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

• Published in: JNCI : Journal of the National Cancer Institute Vol. 112; no. 6; pp. 607 - 616
• Main Authors: Fahrmann, Johannes F, Vykoukal, Jody, Fleury, Alia, Tripathi, Satyendra, Dennison, Jennifer B, Murage, Eunice, Wang, Peng, Yu, Chuan-Yih, Capello, Michela, Creighton, Chad J, Do, Kim-Anh, Long, James P, Irajizad, Ehsan, Peterson, Christine, Katayama, Hiroyuki, Disis, Mary L, Arun, Banu, Hanash, Samir
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.06.2020; Oxford Publishing Limited (England)
• Subjects: Animals; Breast cancer; Chromatography, Liquid; Confidence intervals; ErbB-2 protein; Estrogen receptors; Estrogens; Female; Gene Expression; Genomes; Health hazards; Humans; Liquid chromatography; Mass spectrometry; Mass spectroscopy; Metabolism; Metabolomics; Metastases; Metastasis; Mice; Mice, Transgenic; Myc protein; Neoplasm Metastasis; Neoplasm Staging; Ornithine decarboxylase; Plasma; Plasma levels; Polyamines; Progesterone; Prognosis; Receptors; Spermine; Spermine - analogs & derivatives; Spermine - biosynthesis; Spermine - blood; Spermine synthase; Spermine Synthase - biosynthesis; Spermine Synthase - blood; Spermine Synthase - genetics; Spermine Synthase - immunology; Statistical models; Survival; Tandem Mass Spectrometry; Transcription; Triple Negative Breast Neoplasms - blood; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - immunology; Triple Negative Breast Neoplasms - pathology; Tumors
• DOI: 10.1093/jnci/djz182
• ISSN: 0027-8874; 1460-2105

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.