scholarly journals Bulk and Single-Cell Profiling of Breast Tumors Identifies TREM-1 as a Dominant Immune Suppressive Marker Associated With Poor Outcomes

2021 ◽  
Vol 11 ◽  
Author(s):  
Ashok K. Pullikuth ◽  
Eric D. Routh ◽  
Kip D. Zimmerman ◽  
Julia Chifman ◽  
Jeff W. Chou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Cell ◽  
Cancer Progression ◽  
Distant Metastasis ◽  
Cox Regression ◽  
Expression Profiles ◽  
Breast Tumors ◽  
Prognostic Impact ◽  
Free Survival ◽  
Distant Metastasis Free Survival

BackgroundTriggering receptor expressed on myeloid cells (TREM)-1 is a key mediator of innate immunity previously associated with the severity of inflammatory disorders, and more recently, the inferior survival of lung and liver cancer patients. Here, we investigated the prognostic impact and immunological correlates of TREM1 expression in breast tumors.MethodsBreast tumor microarray and RNAseq expression profiles (n=4,364 tumors) were analyzed for associations between gene expression, tumor immune subtypes, distant metastasis-free survival (DMFS) and clinical response to neoadjuvant chemotherapy (NAC). Single-cell (sc)RNAseq was performed using the 10X Genomics platform. Statistical associations were assessed by logistic regression, Cox regression, Kaplan-Meier analysis, Spearman correlation, Student’s t-test and Chi-square test.ResultsIn pre-treatment biopsies, TREM1 and known TREM-1 inducible cytokines (IL1B, IL8) were discovered by a statistical ranking procedure as top genes for which high expression was associated with reduced response to NAC, but only in the context of immunologically “hot” tumors otherwise associated with a high NAC response rate. In surgical specimens, TREM1 expression varied among tumor molecular subtypes, with highest expression in the more aggressive subtypes (Basal-like, HER2-E). High TREM1 significantly and reproducibly associated with inferior distant metastasis-free survival (DMFS), independent of conventional prognostic markers. Notably, the association between high TREM1 and inferior DMFS was most prominent in the subset of immunogenic tumors that exhibited the immunologically hot phenotype and otherwise associated with superior DMFS. Further observations from bulk and single-cell RNAseq analyses indicated that TREM1 expression was significantly enriched in polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and M2-like macrophages, and correlated with downstream transcriptional targets of TREM-1 (IL8, IL-1B, IL6, MCP-1, SPP1, IL1RN, INHBA) which have been previously associated with pro-tumorigenic and immunosuppressive functions.ConclusionsTogether, these findings indicate that increased TREM1 expression is prognostic of inferior breast cancer outcomes and may contribute to myeloid-mediated breast cancer progression and immune suppression.

Tumour immune characterization in adenoid cystic carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15191-e15191
Author(s):  
Shengjin Dou ◽  
Di Chen ◽  
Rongrong Li ◽  
Yining Yang ◽  
Ning He ◽  
...  
Keyword(s):  
Adenoid Cystic Carcinoma ◽  
Survival Time ◽  
Distant Metastasis ◽  
Cox Regression ◽  
Expression Profiles ◽  
Univariate Analysis ◽  
Free Survival ◽  
Immune Infiltration ◽  
Adenoid Cystic ◽  
Distant Metastasis Free Survival

e15191 Background: Here, we profiled genetic hallmarks of Chinese adenoid cystic carcinoma (ACC) patients and immune cells infiltration levels by gene expression-based computational methods to investigate the correlation with immunotherapy. Methods: 54 patients with pathologically confirmed ACC admitted from January 2016 to October 2019 were included. Mutation and expression profiles were obtained by whole-exome sequencing (WES) and RNA-seq, respectively. A nomogram that integrated clinicopathological features with the immune signature to predict recurrence or distant metastasis probability was constructed by multivariate Cox regression. Results: As expected, we observed MYB fusion and somatic mutations in our cohort (57%, 31/54), strengthening the role of these aberrations as critical events in ACC. Mutations in NOTCH1 were also found in our cohort (19%, 10/54). Median tumour mutational burden (TMB) of these patients is 0.85 Muts/Mbp (0-11 Muts/Mbp). Analysis of WES data showed that all patients were microsatellite instability (MSI)-negative, and 17 of them were confirmed by conventional MSI-PCR testing. Lack of PD-L1 expression is 96.0% (n = 46/48) at a tumour proportion score 0% and 22.9% (11/48) of cases showed more than 10% CD8+ prevalence. We compared cancer types using an immune infiltration score (IIS) and an antigen presenting machinery expression (APM) score and find that ACC is among the lowest for both scores. Statistically significant correlations were found between IIS and distant metastasis-free survival (univariate analysis, HR = 2.64, 95% confidence interval [CI], 1.134 to 6.145, p = 0.023). Patients with higher IIS had shorter distant metastasis-free survival time (log-rank p = 0.020), and patients with higher T cell infiltration score (TIS) had shorter locoregional recurrence-free survival time (log-rank p = 0.050). In addition, we investigated the pretreatment immune profile of five ACC patients treated with PD-1 checkpoint inhibitors, and found that both TIS and APM were elevated in responding patient (with a partial response to camrelizumab) whereas they were in the lowest for patients with progressive disease on camrelizumab or pembrolizumab. Conclusions: Our study highlights the immune infiltration patterns and unravels mRNA signatures with prognostic utility and immunotherapeutic biomarker potential in ACC.

Multicenter Validation of a Gene Expression–Based Prognostic Signature in Lymph Node–Negative Primary Breast Cancer

2006 ◽  
Vol 24 (11) ◽  
pp. 1665-1671 ◽  
Author(s):  
John A. Foekens ◽  
David Atkins ◽  
Yi Zhang ◽  
Fred C.G.J. Sweep ◽  
Nadia Harbeck ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Distant Metastasis ◽  
Gene Signature ◽  
Breast Cancer Patients ◽  
Prognostic Signature ◽  
Free Survival ◽  
Node Negative ◽  
Distant Metastasis Free Survival ◽  
Multicenter Validation

Purpose We previously identified in a single-center study a 76-gene prognostic signature for lymph node-negative (LNN) breast cancer patients. The aim of this study was to validate this gene signature in an independent more diverse population of LNN patients from multiple institutions. Patients and Methods Using custom-designed DNA chips we analyzed the expression of the 76 genes in RNA of frozen tumor samples from 180 LNN patients who did not receive adjuvant systemic treatment. Results In this independent validation, the 76-gene signature was highly informative in identifying patients with distant metastasis within 5 years (hazard ratio, [HR], 7.41; 95% CI, 2.63 to 20.9), even when corrected for traditional prognostic factors in multivariate analysis (HR, 11.36; 95% CI, 2.67 to 48.4). The actuarial 5- and 10-year distant metastasis-free survival were 96% (95% CI, 89% to 99%) and 94% (95% CI, 83% to 98%), respectively, for the good profile group and 74% (95% CI, 64% to 81%) and 65% (53% to 74%), respectively for the poor profile group. The sensitivity for 5-yr distant metastasis-free survival was 90%, and the specificity was 50%. The positive and negative predictive values were 38% (95% CI, 29% to 47%) and 94% (95% CI, 86% to 97%), respectively. The 76-gene signature was confirmed as a strong prognostic factor in subgroups of estrogen receptor-positive patients, pre- and postmenopausal patients, and patients with tumor sizes 20 mm or smaller. The subgroup of patients with estrogen receptor-negative tumors was considered too small to perform a separate analysis. Conclusion Our data provide a strong methodologic and clinical multicenter validation of the predefined prognostic 76-gene signature in LNN breast cancer patients.

scholarly journals Histopathological and Genomic Grading Provide Complementary Prognostic Information in Breast Cancer: A Study on Publicly Available Datasets

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Nilotpal Chowdhury
Keyword(s):  
Breast Cancer ◽  
Cox Regression ◽  
Prognostic Indicator ◽  
Rank Test ◽  
Prognostic Impact ◽  
Prognostic Information ◽  
Free Survival ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
Significant Prognostic Indicator

The genomic grade (GG) for breast cancer is thought to be the genomic counterpart of histopathological grade (HG). The motivation behind this study was to see whether HG retains its prognostic impact even when adjusted for GG, or whether it can be replaced by the latter. Four publicly available gene expression datasets were analyzed. Kaplan-Meier curves, log rank test, and Cox regression were used to study recurrence-free survival (RFS) and distant metastasis-free survival (DMFS). HG remained a significant prognostic indicator in low GG tumors (P = 0.003 for DMFS, P< 0.001 for RFS) but not in high GG tumors. HG grade 2 tumors differed significantly from HG grade 1 tumors, underlining the prognostic role of intermediate HG tumors. Additionally, GG could stratify HG 1 as well as HG 2 tumors into distinct prognostic groups. HG and GG add independent prognostic information to each other. However, the prognostic effects of both HG and GG are time varying, with the hazard ratios of high HG and GG tumors being markedly attenuated over time.

Validation of an RT-PCR multi-gene prognostic signature for distant metastasis in node negative (N-), ER positive (ER+) breast cancer patients using FFPE sections

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21009-21009
Author(s):  
A. Tutt ◽  
A. Wang ◽  
R. Springall ◽  
K. Lau ◽  
K. Ryder ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Distant Metastasis ◽  
Tumor Size ◽  
Cox Regression ◽  
Risk Groups ◽  
Breast Cancer Patients ◽  
Prognostic Signature ◽  
Rt Pcr ◽  
Free Survival

21009 Background: We sought to validate a previously developed 14-gene prognostic signature and a metastasis score (MS) that predicted distant metastasis in N-, ER+ breast cancer patients in an independent sample set of patients without systemic treatment. The genes consisted primarily of proliferation genes involved in p53 and TNF signaling pathways. Methods: : A cohort of 294 N-, ER+ breast cancer patients from Guy's Hospitals, London, UK without systemic therapy were tested. The cohort had a mean age of 55.5 yrs with 49% > 55 yrs, mean tumor size of 1.93 (max. 3) cm, and a median follow up of 14.3 yrs. The primary endpoint was distant metastasis free survival. RT-PCR was carried out on fixed sections. The MS was calculated. Results: The mean MS (SD) was 0.44 (0.59) with a range of -1.31 to 2.0. Hazard of distant metastasis increased 3.02 fold (95% CI 1.91–4.76, p <0.0001) per unit increase in MS from Cox model. The pre-determined cut point of zero was used to stratify patients into low- and high-risk groups. The 5-yr distant-metastasis-free survival rate (DMFSR) for low- and high-risk groups were 1 and 0.86 (SE 0.024); the 10-yr DMFSR were 0.97 (0.021) and 0.77 (0.030), respectively. Univariate Cox regression analyses indicated that MS (hazard ratio (HR) 5.65, 95% CI 2.05–15.56, p=0.008), tumor size (HR 1.62, p=0.0047) and tumor grade (HR 2.52, p=0.036) were significant but age was not. Multivariate Cox regression indicated that the signature had independent prognostic value with a HR of 4.71 (1.42–15.61, p=0.011) after adjusting for age, tumor size and grade. AUC of MS at 5-and 10-yr were 0.78 (0.71–0.85, p<0.001) and 0.73 (0.66–0.80, p<0.001) with sensitivities of 1 and 0.96 and specificities of 0.31 and 0.31 at zero cut point, respectively. The differential risk between the median MS scores of the lowest and highest deciles was 8-fold. Conclusions: A previously defined RT-PCR prognostic signature for N-, ER+ patients has been confirmed. A metastasis score that quantifies distant metastasis risk, not confounded with treatment effect can complement treatment response predictors. Insight on natural history of tumors is critical for evaluating impact of therapy. No significant financial relationships to disclose.

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