Tumor infiltrating lymphocyte stratification of prognostic staging of early-stage triple negative breast cancer.
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ABSTRACT:
SUBMITTER: Loi S
PROVIDER: S-EPMC8752727 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
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Tumor infiltrating lymphocyte stratification of prognostic staging of early-stage triple negative breast cancer.
Loi Sherene S Salgado Roberto R Adams Sylvia S Pruneri Giancarlo G Francis Prudence A PA Lacroix-Triki Magali M Joensuu Heikki H Dieci Maria Vittoria MV Badve Sunil S Demaria Sandra S Gray Robert R Munzone Elisabetta E Drubay Damien D Lemonnier Jerome J Sotiriou Christos C Kellokumpu-Lehtinen Pirkko Liisa PL Vingiani Andrea A Gray Kathryn K André Fabrice F Denkert Carsten C Piccart Martine M Roblin Elvire E Michiels Stefan S
NPJ breast cancer 20220111 1
The importance of integrating biomarkers into the TNM staging has been emphasized in the 8<sup>th</sup> Edition of the American Joint Committee on Cancer (AJCC) Staging system. In a pooled analysis of 2148 TNBC-patients in the adjuvant setting, TILs are found to strongly up and downstage traditional pathological-staging in the Pathological and Clinical Prognostic Stage Groups from the AJJC 8<sup>th</sup> edition Cancer Staging System. This suggest that clinical and research studies on TNBC shoul ...[more]
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Project description:BACKGROUND:Tumor-infiltrating lymphocytes (TILs) have recently been reported as an important factor in the tumor microenvironment and influence the growth and progression of cancer. However, the relationship between immune cell subpopulations, such as CD4+, CD8+, and FOXP3+, in breast cancer, especially in triple negative carcinoma (TNC), remains unclear. METHODS:The subjects were 107 patients with TNC that were surgically resected at Dokkyo Medical University Hospital between 2006 and 2018. The expression of CD4+, CD8+, and FOXP3+ was evaluated in TILs and expressed as the numbers of positive cells. RESULTS:Univariate analysis revealed that the TILs were not prognostically significant. In multivariate analyses, increased infiltration of intratumoral (i) CD4+?TILs was found to have a good prognosis in relapse-free survival (RFS). In contrast, a high stromal CD8+?TILs level was found to be a favorable prognostic factor in RFS (p?=?0.038) and overall survival (OS) (p?=?0.046). A low sFOXP3?+?TILs level was significantly associated with favorable RFS (p?<?0.001) and OS (p?=?0.029). CONCLUSIONS:The present study demonstrated no difference in TILs and survival in TNC. However, there was a significant correlation in prognosis with levels of iCD4+, sCD8+, and sFOXP3?+?TILs in TNC. The difference in TNC clinical outcome may be due to the subtype of the infiltrating TILs.
| S-EPMC7438376 | biostudies-literature
Project description:ObjectiveThis study aimed to examine the prevalence and prognostic role of tumor microenvironment (TME) in triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NACT) through immunohistochemical characterization.MethodsThe internal database of the Brazilian National Cancer Institute for women diagnosed with TNBC who underwent NACT and thereafter curative surgery between January 2010 and December 2014 was queried out. Core biopsy specimens and tissue microarrays containing surgical samples of TNBC from 171 and 134 women, respectively, were assessed by immunohistochemistry for CD3, CD4, CD8, CD14, CD56, CD68, CD117, FOXP3, PD-1, PD-L1, and PD-L2. Immune cell profiles were analyzed and correlated with response and survival.ResultsMean age was 50.5 years, and most cases were clinical stage III [143 cases (83.6%)]. According to the multivariate analysis, only Ki67 and clinical stage significantly influenced the pattern of response to systemic treatment (p = 0.019 and p = 0.033, respectively). None of the pre-NACT IHC markers showed a significant association with event-free survival (EFS) or overall survival (OS). As for post-NACT markers, patients with high CD14 had significantly shorter EFS (p = 0.015), while patients with high CD3 (p = 0.025), CD4 (p = 0.025), CD8 (p = 0.030), CD14 (p = 0.015), FOXP3 (p = 0.005), high CD4/FOXP3 (p = 0.034), and CD8/FOXP3 (p = 0.008) showed longer EFS. Only high post-NACT CD4 showed significantly influenced OS (p = 0.038).ConclusionThe present study demonstrated that the post-NACT TIL subtype can be a determining factor in the prognosis of patients with TNBC.
| S-EPMC8630741 | biostudies-literature
Project description:In breast cancer, humoral immune responses may contribute to clinical outcomes, especially in more immunogenic subtypes. Here, we investigated B lymphocyte subsets, immunoglobulin expression, and clonal features in breast tumors, focusing on aggressive triple-negative breast cancers (TNBC). In samples from patients with TNBC and healthy volunteers, circulating and tumor-infiltrating B lymphocytes (TIL-B) were evaluated. CD20+CD27+IgD- isotype-switched B lymphocytes were increased in tumors, compared with matched blood. TIL-B frequently formed stromal clusters with T lymphocytes and engaged in bidirectional functional cross-talk, consistent with gene signatures associated with lymphoid assembly, costimulation, cytokine-cytokine receptor interactions, cytotoxic T-cell activation, and T-cell-dependent B-cell activation. TIL-B-upregulated B-cell receptor (BCR) pathway molecules FOS and JUN, germinal center chemokine regulator RGS1, activation marker CD69, and TNFα signal transduction via NFκB, suggesting BCR-immune complex formation. Expression of genes associated with B lymphocyte recruitment and lymphoid assembly, including CXCL13, CXCR4, and DC-LAMP, was elevated in TNBC compared with other subtypes and normal breast. TIL-B-rich tumors showed expansion of IgG but not IgA isotypes, and IgG isotype switching positively associated with survival outcomes in TNBC. Clonal expansion was biased toward IgG, showing expansive clonal families with specific variable region gene combinations and narrow repertoires. Stronger positive selection pressure was present in the complementarity determining regions of IgG compared with their clonally related IgA in tumor samples. Overall, class-switched B lymphocyte lineage traits were conspicuous in TNBC, associated with improved clinical outcomes, and conferred IgG-biased, clonally expanded, and likely antigen-driven humoral responses. SIGNIFICANCE: Tumor-infiltrating B lymphocytes assemble in clusters, undergoing B-cell receptor-driven activation, proliferation, and isotype switching. Clonally expanded, IgG isotype-biased humoral immunity associates with favorable prognosis primarily in triple-negative breast cancers.
| S-EPMC7611538 | biostudies-literature
Project description:High stromal tumor-infiltrating lymphocytes (sTILs) are associated with an improved pathologic complete response (pCR) and survival in triple-negative breast cancer (TNBC). We hypothesized that high baseline sTILs would have a favorable prognostic impact in TNBC patients without a pCR after neoadjuvant chemotherapy (NACT). In this prospective NACT study, pretreatment biopsies from 318 patients with early-stage TNBC were evaluated for sTILs. Recursive partitioning analysis (RPA) was applied to search for the sTIL cutoff best associated with a pCR. With ≥20% sTILs identified as the optimal cutoff, 33% patients had high sTILs (pCR rate 64%) and 67% had low sTILs (pCR rate 29%). Patients were stratified according to the sTIL cutoff (low vs. high) and response to NACT (pCR vs. residual disease (RD)). The primary endpoint was event-free survival (EFS), with hazard ratios calculated using the Cox proportional hazards regression model and the 3-year restricted mean survival time (RMST) as primary measures. Within the high-sTIL group, EFS was better in patients with a pCR compared with those with RD (HR 0.05; 95% CI 0.01-0.39; p = 0.004). The difference in the 3-year RMST for EFS between the two groups was 5.6 months (95% CI 2.3-8.8; p = 0.001). However, among patients with RD, EFS was not significantly different between those with high sTILs and those with low sTILs (p = 0.7). RNA-seq analysis predicted more CD8+ T cells in the high-sTIL group with favorable EFS compared with the high-sTIL group with unfavorable EFS. This study did not demonstrate that high baseline sTILs confer a benefit in EFS in the absence of a pCR.
| S-EPMC8909018 | biostudies-literature
Project description:PurposeThe aim of the current study was to conduct a pooled analysis of studies that have investigated the prognostic value of tumor-infiltrating lymphocytes (TILs) in early-stage triple negative breast cancer (TNBC).MethodsParticipating studies had evaluated the percentage infiltration of stromally located TILs (sTILs) that were quantified in the same manner in patient diagnostic samples of early-stage TNBC treated with anthracycline-based chemotherapy with or without taxanes. Cox proportional hazards regression models stratified by trial were used for invasive disease-free survival (iDFS; primary end point), distant disease-free survival (D-DFS), and overall survival (OS), fitting sTILs as a continuous variable adjusted for clinicopathologic factors.ResultsWe collected individual data from 2,148 patients from nine studies. Average age was 50 years (range, 22 to 85 years), and 33% of patients were node negative. The average value of sTILs was 23% (standard deviation, 20%), and 77% of patients had 1% or more sTILs. sTILs were significantly lower with older age ( P = .001), larger tumor size ( P = .01), more nodal involvement ( P = .02), and lower histologic grade ( P = .001). A total of 736 iDFS and 548 D-DFS events and 533 deaths were observed. In the multivariable model, sTILs added significant independent prognostic information for all end points (likelihood ratio χ2, 48.9 iDFS; P < .001; χ2, 55.8 D-DFS; P < .001; χ2, 48.5 OS; P < .001). Each 10% increment in sTILs corresponded to an iDFS hazard ratio of 0.87 (95% CI, 0.83 to 0.91) for iDFS, 0.83 (95% CI, 0.79 to 0.88) for D-DFS, and 0.84 (95% CI, 0.79 to 0.89) for OS. In node-negative patients with sTILs ≥ 30%, 3-year iDFS was 92% (95% CI, 89% to 98%), D-DFS was 97% (95% CI, 95% to 99%), and OS was 99% (95% CI, 97% to 100%).ConclusionThis pooled data analysis confirms the strong prognostic role of sTILs in early-stage TNBC and excellent survival of patients with high sTILs after adjuvant chemotherapy and supports the integration of sTILs in a clinicopathologic prognostic model for patients with TNBC. This model can be found at www.tilsinbreastcancer.org .
| S-EPMC7010425 | biostudies-literature
Project description:PurposeTumor-infiltrating lymphocyte (TIL), programmed death-ligand 1 (PD-L1) expression and neutrophil-to-lymphocyte ratio (NLR) is associated to immunogenicity and prognosis of breast cancer. We analyzed baseline NLR, changes of NLR, TIL, and PD-L1 during neoadjuvant chemotherapy (NAC) and their clinical implication in triple-negative breast cancer (TNBC).Materials and methodsBetween January 2008 to December 2015, 358 TNBC patients were analyzed. Baseline NLR, 50 paired NLR (initial diagnosis, after completion of NAC) and 34 paired tissues (initial diagnosis, surgical specimen after completion of NAC) were collected. Changes of TIL, CD4, CD8, forkhead box P3 (FOXP3), and PD-L1 expression were assessed with immunohistochemical stain.ResultsLow NLR (≤ 3.16) was associated to superior survival (overall survival: 41.83 months vs. 36.5 months, p=0.002; disease-free survival [DFS]: 37.85 months vs. 32.14 months, p=0.032). Modest NLR change after NAC (-30% < NLR change < 100%) showed prolonged DFS (38.37 months vs. 22.37 months, p=0.015). During NAC, negative or negative conversion of tumor PD-L1 expression was associated to poor DFS (34.77 months vs. 16.03 months, p=0.037), and same or increased TIL showed trends for superior DFS, but without statistical significance. Positive tumor PD-L1 expression (H-score ≥ 5) in baseline or post- NAC tissue was associated to superior DFS (57.6 months vs. 12.5 months, p=0.001 and 53.3 months vs. 18.9 months, p=0.040). Positive stromal PD-L1 expression in baseline was also associated to superior DFS (50.2 months vs. 20.4 months, p=0.002).ConclusionIn locally advanced TNBC, baseline NLR, changes of NLR during NAC was associated to survival. Baseline PD-L1 expression and changes of PD-L1 expression in tumor tissue during NAC also showed association to prognosis.
| S-EPMC6473269 | biostudies-literature
Project description:PurposeAlthough tumor-infiltrating lymphocytes (TIL) assessment has been acknowledged to have both prognostic and predictive importance in triple-negative breast cancer (TNBC), it is subject to inter and intraobserver variability that has prevented widespread adoption. Here we constructed a machine-learning based breast cancer TIL scoring approach and validated its prognostic potential in multiple TNBC cohorts.Experimental designUsing the QuPath open-source software, we built a neural-network classifier for tumor cells, lymphocytes, fibroblasts, and "other" cells on hematoxylin-eosin (H&E)-stained sections. We analyzed the classifier-derived TIL measurements with five unique constructed TIL variables. A retrospective collection of 171 TNBC cases was used as the discovery set to identify the optimal association of machine-read TIL variables with patient outcome. For validation, we evaluated a retrospective collection of 749 TNBC patients comprised of four independent validation subsets.ResultsWe found that all five machine TIL variables had significant prognostic association with outcomes (P ≤ 0.01 for all comparisons) but showed cell-specific variation in validation sets. Cox regression analysis demonstrated that all five TIL variables were independently associated with improved overall survival after adjusting for clinicopathologic factors including stage, age, and histologic grade (P ≤ 0.0003 for all analyses).ConclusionsNeural net-driven cell classifier-defined TIL variables were robust and independent prognostic factors in several independent validation cohorts of TNBC patients. These objective, open-source TIL variables are freely available to download and can now be considered for testing in a prospective setting to assess clinical utility.See related commentary by Symmans, p. 5446.
| S-EPMC8530841 | biostudies-literature
Project description:The tumour microenvironment has been shown to be a valuable source of prognostic information for different cancer types. This holds in particular for triple negative breast cancer (TNBC), a breast cancer subtype for which currently no prognostic biomarkers are established. Although different methods to assess tumour infiltrating lymphocytes (TILs) have been published, it remains unclear which method (marker, region) yields the most optimal prognostic information. In addition, to date, no objective TILs assessment methods are available. For this proof of concept study, a subset of our previously described TNBC cohort (n = 94) was stained for CD3, CD8 and FOXP3 using multiplex immunohistochemistry and subsequently imaged by a multispectral imaging system. Advanced whole-slide image analysis algorithms, including convolutional neural networks (CNN) were used to register unmixed multispectral images and corresponding H&E sections, to segment the different tissue compartments (tumour, stroma) and to detect all individual positive lymphocytes. Densities of positive lymphocytes were analysed in different regions within the tumour and its neighbouring environment and correlated to relapse free survival (RFS) and overall survival (OS). We found that for all TILs markers the presence of a high density of positive cells correlated with an improved survival. None of the TILs markers was superior to the others. The results of TILs assessment in the various regions did not show marked differences between each other. The negative correlation between TILs and survival in our cohort are in line with previous studies. Our results provide directions for optimizing TILs assessment methodology.
| S-EPMC7933536 | biostudies-literature
Project description:Purpose: Tumor-infiltrating lymphocytes (TIL) in pretreatment biopsies are associated with improved survival in triple-negative breast cancer (TNBC). We investigated whether higher peripheral lymphocyte counts are associated with lower breast cancer-specific mortality (BCM) and overall mortality (OM) in TNBC.Experimental Design: Data on treatments and diagnostic tests from electronic medical records of two health care systems were linked with demographic, clinical, pathologic, and mortality data from the California Cancer Registry. Multivariable regression models adjusted for age, race/ethnicity, socioeconomic status, cancer stage, grade, neoadjuvant/adjuvant chemotherapy use, radiotherapy use, and germline BRCA1/2 mutations were used to evaluate associations between absolute lymphocyte count (ALC), BCM, and OM. For a subgroup with TIL data available, we explored the relationship between TILs and peripheral lymphocyte counts.Results: A total of 1,463 stage I-III TNBC patients were diagnosed from 2000 to 2014; 1,113 (76%) received neoadjuvant/adjuvant chemotherapy within 1 year of diagnosis. Of 759 patients with available ALC data, 481 (63.4%) were ever lymphopenic (minimum ALC <1.0 K/μL). On multivariable analysis, higher minimum ALC, but not absolute neutrophil count, predicted lower OM [HR = 0.23; 95% confidence interval (CI), 0.16-0.35] and BCM (HR = 0.19; CI, 0.11-0.34). Five-year probability of BCM was 15% for patients who were ever lymphopenic versus 4% for those who were not. An exploratory analysis (n = 70) showed a significant association between TILs and higher peripheral lymphocyte counts during neoadjuvant chemotherapy.Conclusions: Higher peripheral lymphocyte counts predicted lower mortality from early-stage, potentially curable TNBC, suggesting that immune function may enhance the effectiveness of early TNBC treatment. Clin Cancer Res; 24(12); 2851-8. ©2018 AACR.
| S-EPMC6366842 | biostudies-literature
Project description:BackgroundTumor-infiltrating lymphocytes (TILs) are clinically significant in triple-negative breast cancer (TNBC). Although a standardized methodology for visual TILs assessment (VTA) exists, it has several inherent limitations. We established a deep learning-based computational TIL assessment (CTA) method broadly following VTA guideline and compared it with VTA for TNBC to determine the prognostic value of the CTA and a reasonable CTA workflow for clinical practice.MethodsWe trained three deep neural networks for nuclei segmentation, nuclei classification and necrosis classification to establish a CTA workflow. The automatic TIL (aTIL) score generated was compared with manual TIL (mTIL) scores provided by three pathologists in an Asian (n = 184) and a Caucasian (n = 117) TNBC cohort to evaluate scoring concordance and prognostic value.FindingsThe intraclass correlations (ICCs) between aTILs and mTILs varied from 0.40 to 0.70 in two cohorts. Multivariate Cox proportional hazards analysis revealed that the aTIL score was associated with disease free survival (DFS) in both cohorts, as either a continuous [hazard ratio (HR)=0.96, 95% CI 0.94-0.99] or dichotomous variable (HR=0.29, 95% CI 0.12-0.72). A higher C-index was observed in a composite mTIL/aTIL three-tier stratification model than in the dichotomous model, using either mTILs or aTILs alone.InterpretationThe current study provides a useful tool for stromal TIL assessment and prognosis evaluation for patients with TNBC. A workflow integrating both VTA and CTA may aid pathologists in performing risk management and decision-making tasks.FundingNational Natural Science Foundation of China, Guangdong Medical Research Foundation, Guangdong Natural Science Foundation.
| S-EPMC8318866 | biostudies-literature