Tumor-infiltrating lymphocytes are significantly associated with better overall survival and disease-free survival in triple-negative but not estrogen receptor–positive breast cancers

Krishnamurti, Uma; Wetherilt, Ceyda Sönmez; Yang, Jing; Peng, Limin; Li, Xiaoxian

doi:10.1016/j.humpath.2017.01.004

Cited by 68 publications

(40 citation statements)

References 20 publications

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“…For example, in the 122 TILs genes, the elevated expression of 73 and 68 genes was associated with better OS and DFS prognosis in TNBC, respectively, and none was associated with worse OS or DFS prognosis in TNBC. This is consistent with prior studies showing that higher TILs densities were associated with better OS and DFS in TNBC [54, 55]. In the 47 immune checkpoint genes, the elevated expression of a number of genes was associated with better OS (17 genes) and DFS (17 genes) prognosis in TNBC, respectively.…”

Section: Resultssupporting

confidence: 91%

“…In total, we have analyzed 26 immune gene-sets including 15 immune cell type and function, HLA, CT, immune cell infiltration, Treg, immune checkpoint, TILs, CCR, metastasis-promoting, metastasis-inhibiting, pro-inflammatory, and PI gene-sets that involved 820 immune-related genes. In addition, although a number of studies have associated expression levels of immune genes with clinical outcomes in TNBC [22, 24, 36, 54, 55], none of these studies have performed a comprehensive analysis of the association between a wide variety of immunogenic signatures and clinical outcomes in TNBC as in the present study. To summarize, this study provided a solid foundation for the concept that of the various BC subtypes, TNBC likely exhibits the strongest immunogenicity.…”

Section: Discussionmentioning

confidence: 99%

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A Comprehensive Immunologic Portrait of Triple-Negative Breast Cancer

Liu

Jiang

et al. 2017

Preprint

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Background: Triple-negative breast cancer (TNBC) is a high-risk malignancy due to its high capacity for invasion and lack of targeted therapy. Immunotherapy continues to demonstrate efficacy in a variety of cancers, and thus may be a promising strategy for TNBC given the limited therapeutic options currently available for TNBC. In this study, we performed a comprehensive portrait of immunologic landscape of TNBC based on 2 large-scale breast cancer genomic data. Methods:We compared expression levels of immune-related genes and gene-sets among TNBC, non-TNBC, and normal tissue, and within TNBCs of different genotypic or phenotypic features. Moreover, we explored the association of immune-related genes or gene-sets expression and survival prognosis in TNBC patients. Results:We found that almost all analyzed immune-related gene-sets had significantly higher expression levels in TNBC than non-TNBC. These highly expressed gene-sets in TNBC included 15 immune cell type and function, human leukocyte antigen (HLA), cancer testis (CT), tumor-infiltrating lymphocytes (TILs), immune cell infiltrate, regulatory T (Treg) cells, immune checkpoint, cytokine and cytokine receptor, metastasis-promoting, pro-inflammatory and parainflammation (PI) gene-sets. Moreover, TP53-mutated TNBC had significantly higher expression levels of the immune checkpoint, Treg, PI, and CT gene-sets, and lower expression levels of the immune cell infiltrate gene-set than TP53-wildtype TNBC. Furthermore, we found that elevated expression of most of the immune-related genes in TNBC was associated with the ER-status, while some were associated with both ER-and HER2-status. Elevated expression of the immune-related genes in TNBC was also associated with the high tumor mutation burden 3 (TMB) in TNBC. Finally, elevated expression of the immune-related gene-sets was likely to be associated with better survival prognosis in TNBC. Conclusions:Our findings suggest that TNBC is a breast cancer subtype with particularly strong immunogenicity, and therefore could be propitious to immunotherapeutic options. BackgroundBreast cancer (BC) is the most common cancer in women [1], of which 15-20% are the triplenegative breast cancer (TNBC) subtype. TNBC is clinically negative for expression of the estrogen receptor (ER) and progesterone receptor (PR), and lacks overexpression of the human epidermal growth factor receptor 2 (HER2) [2]. TNBC has a poor prognosis due to its aggressive clinical characteristics and lack of response to hormonal or HER2 receptor-targeted therapy. Thus far, chemotherapy is the only possible therapeutic strategy in the adjuvant or metastatic setting for TNBC [3]. Some potential targeted therapies for TNBC have been investigated such as targeting VEGF, EGFR, mTOR, PARP1, FGFR, AR, NOTCH, HDAC, CDK, PI3K, MET, and TROP2 [4-7]. However, clinical trial efficacies of most TNBC targeted therapies remain unclear. Recently, cancer immunotherapy has demonstrated high efficacy in treating a variety of cancers including refractory malignancies such as meta...

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

A Comprehensive Immunologic Portrait of Triple-Negative Breast Cancer

Liu

Jiang

et al. 2017

Preprint

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“…It was revealed that both higher scores of sTILs and iTILs were related with higher Ki-67 index and higher histological grade, and higher iTILs scores were positively correlated with negative LVI in TNBCs. Krishnamurti et al found that TILs was significantly associated with histologic grade 3 in TNBCs [37]. The study of Chung et al showed that infiltration of CD4+, CD8+, and FOXP3+ TILs was significantly higher in tumors with high Ki-67 index [38].…”

Section: Discussionmentioning

confidence: 99%

Predictive value of tumor-infiltrating lymphocytes to pathological complete response in neoadjuvant treated triple-negative breast cancers

et al. 2018

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BackgroundTriple-negative breast cancers (TNBCs) are a group of heterogeneous diseases with various morphology, prognosis, and treatment response. Therefore, it is important to identify valuable biomarkers to predict the therapeutic response and prognosis for TNBCs. Tumor-infiltrating lymphocytes (TILs) may have predictive value to pathological complete response (pCR) in neoadjuvant treated TNBCs. However, absence of standardized methodologies for TILs measurement has limited its evaluation and application in practice. In 2014, the International TILs Working Group formulated the recommendations of pathologic evaluation for TILs in breast cancers.MethodsTo evaluate the predictive value of TILs scored by methods recommended by International TILs Working Group 2014, we performed a retrospective study of TILs in 166 core needle biopsy specimens of primary invasive TNBCs with neoadjuvant chemotherapy (NAC) in a Chinese population. Intratumoral TILs (iTILs) and stromal TILs (sTILs) were scored respectively. The associations between TILs and pCR were analyzed.ResultsBoth sTILs (p = 0.0001) and iTILs (P = 0.001) were associated with pCR in univariate logistic regression analysis. Multivariate logistic regression analysis indicated that both sTILs (P = 0.006) and iTILs (P = 0.04) were independent predictors for pCR. Receiver operating characteristics (ROC) curve analysis was used to identify the optimal thresholds of TILs. TNBCs with more than 20% sTILs (P = 0.001) or with more than 10% iTILs (P = 0.003) were associated with higher pCR rates in univariate analysis. Multivariate analysis showed that a 20% threshold of sTILs (P = 0.005) was an independent predictive factor for pCR.ConclusionsOur study indicated that TILs scored by recommendations of International TILs Working Group 2014 in pre-NAC core needle biopsy specimens was significantly correlated with pCR in TNBCs, higher TILs scores predicting higher pCR rate. Both sTILs and iTILs were independent predictors for pCR in TNBCs. A 20% threshold for sTILs may be feasible to predict pCR to NAC in TNBCs.

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“…Factors playing a pivotal role in this interaction include tumor infiltrating lymphocytes (TILs), tumor associated macrophages, cancer associated fibroblasts and adipocytes as well as expression of genes implicated in the epithelial-mesenchymal transition (EMT). Elevated levels of peripheral and overall TILs in pre-treatment resection specimens are associated with more advanced Nottingham histologic grade but not lymph node status or lymphovascular invasion, and elevated peripheral TILs predict better overall and disease-free survival [10]. Higher TILs also serve as a biomarker for improved NAC response [11].…”

Section: Divide and Conquer: Parsing Tnbcs To Find Ways To Tailor Trementioning

confidence: 99%

First international TNBC conference meeting report

Rida

Ogden

Ellis

et al. 2018

Breast Cancer Res Treat

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Recently, Georgia State University's Centennial Hall was the premier location for the 2017 International Conference on Triple Negative Breast Cancer (TNBC): Illuminating Actionable Biology, which was held from Sept. 18 to 20, 2017, in Atlanta, USA. The conference featured a stellar line-up of domestic and international speakers and diverse participants including TNBC survivors, luminaries in breast cancer research, medical students and fellows, clinicians, translational researchers, epidemiologists, biostatisticians, bioinformaticians, and representatives from the industry. This report distills the burning questions that spiked the event and summarizes key themes, findings, unique opportunities and future directions that emerged from this confluence of thought leaders.

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Tumor-infiltrating lymphocytes are significantly associated with better overall survival and disease-free survival in triple-negative but not estrogen receptor–positive breast cancers

Cited by 68 publications

References 20 publications

A Comprehensive Immunologic Portrait of Triple-Negative Breast Cancer

A Comprehensive Immunologic Portrait of Triple-Negative Breast Cancer

Predictive value of tumor-infiltrating lymphocytes to pathological complete response in neoadjuvant treated triple-negative breast cancers

First international TNBC conference meeting report

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