Identification of metabolic pathways contributing to ER+ breast cancer disparities using a machine-learning pipeline.

African American (AA) women in the United States have a 40% higher breast cancer mortality rate than Non-Hispanic White (NHW) women. The survival disparity is particularly striking among (estrogen receptor positive) ER+ breast cancer cases. The purpose of this study is to examine whether there are racial differences in metabolic pathways typically activated in patients with ER+ breast cancer. We collected pretreatment plasma from AA and NHW ER+ breast cancer cases (AA n = 48, NHW n = 54) and cancer-free controls (AA n = 100, NHW n = 48) to conduct an untargeted metabolomics analysis using gas chromatography mass spectrometry (GC-MS) to identify metabolites that may be altered in the different racial groups. Unpaired t-test combined with multiple feature selection and prediction models were employed to identify race-specific altered metabolic signatures. This was followed by the identification of altered metabolic pathways with a focus in AA patients with breast cancer. The clinical relevance of the identified pathways was further examined in PanCancer Atlas breast cancer data set from The Cancer Genome Atlas Program (TCGA). We identified differential metabolic signatures between NHW and AA patients. In AA patients, we observed decreased circulating levels of amino acids compared to healthy controls, while fatty acids were significantly higher in NHW patients. By mapping these metabolites to potential epigenetic regulatory mechanisms, this study identified significant associations with regulators of metabolism such as methionine adenosyltransferase 1A (MAT1A), DNA Methyltransferases and Histone methyltransferases for AA individuals, and Fatty acid Synthase (FASN) and Monoacylglycerol lipase (MGL) for NHW individuals. Specific gene Negative Elongation Factor Complex E (NELFE) with histone methyltransferase activity, was associated with poor survival exclusively for AA individuals. We employed a comprehensive and novel approach that integrates multiple machine learning and statistical methods, coupled with human functional pathway analyses. The metabolic profile of plasma samples identified may help elucidate underlying molecular drivers of disproportionately aggressive ER+ tumor biology in AA women. It may ultimately lead to the identification of novel therapeutic targets. To our knowledge, this is a novel finding that describes a link between metabolic alterations and epigenetic regulation in AA breast cancer and underscores the need for detailed investigations into the biological underpinnings of breast cancer health disparities.

Duration of Symptoms Does Not Affect Clinical Outcome After Lumbar Arthrodesis.

STUDY DESIGN: Retrospective cohort study at a single institution. OBJECTIVE: To examine the effect of symptom duration on clinical outcomes after posterolateral lumbar fusion. SUMMARY OF BACKGROUND DATA: Nonoperative measures are generally exhausted before patients are indicated for surgical intervention, leaving patients with their symptomatology for varying lengths of time. It is unclear at what point in time surgical intervention may become less efficacious at alleviating preoperative symptoms. MATERIALS AND METHODS: Consecutive patients who underwent primary elective open posterior lumbar spinal fusion at a single academic institution were included. Patient and operative characteristics were compared between symptom duration groups (group 1: <12 mo of pain, group 2: ≥12 mo of pain). Preoperative and final postoperative visual analog scale back/leg pain, and Oswestry Disability Index, were collected. Preoperative, immediate postoperative, and final radiographs were assessed to measure lumbar lordosis (LL), pelvic tilt (PT), pelvic incidence (PI), and the PI-LL difference was calculated. RESULTS: In total, 167 patients were included in group 1, whereas 359 patients were included in group 2. Baseline demographics and operative characteristics were similar between the 2 groups. Both groups had similar changes in sagittal parameters and had no significant difference in rates of complication, reoperation, discharge to rehabilitation facility, or early adjacent segment degeneration. Both groups demonstrated similar improvement in clinical outcome measures. CONCLUSIONS: Despite differences in symptom duration, patients who had pain for ≥12 months demonstrated similar improvement after posterolateral lumbar arthrodesis than those who had pain for <12 months. Extended effort of conservative treatments or delay of operative intervention does not appear to negatively impact the eventual outcome of surgery. LEVEL OF EVIDENCE: Level III.