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Association Between Plasma Diacetylspermine and Tumor Spermine Synthase With Outcome in Triple-Negative Breast Cancer.

ABSTRACT: BACKGROUND:MYC is an oncogenic driver of development and progression in triple-negative breast cancer (TNBC). Ornithine decarboxylase, the rate-limiting enzyme in polyamine metabolism, is a transcriptional target of MYC. We therefore hypothesized that a plasma polyamine signature may be predictive of TNBC development and progression. METHODS:Using liquid chromatography mass spectrometry, polyamine levels were determined in plasma samples from newly diagnosed patients with TNBC (n?=?87) and cancer-free controls (n?=?115). Findings were validated in plasma samples from an independent prospective cohort of 54 TNBC, 55 estrogen receptor negative (ER-) and progesterone receptor negative (PR-) and HER2 positive (HER2+), and 73 ER+ case patients, and 30 cancer-free control subjects. Gene expression data and clinical data for 921 and 2359 breast cancer tumors were obtained from The Cancer Genome Atlas repository and the Oncomine database, respectively. Relationships between plasma diacetylspermine (DAS) and tumor spermine synthase (SMS) mRNA expression with metastasis-free survival and overall survival were determined using Cox proportional hazard models; Fisher exact tests were used to assess risk of distant metastasis in relation to tumor SMS mRNA expression. RESULTS:An increase in plasma DAS, a catabolic product of spermine mediated through SMS, was observed in the TNBC subtype of breast cancer. Plasma levels of DAS in TNBC associated with increased risk of metastasis (plasma DAS value ? 1.16, hazard ratio = 3.06, 95% confidence interval [CI] = 1.15 to 8.13, two-sided P = .03). SMS mRNA expression in TNBC tumor tissue was also found to be predictive of poor overall survival (top 25th percentile hazard ratio = 2.06, 95% CI = 1.04 to 4.08, one-sided P = .04) and increased risk of distant metastasis in TNBC (comparison of lowest SMS quartile [reference] to highest SMS quartile relative risk = 1.90, 95% CI?=?0.97 to 4.06, one-sided Fisher exact test P=.03). CONCLUSIONS:Metabolomic profiling identified plasma DAS as a predictive marker for TNBC progression and metastasis.

SUBMITTER: Fahrmann JF

PROVIDER: S-EPMC7301069 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Association Between Plasma Diacetylspermine and Tumor Spermine Synthase With Outcome in Triple-Negative Breast Cancer.

Fahrmann Johannes F JF Vykoukal Jody J Fleury Alia A Tripathi Satyendra S Dennison Jennifer B JB Murage Eunice E Wang Peng P Yu Chuan-Yih CY Capello Michela M Creighton Chad J CJ Do Kim-Anh KA Long James P JP Irajizad Ehsan E Peterson Christine C Katayama Hiroyuki H Disis Mary L ML Arun Banu B Hanash Samir S

Journal of the National Cancer Institute 20200601 6

<h4>Background</h4>MYC is an oncogenic driver of development and progression in triple-negative breast cancer (TNBC). Ornithine decarboxylase, the rate-limiting enzyme in polyamine metabolism, is a transcriptional target of MYC. We therefore hypothesized that a plasma polyamine signature may be predictive of TNBC development and progression.<h4>Methods</h4>Using liquid chromatography mass spectrometry, polyamine levels were determined in plasma samples from newly diagnosed patients with TNBC (n ...[more]

PMID: 31503278

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Project description:ImportanceWhy some triple-negative breast cancers (TNBCs) have high and others have low immune cell infiltration is unknown. Understanding how immune surveillance shapes the cancer genome could help in the selection of patients and the development of more effective immunotherapy strategies.ObjectiveTo examine the association between genomic metrics and the extent of immune infiltration in TNBCs.Design, setting, and participantsThis study, performed from June 1, 2015, through January 31, 2017, used DNA and RNA sequencing data and messenger RNA expression results from The Cancer Genome Atlas (TCGA) breast cancer data set (n = 1215) to calculate previously described immune metagene expression values and histologic lymphocyte counts to quantify immune infiltration and assign prognostic categories to TNBCs. It used the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data set as an independent validation cohort. The study compared clonal heterogeneity, somatic total mutational load, neoantigen load, and somatic copy number alteration levels between immune-rich TNBC cohorts with good prognosis and immune-poor TNBC cohorts with poor prognosis. The study also compared the distribution of mutations in 119 canonical cancer genes.Main outcomes and measuresCorrelation between immune prognostic category and genomic metrics of the cancer.ResultsThis study of 193 TNBC samples with patient survival information found an inverse association between clonal heterogeneity and immune metagene expression (ρ = −0.395, P = 2 × 10−8). The study also found an inverse association between immune metagene expression and somatic copy number alteration levels (ρ = −0.484, P = 2 × 10−10). Lymphocyte-rich TNBCs with good prognosis had significantly lower mutation and neoantigen counts than did lymphocyte-poor TNBCs with poor prognosis. The robustness of the study results was confirmed by using various immune metagenes in the same TCGA data set and in the independent METABRIC data set.Conclusions and relevanceThis study suggests that immune-rich TNBCs may be under an immune surveillance that continuously eliminates many immunogenic clones, resulting in lower clonal heterogeneity. These cancers may also represent the subset of TNBCs that could derive benefit from immune checkpoint inhibitor therapy to tilt the balance in favor of the immune system.

Project description:Breast cancer is the most common malignancy affecting women, but the heterogeneity of the condition is a significant obstacle to effective treatment. Triple negative breast cancers (TNBCs) do not express HER2 or the receptors for estrogen or progesterone, and so often have a poor prognosis. Tumor-infiltrating T cells have been well-characterized in TNBC, and increased numbers are associated with better outcomes; however, the potential roles of B cells and plasma cells have been large. Here, we conducted a retrospective correlative study on the expression of B cell/plasma cell-related genes, and the abundance and localization of B cells and plasma cells within TNBCs, and clinical outcome. We analyzed 269 TNBC samples and used immunohistochemistry to quantify tumor-infiltrating B cells and plasma cells, coupled with NanoString measurement of expression of immunoglobulin metagenes. Multivariate analysis revealed that patients bearing TNBCs with above-median densities of CD38+ plasma cells had significantly better disease-free survival (DFS) (HR = 0.44; 95% CI 0.26-0.77; p = 0.004) but not overall survival (OS), after adjusting for the effects of known prognostic factors. In contrast, TNBCs with higher immunoglobulin gene expression exhibited improved prognosis (OS p = 0.029 and DFS p = 0.005). The presence of B cells and plasma cells was positively correlated (p < 0.0001, R = 0.558), while immunoglobulin gene IGKC, IGHM, and IGHG1 mRNA expression correlated specifically with the density of CD38+ plasma cells (IGKC p < 0.0001, R = 0.647; IGHM p < 0.0001, R = 0.580; IGHG1 p < 0.0001, R = 0.655). Interestingly, after adjusting the multivariate analysis for the effect of intratumoral CD38+ plasma cell density, the expression levels of all three genes lost significant prognostic value, suggesting a biologically important role of plasma cells. Last but not least, the addition of intratumoral CD38+ plasma cell density to clinicopathological features significantly increased the prognostic value for both DFS (ΔLRχ2 = 17.28, p = 1.71E-08) and OS (ΔLRχ2 = 10.03, p = 6.32E-08), compared to clinicopathological features alone. The best combination was achieved by integrating intratumoral CD38+ plasma cell density and IGHG1 which conferred the best added prognostic value for DFS (ΔLRχ2 = 27.38, p = 5.22E-10) and OS (ΔLRχ2 = 21.29, p = 1.03E-08). Our results demonstrate that the role of plasma cells in TNBC warrants further study to elucidate the relationship between their infiltration of tumors and disease recurrence.

Dataset Information

Association Between Plasma Diacetylspermine and Tumor Spermine Synthase With Outcome in Triple-Negative Breast Cancer.

Publications

Association Between Plasma Diacetylspermine and Tumor Spermine Synthase With Outcome in Triple-Negative Breast Cancer.

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