An iron metabolism and immune related gene signature for the prediction of clinical outcome and molecular characteristics of triple-negative breast cancer.

BACKGROUND: An imbalance of intracellular iron metabolism can lead to the occurrence of ferroptosis. Ferroptosis can be a factor in the remodeling of the immune microenvironment and can affect the efficacy of cancer immunotherapy. How to combine ferroptosis-promoting modalities with immunotherapy to suppress triple-negative breast cancer (TNBC) has become an issue of great interest in cancer therapy. However, potential biomarkers related to iron metabolism and immune regulation in TNBC remain poorly understand. METHODS: We constructed an optimal prognostic TNBC-IMRGs (iron metabolism and immune-related genes) signature using least absolute shrinkage and selection operator (LASSO) cox regression. Survival analysis and ROC curves were analyzed to identify the predictive value in a training cohort and external validation cohorts. The correlations of gene signature with ferroptosis regulators and immune infiltration are also discussed. Finally, we combined the gene signature with the clinical model to construct a combined model, which was further evaluated using a calibration curve and decision curve analysis (DCA). RESULTS: Compared with the high-risk group, TNBC patients with low-risk scores had a remarkably better prognosis in both the training set and external validation sets. Both the IMRGs signature and combined model had a high predictive capacity, 1/3/5- year AUC: 0.866, 0.869, 0.754, and 1/3/5-yaer AUC: 0.942, 0.934, 0.846, respectively. The calibration curve and DCA also indicate a good predictive performance of the combined model. Gene set enrichment analysis (GSEA) suggests that the high-risk group is mainly enriched in metabolic processes, while the low-risk group is mostly clustered in immune related pathways. Multiple algorithms and single sample GSEA further show that the low-risk score is associated with a high tumor immune infiltration level. Differences in expression of ferroptosis regulators are also observed among different risk groups. CONCLUSIONS: The IMRGs signature based on a combination of iron metabolism and immune factors may contribute to evaluating prognosis, understanding molecular characteristics and selecting treatment options in TNBC.

Different Clinicopathological Characteristics and Prognostic Factors for Occult and Non-occult Breast Cancer: Analysis of the SEER Database.

Purpose: The aim of our study was to evaluate the different clinicopathological characteristics and prognostic factors for occult and non-occult breast cancer. Methods: 572 OBC cases and 117,217 non-OBC patients between 2004 and 2015 was selected from Surveillance, Epidemiology, and End Results (SEER) database. We analyzed the clinicopathological characteristics and survival outcomes between OBC and non-OBC patients. Furthermore, the propensity score matching method was utilized to reduce the influences of baseline differences in demographic and clinical characteristics on outcome differences. Univariable and multivariable analyses were used to evaluate the prognostic factors of OBC patients. Results: Compared with non-OBC patients, OBC patients in this study presented a higher proportion of older age, American Joint Committee on Cancer (AJCC) N3 stage, estrogen receptor (ER)-negative status, progesterone receptor (PR)-negative status, and human epidermal growth factor receptor-2 (HER-2)-positive status, and underwent more chemotherapy. Multivariate analysis revealed a better survival in overall patients with OBC patients according to breast cancer-specific survival (BCSS) and overall survival (OS). Propensity score analysis also achieved a similar result for OBC patients. Stratified analyses by nodal status and molecular subtypes indicated that these survival advantage were mainly presented in patients with AJCC N2/N3 stage or hormone receptor (HR)-positive tumors. In addition, nodal status, HER-2 status, and radiation status were demonstrated to be three independent prognostic factors for OBC patients. Conclusion: Patients with OBC retained exclusive clinical characteristics and were shown to have a better outcome compared with non-OBC patients, especially for those with N2/N3 stage or HR-positive tumors.

The Survival Outcomes of T1aN0M0 Triple-Negative Breast Cancer With Adjuvant Chemotherapy.

Purpose: Triple-negative breast cancer (TNBC) is a subtype with distinct heterogeneity, high invasiveness, and poorer prognosis. There is a controversy about adjuvant chemotherapy (ACT) at the T1aN0M0 stage. This study was carried out to assess the survival benefit of ACT for these patients. Methods: We identified 1,099 patients with T1aN0M0 TNBC who were diagnosed between 2010 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariable analyses were conducted to determine factors related to survival. One-to-one (1:1) propensity score matching (PSM) was applied to construct a matched sample consisting of pairs of ACT and non-ACT subjects. Breast cancer-specific survival (BCSS) and overall survival (OS) of the two groups were evaluated by Kaplan-Meier plots and Cox proportional hazard regression models. Stratified analysis according to different variables was also performed. Results: No obvious differences in demographic or clinical characteristics were found between patients who had ACT and those without ACT therapy in terms of race, marital status, laterality, or radiation therapy. A higher proportion of patients who were older, had a higher histological grade tumor, and who received breast-conserving surgery had adjuvant chemotherapy. The ACT group did not exhibit better survival in BCSS or OS before PSM. After PSM, the ACT and non-ACT groups consisted of 255 patients, respectively, and Kaplan-Meier curves and multivariate analysis both indicate that adjuvant chemotherapy was not associated with better survival in terms of BCSS or OS. Furthermore, we did not observe any survival advantage in any subgroup irrespective of age, race, marital status, histological grade, surgery type, or radiotherapy status. Conclusions: The study results indicate that there is no strong association between ACT and better survival in T1aN0M0 TNBC. It implies that the chemotherapy decision should be made cautiously and further research into therapeutic strategies are needed in T1aN0M0 TNBC patients.

The Expression, Clinicopathologic Characteristics, and Prognostic Value of Androgen Receptor in Breast Cancer: A Bioinformatics Analysis Using Public Databases.

The role of androgen receptor (AR) in breast cancer has been unveiled in succession for the past few years. In this study, we conducted a comprehensive analysis based on four online public databases of data from many previous studies. We found that the expression of AR is significantly related to age, histological grade, and subtype but not to lymph node status. The low expression level of AR is strongly associated with poor recurrence-free survival, especially with poor distance metastasis-free survival in luminal A patients, but inverse in HER2 (human epidermal growth factor receptor-2) enriched patients. AR might be a biomarker of chemosensitivity in the basal subtype. Besides, the expression of melanophilin (MLPH) is distinctly in accordance with that of AR. AR could play diverse roles in different subtypes of breast cancer.