Molecular Prognostic Factors for Distant Metastases in Premenopausal Patients with HR+/HER2− Early Breast Cancer

Molecular factors that drive metastasis in premenopausal patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−), early breast cancer (EBC) are largely unknown. To identify markers/signatures contributing to metastasis, we analyzed molecular changes in tumors from premenopausal patients who developed metastasis (M1) and who did not (M0). Ninety-seven premenopausal patients with HR+/HER2− EBC were included (M1, n = 48, median distant metastasis-free survival (DMFS): 54 (7–184) months; M0, n = 49, median follow-up: 149 (121–191) months). Gene expression profiling on tumor RNA (Breast Cancer 360TM panel, Nanostring) was performed, followed by comprehensive bioinformatic and statistical analyses. Significantly enhanced ROR (risk of recurrence) scores and reduced signature scores of PGR (progesterone receptor), claudin-low, and mammary stemness were determined in M1. These differences were significantly associated with shorter DMFS in univariate survival analyses. Gene set enrichment analysis showed an enriched mTORC1 pathway in M1. Moreover, a metastasis signature of 19 differentially expressed genes (DEGs) that were DMFS-related was defined. Multivariate analysis including the four signatures, 19 DEGs, pN, and pT status, identified LRP2, IBSP, and SCUBE2 as independent prognostic factors. We identified prognostic gene signatures and single-gene markers for distant metastasis in premenopausal HR+/HER2− EBC potentially applicable in future clinical practice.

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Mining novel cell glycolysis related gene markers that can predict the survival of colon adenocarcinoma patients

Bioscience Reports ◽

10.1042/bsr20201427 ◽

2020 ◽

Vol 40 (8) ◽

Author(s):

Sihan Chen ◽

Guodong Cao ◽

Wei Wu ◽

Yida Lu ◽

Xiaobo He ◽

...

Keyword(s):

Cox Regression ◽

Mechanistic Model ◽

Single Gene ◽

Colon Adenocarcinoma ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Risk Scores ◽

Gene Markers ◽

Cox Regression Analysis

Abstract Colon adenocarcinoma (COAD) is a malignant gastrointestinal tumor, often occurring in the left colon, which is regulated by glycolysis-related processes. In past studies, multiple genes that influence the prognosis for survival have been discovered through bioinformatics analysis. However, the prediction of disease prognosis using a single gene is not an accurate method. In the present study, a mechanistic model was established to achieve better prediction for the prognosis of COAD. COAD-related data downloaded from The Cancer Genome Atlas (TCGA) were correlated with the glycolysis process using gene set enrichment analysis (GSEA) to determine the glycolysis-related genes that regulate COAD. Using COX regression analysis, glycolysis-related genes associated with the prognosis of COAD were identified, and the genes screened to establish a predictive model. The risk scores of this model were correlated with relevant clinical data to obtain a connection diagram between the model and survival rate, tumor characteristic data, etc. Finally, genes in the model were correlated with cells in the tumor microenvironment, finding that they affected specific immune cells in the model. Seven genes related to glycolysis were identified (PPARGC1A, DLAT, 6PC2, P4HA1, STC2, ANKZF1, and GPC1), which affect the prognosis of patients with COAD and constitute the model for prediction of survival of COAD patients.

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Overexpression of SKA3 correlates with poor prognosis in female early breast cancer

PeerJ ◽

10.7717/peerj.12506 ◽

2021 ◽

Vol 9 ◽

pp. e12506

Author(s):

Yue Zhong ◽

Zhenjie Zhuang ◽

Peiju Mo ◽

Mandi Lin ◽

Jiaqian Gong ◽

...

Keyword(s):

Breast Cancer ◽

Early Breast Cancer ◽

Poor Prognosis ◽

Cox Regression ◽

Molecular Subtype ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Chi Square ◽

Exact Test ◽

Chi Square Test

Background Spindle and kinetochore associated complex subunit 3 (SKA3) plays an important role in tumorigenesis and the progression of various tumors. But the relationship between SKA3 and early breast cancer remains unclear. The study aimed to explore the prognostic significance of SKA3 in breast cancer. Methods In the study, SKA3 expression was initially assessed using the Oncomine database and The Cancer Genome Atlas database (TCGA). Then, we presented validation results for RT-qPCR (quantitative reverse transcription PCR) and ELISA (enzyme-linked immunosorbent assay). The relationship between clinical characteristics and SKA3 expression was assessed by Chi-square test and Fisher’s exact test. Kaplan–Meier method and Cox regression analysis were conducted to evaluate the prognostic value of SKA3. Gene set enrichment analysis (GSEA) was performed to screen biological pathways using the TCGA dataset. Besides, single sample gene set enrichment analysis (ssGSEA) was utilized to identify immune infiltration cells about SKA3. Results SKA3 mRNA was expressed at high levels in breast cancer tissues compared with normal tissues. Chi-square test and Fisher’s exact test showed SKA3 expression was related to age, tumor (T) classification, node (N) classification, tumor-node-metastasis (TNM) stage, estrogen receptor (ER), progesterone receptor (PR), molecular subtype, and race. RT-qPCR results showed that SKA3 expression was overexpressed in ER, PR status, and molecular subtype in Chinese people. Kaplan–Meier curves implicated that high SKA3 expression was related to a poor prognosis in female early breast cancer patients. Cox regression models showed that high SKA3 expression could be used as an independent risk factor for female early breast cancer. Four signaling pathways were enriched in the high SKA3 expression group, including mTORC1 signaling pathway, MYC targets v1, mitotic spindle, estrogen response early. Besides, the SKA3 expression level was associate with infiltrating levels of activated CD4 T cells and eosinophils in breast cancer. Conclusion High SKA3 expression correlates with poor prognosis and immune infiltrates in breast cancer. SKA3 may become a biomarker for the prognosis of breast cancer.

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How Different Are the Molecular Mechanisms of Nodal and Distant Metastasis in Luminal A Breast Cancer?

Cancers ◽

10.3390/cancers12092638 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2638

Author(s):

Petr Lapcik ◽

Anna Pospisilova ◽

Lucia Janacova ◽

Peter Grell ◽

Pavel Fabian ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Node ◽

Distant Metastasis ◽

Molecular Mechanisms ◽

Molecular Subtypes ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Lymph Node Status ◽

Luminal A ◽

Primary Tumors

Lymph node status is one of the best prognostic factors in breast cancer, however, its association with distant metastasis is not straightforward. Here we compare molecular mechanisms of nodal and distant metastasis in molecular subtypes of breast cancer, with major focus on luminal A patients. We analyze a new cohort of 706 patients (MMCI_706) as well as an independent cohort of 836 primary tumors with full gene expression information (SUPERTAM_HGU133A). We evaluate the risk of distant metastasis, analyze targetable molecular mechanisms in Gene Set Enrichment Analysis and identify relevant inhibitors. Lymph node positivity is generally associated with NF-κB and Src pathways and is related to high risk (OR: 5.062 and 2.401 in MMCI_706 and SUPERTAM_HGU133A, respectively, p < 0.05) of distant metastasis in luminal A patients. However, a part (≤15%) of lymph node negative tumors at the diagnosis develop the distant metastasis which is related to cell proliferation control and thrombolysis. Distant metastasis of lymph node positive patients is mostly associated with immune response. These pro-metastatic mechanisms further vary in other molecular subtypes. Our data indicate that the management of breast cancer and prevention of distant metastasis requires stratified approach based on targeted strategies.

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Goserelin Versus Cyclophosphamide, Methotrexate, and Fluorouracil as Adjuvant Therapy in Premenopausal Patients With Node-Positive Breast Cancer: The Zoladex Early Breast Cancer Research Association Study

Journal of Clinical Oncology ◽

10.1200/jco.2002.05.042 ◽

2002 ◽

Vol 20 (24) ◽

pp. 4628-4635 ◽

Cited By ~ 242

Author(s):

W. Jonat ◽

M. Kaufmann ◽

W. Sauerbrei ◽

R. Blamey ◽

J. Cuzick ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Research ◽

Side Effects ◽

Association Study ◽

Early Breast Cancer ◽

Research Association ◽

Node Positive ◽

Er Positive ◽

Premenopausal Patients ◽

Positive Breast Cancer

PURPOSE: Current adjuvant therapies have improved survival for premenopausal patients with breast cancer but may have short-term toxic effects and long-term effects associated with premature menopause. PATIENTS AND METHODS: The Zoladex Early Breast Cancer Research Association study assessed the efficacy and tolerability of goserelin (3.6 mg every 28 days for 2 years; n = 817) versus cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy (six 28-day cycles; n = 823) for adjuvant treatment in premenopausal patients with node-positive breast cancer. RESULTS: Analysis was performed when 684 events had been achieved, and the median follow-up was 6 years. A significant interaction between treatment and estrogen receptor (ER) status was found (P = .0016). In ER-positive patients (approximately 74%), goserelin was equivalent to CMF for disease-free survival (DFS) (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.84 to 1.20). In ER-negative patients, goserelin was inferior to CMF for DFS (HR, 1.76; 95% CI, 1.27 to 2.44). Amenorrhea occurred in more than 95% of goserelin patients by 6 months versus 58.6% of CMF patients. Menses returned in most goserelin patients after therapy stopped, whereas amenorrhea was generally permanent in CMF patients (22.6% v 76.9% amenorrheic at 3 years). Chemotherapy-related side effects such as nausea/vomiting, alopecia, and infection were higher with CMF than with goserelin during CMF treatment. Side effects related to estrogen suppression were initially higher with goserelin, but when goserelin treatment stopped, reduced to a level below that observed in the CMF group. CONCLUSION: Goserelin offers an effective, well-tolerated alternative to CMF in premenopausal patients with ER-positive and node-positive early breast cancer.

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Randomized trial of adjuvant ovarian suppression in 926 premenopausal patients with early breast cancer treated with adjuvant chemotherapy

Annals of Oncology ◽

10.1093/annonc/mdi085 ◽

2005 ◽

Vol 16 (3) ◽

pp. 389-396 ◽

Cited By ~ 55

Author(s):

R. Arriagada ◽

M.G. Lê ◽

M. Spielmann ◽

L. Mauriac ◽

J. Bonneterre ◽

...

Keyword(s):

Breast Cancer ◽

Adjuvant Chemotherapy ◽

Randomized Trial ◽

Early Breast Cancer ◽

Ovarian Suppression ◽

Premenopausal Patients

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Factors Predictive of Distant Metastases in Patients With Breast Cancer Who Have a Pathologic Complete Response After Neoadjuvant Chemotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2005.11.124 ◽

2005 ◽

Vol 23 (28) ◽

pp. 7098-7104 ◽

Cited By ~ 78

Author(s):

Ana M. Gonzalez-Angulo ◽

Sean E. McGuire ◽

Thomas A. Buchholz ◽

Susan L. Tucker ◽

Henry M. Kuerer ◽

...

Keyword(s):

Breast Cancer ◽

Regression Analysis ◽

Neoadjuvant Chemotherapy ◽

Distant Metastasis ◽

Cox Regression ◽

Clinical Stage ◽

Pathologic Complete Response ◽

Distant Metastases ◽

Complete Response ◽

Cox Regression Analysis

Purpose To identify clinicopathological factors predictive of distant metastasis in patients who had a pathologic complete response (pCR) after neoadjuvant chemotherapy (NC). Methods Retrospective review of 226 patients at our institution identified as having a pCR was performed. Clinical stage at diagnosis was I (2%), II (36%), IIIA (27%), IIIB (23%), and IIIC (12%). Eleven percent of all patients were inflammatory breast cancers (IBC). Ninety-five percent received anthracycline-based chemotherapy; 42% also received taxane-based therapy. The relationship of distant metastasis with clinicopathologic factors was evaluated, and Cox regression analysis was performed to identify independent predictors of development of distant metastasis. Results Median follow-up was 63 months. There were 31 distant metastases. Ten-year distant metastasis-free rate was 82%. Multivariate Cox regression analysis using combined stage revealed that clinical stages IIIB, IIIC, and IBC (hazard ratio [HR], 4.24; 95% CI, 1.96 to 9.18; P < .0001), identification of ≤ 10 lymph nodes (HR, 2.94; 95% CI, 1.40 to 6.15; P = .004), and premenopausal status (HR, 3.08; 95% CI, 1.25 to 7.59; P = .015) predicted for distant metastasis. Freedom from distant metastasis at 10 years was 97% for no factors, 88% for one factor, 77% for two factors, and 31% for three factors (P < .0001). Conclusion A small percentage of breast cancer patients with pCR experience recurrence. We identified factors that independently predicted for distant metastasis development. Our data suggest that premenopausal patients with advanced local disease and suboptimal axillary node evaluation may be candidates for clinical trials to determine whether more aggressive or investigational adjuvant therapy will be of benefit.

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Development of a Novel Prognostic Signature Based on Antigen Processing and Presentation in Patients with Breast Cancer

Pathology & Oncology Research ◽

10.3389/pore.2021.600727 ◽

2021 ◽

Vol 27 ◽

Author(s):

Aoshuang Qi ◽

Mingyi Ju ◽

Yinfeng Liu ◽

Jia Bi ◽

Qian Wei ◽

...

Keyword(s):

Breast Cancer ◽

Antigen Processing ◽

Cox Regression ◽

Enrichment Analysis ◽

Gene Signature ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Prognostic Indicators ◽

Gene Set ◽

Antigen Processing And Presentation

Background: Complex antigen processing and presentation processes are involved in the development and progression of breast cancer (BC). A single biomarker is unlikely to adequately reflect the complex interplay between immune cells and cancer; however, there have been few attempts to find a robust antigen processing and presentation-related signature to predict the survival outcome of BC patients with respect to tumor immunology. Therefore, we aimed to develop an accurate gene signature based on immune-related genes for prognosis prediction of BC.Methods: Information on BC patients was obtained from The Cancer Genome Atlas. Gene set enrichment analysis was used to confirm the gene set related to antigen processing and presentation that contributed to BC. Cox proportional regression, multivariate Cox regression, and stratified analysis were used to identify the prognostic power of the gene signature. Differentially expressed mRNAs between high- and low-risk groups were determined by KEGG analysis.Results: A three-gene signature comprising HSPA5 (heat shock protein family A member 5), PSME2 (proteasome activator subunit 2), and HLA-F (major histocompatibility complex, class I, F) was significantly associated with OS. HSPA5 and PSME2 were protective (hazard ratio (HR) < 1), and HLA-F was risky (HR > 1). Risk score, estrogen receptor (ER), progesterone receptor (PR) and PD-L1 were independent prognostic indicators. KIT and ACACB may have important roles in the mechanism by which the gene signature regulates prognosis of BC.Conclusion: The proposed three-gene signature is a promising biomarker for estimating survival outcomes in BC patients.

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Prognostic factors of recurrence or distant metastasis in elderly breast cancer patients

Annals of Oncology ◽

10.1093/annonc/mdz418.013 ◽

2019 ◽

Vol 30 ◽

pp. ix18

Author(s):

S. Lee

Keyword(s):

Breast Cancer ◽

Prognostic Factors ◽

Cancer Patients ◽

Distant Metastasis ◽

Breast Cancer Patients

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Prognostic Significance of SQSTM1 in Breast Cancer: A Comprehensive Analysis

10.21203/rs.3.rs-64416/v1 ◽

2020 ◽

Author(s):

Yang Liu ◽

Qian Du ◽

Dan Sun ◽

Ruiying Han ◽

Mengmeng Teng ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Somatic Mutation ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Functional Enrichment ◽

Regulation Mechanism ◽

Breast Cancer Patients ◽

Gene Set ◽

Multiple Datasets

Abstract Background: SQSTM1 (Sequestosome 1, p62) is degraded by activated autophagy and involved in the progression of in various types of cancers. However, the prognostic role and underlying regulation mechanism of SQSTM1 in the progression and development of breast cancer remain unclear.Methods: In this study, 1336 samples with available mRNA data from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database and 27 formalin fixation and paraffin embedding (FFPE) tissue samples from the First Affiliated Hospital of Xi’an Jiaotong University were collected to evaluate SQSTM1 expression in mRNA and protein levels. Kaplan–Meier and Cox regression were used for revealing prognostic value in three independent breast cancer independent datasets. Tumor Immune Estimation Resource (TIMER) database and Gene Set Variation Analysis (GSVA) was used to explore the relationship of SQSTM1 mRNA expression and immune infiltration level in breast cancer. Dysregulation mechanisms of SQSTM1 were also explored including copy number variation (CNV), somatic mutation, epigenetic alterations and other transcription and post-transcription level using multiple datasets. Finally, Gene Set Enrichment Analysis (GSEA) was constructed to elucidate functional regulating performance of SQSTM1 in breast cancer.Results: The results showed that mRNA and protein level of SQSTM1 were significantly elevated in breast cancer and receiver operating characteristic (ROC) curve showed that p62 may act as diagnostic biomarker. Lower expression of SQSTM1 predicted better outcome through multiple datasets. It was also found that SQSTM1 correlated with immune infiltrates in breast cancer. Moreover, CNV and methylation of SQSTM1 DNA was correlated with SQSTM1 dysregulation and act as prognostic factors for breast cancer patients. Yet, somatic mutation status of SQSTM1 didn’t show any prognostic relevance. We also identified diverse transcription factors that directly bound to SQSTM1 DNA and the miRNAs which may regulate SQSTM1 mRNA. Finally, functional enrichment analysis revealed that SQSTM1 is related to cell signal transduction, oxidative stress and autophagy in breast cancer.Conclusion: Our findings revealed that SQSTM1 plays a key role in the progression of breast cancer and might be a promising biomarker for the diagnosis and personalized treatment of breast cancer patients.

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