cancer patients receiving neoadjuvant therapy : A systematic review and meta-analysis
- 2022
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In: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 40:16
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Journal article (other academic/artistic)abstract
- Background: Increased baseline tumor-infiltrating lymphocytes (TILs) are associated with improved pathological complete response rates and better prognosis in HER2+ and triple negative breast cancer (TNBC) patients receiving neoadjuvant therapy (NAT). However, the role of TILs dynamics/change (DTILs) at the neoadjuvant setting remains unclear, thus a meta-analysis of the published studies was carried out.Methods: Medline, Embase, Cochrane Library and Web of Science Core Collection were searched for studies reporting on TILs expression in paired invasive breast cancer patient tissue samples before and after NAT. Data were extracted by two investigators (Y.Z., E.T.) and discordances were resolved by a third (I.Z.). Outcomes included pooled TILs rates pre- & post-treatment (also per subtype), pooled rates of DTILs and direction of change after NAT as well as correlation of DTILs with survival outcomes. Heterogeneity was assessed using the I2 statistic.Results: Of 1569 identified entries, 22 studies fulfilled the criteria and provided adequate data for the outcomes of interest. Overall, a significantly decreased level of TILs was observed after NAT in paired samples (pooled OR = 1.60, 95% CI: 1.12-2.30, p = 0.01; TILs as categorical variable). Regarding pooled rates of DTILs, a change was observed after NAT, irrespective of BC subtype. Among the different subtypes, the effect of NAT on TILs was most prominent in HER2+ disease with a direction towards decreased TILs to be more common (pooled DTILs rates: 14.4% increased vs 46.2%, decreased). In TNBC, bi-directional TIL kinetics were noted (pooled DTILs rates: 41.6% increased vs 37.1% decreased). An increase in DTILs in TNBC was associated with better disease-free/relapse-free survival in univariate analysis (HR = 0.59, 95% CI: 0.37–0.95, p = 0.03). Substantial between-study heterogeneity was observed in most analyses.Conclusions: The first to our knowledge meta-analysis on TILs dynamics during NAT in BC informs about differences in matched pre- and post-treatment patient samples and the prognostic implications of DTILs in TNBC. The potential clinical utility of the longitudinal assessment of immune response during neoadjuvant therapy warrants further investigation in prospective trials.
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| 3. |
- Zhu, Yajing, et al.
(author)
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Expression patterns and prognostic implications of tumor-infiltrating lymphocytes dynamics in early breast cancer patients receiving neoadjuvant therapy : A systematic review and meta-analysis
- 2022
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In: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 12
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Research review (peer-reviewed)abstract
- PURPOSE: High levels of tumor-infiltrating lymphocytes (TILs) are associated with better outcomes in early breast cancer and higher pathological response rates to neoadjuvant chemotherapy especially in the triple-negative (TNBC) and HER2+ subtypes. However, the dynamic changes in TILs levels after neoadjuvant treatment (NAT) are less studied. This systematic review and meta-analysis aimed to investigate the patterns and role of TILs dynamics change in early breast cancer patients receiving NAT.METHODS: Medline, Embase, Web of Science Core Collection and PubMed Central databases were searched for eligible studies. Data were extracted independently by two researchers and discordances were resolved by a third. Pooled TILs rates pre- & post-treatment (overall and per subtype), pooled rates of ΔTILs and direction of change after NAT as well as correlation of ΔTILs with survival outcomes were generated in the outcome analysis.RESULTS: Of 2116 identified entries, 34 studies fulfilled the criteria and provided adequate data for the outcomes of interest. A decreased level of TILs was observed after NAT in paired samples across all subtypes. The effect of NAT on TILs was most prominent in TNBC subtype with a substantial change, either increase or decrease, in 79.3% (95% CI 61.7-92.6%) of the patients as well as in HER2+ disease (14.4% increased vs 46.2% decreased). An increase in ΔTILs in TNBC was associated with better disease-free/relapse-free survival in pooled analysis (univariate HR = 0.59, 95% CI: 0.37-0.95, p = 0.03).CONCLUSION: This meta-analysis illustrates the TILs dynamics during NAT for breast cancer and indicates prognostic implications of ΔTILs in TNBC. The potential clinical utility of the longitudinal assessment of TILs during neoadjuvant therapy warrants further validation.
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