scholarly journals Metabolic Footprints and Molecular Subtypes in Breast Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-19 ◽  
Author(s):  
Vera Cappelletti ◽  
Egidio Iorio ◽  
Patrizia Miodini ◽  
Marco Silvestri ◽  
Matteo Dugo ◽  
...  

Cancer treatment options are increasing. However, even among the same tumor histotype, interpatient tumor heterogeneity should be considered for best therapeutic result. Metabolomics represents the last addition to promising “omic” sciences such as genomics, transcriptomics, and proteomics. Biochemical transformation processes underlying energy production and biosynthetic processes have been recognized as a hallmark of the cancer cell and hold a promise to build a bridge between genotype and phenotype. Since breast tumors represent a collection of different diseases, understanding metabolic differences between molecular subtypes offers a way to identify new subtype-specific treatment strategies, especially if metabolite changes are evaluated in the broader context of the network of enzymatic reactions and pathways. Here, after a brief overview of the literature, original metabolomics data in a series of 92 primary breast cancer patients undergoing surgery at the Istituto Nazionale dei Tumori of Milano are reported highlighting a series of metabolic differences across various molecular subtypes. In particular, the difficult-to-treat luminal B subgroup represents a tumor type which preferentially relies on fatty acids for energy, whereas HER2 and basal-like ones show prevalently alterations in glucose/glutamine metabolism.

2013 ◽  
Vol 20 (3) ◽  
pp. 339-348 ◽  
Author(s):  
Sewha Kim ◽  
Do Hee Kim ◽  
Woo-Hee Jung ◽  
Ja Seung Koo

The aim of this study was to investigate the expression of glutamine metabolism-related proteins to determine whether glutamine is metabolized differently according to breast cancer molecular subtype. We generated a tissue microarray of 702 breast cancer patients and performed immunohistochemical staining for glutamine metabolism-related proteins, including glutaminase 1 (GLS1 (GLS)), glutamate dehydrogenase (GDH (H6PD)), and amino acid transporter-2 (ASCT2 (SLC1A5)), which were separately evaluated in tumor and stroma compartments and then analyzed by breast cancer molecular subtypes. Breast cancers were classified as follows: 293 luminal A (41.7%), 166 luminal B (23.6%), 67 HER2 type (9.6%), and 176 TNBC (25.1%). HER2 type showed the highest stromal GLS1 (P=0.001), tumoral GDH (P=0.001), stromal GDH (P<0.001), and tumoral ASCT (P<0.001) expression. We identified differential expression of glutamine metabolism-related proteins according to molecular subtype of breast cancer. The highest glutamine metabolic activity was seen in HER2-type breast cancer.


Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3146
Author(s):  
Patricia Fernández-Nogueira ◽  
Gemma Fuster ◽  
Álvaro Gutierrez-Uzquiza ◽  
Pere Gascón ◽  
Neus Carbó ◽  
...  

Breast cancer (BrCa) is the leading cause of death among women worldwide, with about one million new cases diagnosed each year. In spite of the improvements in diagnosis, early detection and treatment, there is still a high incidence of mortality and failure to respond to current therapies. With the use of several well-established biomarkers, such as hormone receptors and human epidermal growth factor receptor-2 (HER2), as well as genetic analysis, BrCa patients can be categorized into multiple subgroups: Luminal A, Luminal B, HER2-enriched, and Basal-like, with specific treatment strategies. Although chemotherapy and targeted therapies have greatly improved the survival of patients with BrCa, there is still a large number of patients who relapse or who fail to respond. The role of the tumor microenvironment in BrCa progression is becoming increasingly understood. Cancer-associated fibroblasts (CAFs) are the principal population of stromal cells in breast tumors. In this review, we discuss the current understanding of CAFs’ role in altering the tumor response to therapeutic agents as well as in fostering metastasis in BrCa. In addition, we also review the available CAFs-directed molecular therapies and their potential implications for BrCa management.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 572-572
Author(s):  
Yunan Han ◽  
Shuai Xu ◽  
Graham A. Colditz ◽  
Adetunji T. Toriola

572 Background: Breast cancer is the second leading cause of cancer death in U.S. women. On the molecular level, breast cancer is a heterogeneous disease. Heterogeneous expressions of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) are etiologically and clinically meaningful, as they map to distinct risk factors and different treatment strategies. Although breast cancer mortality has been declining since 1990, little is known about mortality trends according to molecular subtypes at the population level. Methods: We examined the incidence-based mortality rates and trends among women who were diagnosed with invasive breast cancer from 2010 through 2017 using the Surveillance, Epidemiology, and End Results (SEER) database. We defined incidence-based mortality using a moving 5-year calendar period starting in 2014. We further assessed mortality according to breast cancer molecular subtypes: luminal A (ER and/or PR positive, HER2 negative), luminal B (ER and/or PR positive, HER2 positive), HER2-enriched (HER2 over-expressed or amplified, ER and PR negative) and triple-negative (ER and PR negative, HER2 negative) tumors. We calculated annual percent changes (APC) in incidence-based mortality using joinpoint regression models. Results: Overall, incidence-based mortality for breast cancer significantly decreased by 1.5% annually from 2014 through 2017 (APC, -1.5%; 95% coefficient interval [CI], -2.3% to -0.7%; p<0.001). Incidence-based mortality decreased annually by 2.0% for luminal A breast cancer (APC, -2.0%; 95% CI, -3.7% to -0.3%; p<0.001), 2.1% for luminal B breast cancer (APC, -2.1%; 95% CI, -5.4% to 1.4%; p=0.1), 1.1% for triple-negative breast cancer (TNBC) (APC, -1.1%; 95% CI, -2.1% to -0.0%; p<0.001). However, incidence-based mortality for HER2-enriched breast cancer increased 2.3% annually during the study period (APC, 2.3%; 95% CI, -2.4% to 7.2%; p=0.2). Conclusions: Between 2014 and 2017, incidence-based mortality for luminal A, luminal B, and TNBC decreased among U.S. women, with a larger decrease observed for luminal tumors. However, incidence-based mortality for HER2-enriched breast cancer increased. The favorable incidence-based mortality trends for luminal tumors and TNBC are likely due to the continuing improvement in treatments and early detection. The increasing trend of incidence-based mortality for HER2-enriched breast cancer constitutes a priority for cancer control activities and further research.


2021 ◽  
Vol 11 ◽  
Author(s):  
Kyoungmin Lee ◽  
Sung Hoon Sim ◽  
Eun Joo Kang ◽  
Jae Hong Seo ◽  
Heejung Chae ◽  
...  

Background: The role of chemotherapy for isolated locoregional recurrence (iLRR) of breast cancer has not been firmly established after local therapies.Methods: We performed a multicenter, retrospective analysis to evaluate the clinical implications of chemotherapy in breast cancer patients with HER2-negative iLRR.Results: Of a total of 277 patients, 146 (52.7%) received chemotherapy for iLRR. Median follow-up duration was 56.1 months. Eighty-six (31.0%) patients had luminal B-like and 100 (36.1%) had TNBC iLRR. There was a trend of longer disease free survival (DFS) in the chemotherapy group (4-year DFS: 70.4 vs. 59.5%, HR = 0.68, 95% CI 0.45–1.02, log-rank p = 0.059). When adjusted with clinically relevant factors, DFS was significantly prolonged with chemotherapy (adjusted HR = 0.61, 95% CI 0.40–0.94, p = 0.023). Subgroup analyses for DFS showed patients with disease free interval (DFI) &lt;5 years or prior chemotherapy had a benefit from chemotherapy (adjusted HR = 0.57, p = 0.018; adjusted HR = 0.51, p = 0.005, respectively). Regarding the molecular subtypes, a longer DFS with chemotherapy was observed both in luminal B-like (4-year DFS: 77.8 vs. 55.0%, HR = 0.51, 95% CI 0.27–0.99, log-rank p = 0.048) and in TNBC patients (4-year DFS: 61.9 vs. 42.8%, HR = 0.49, 95% CI 0.24–1.02, log-rank p = 0.056), but not in luminal A-like.Conclusions: The chemotherapy for iLRR of breast cancer should be individualized for each patient, considering DFI, prior chemotherapy, and molecular subtypes.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13000-e13000
Author(s):  
Ivonne Nel ◽  
Laura Weydandt ◽  
Annekathrin Höhn ◽  
Bahriye Aktas

e13000 Background: Despite successful treatment of the primary tumor, recurrence occurs in about 30% of breast cancer patients. One reason might be hematogenous spread during early disease stages. Disseminated breast cancer cells (DTCs) preferentially migrate into the bone marrow (BM) at early stages of the disease. Due to low proliferation, DTCs are persistent against systemic chemotherapy and might cause metastatic relapse at a later stage. Methods: BM aspirates were collected from the anterior iliac crest of patients with primary mamma carcinoma during surgery. After density gradient centrifugation cell suspensions were transferred onto glass slides and subjected to immunocytochemical staining against pan-cytokeratin. DTCs were visualized in pink using alkaline phosphatase and short counterstaining with hematoxylin which colored the nuclei light blue. DTCs were semi-automatically detected and enumerated using the Aperio Versa microscope based scanning system with a rare events algorithm that was trained to identify DTC candidates according to color, shape, intensity and size. As a positive control with each run, we used reference slides with a mix of bone marrow cells and a defined number of HCT116 cells. Results: Between February 2019 and December 2020 BM aspirates from 158 primary breast cancer patients were collected. Per patient about 4 million BM cells were analyzed. DTC detection revealed a positivity rate of 29% (46 patients). Molecular subtype analysis of DTC positive patients showed that 37% of the primary tumors (17 patients) were luminal A and 37% (17 patients) luminal B. In 9% of the cases (4 patients), tumors were HER2 enriched and 15% (8 patients) were triple negative. DTC count indicated that the majority of luminal B patients had 11-20 DTCs whereas luminal A patients tended to have lower DTC quantities varying between 1 and 10 DTCs. Conclusions: DTCs may serve as independent prognostic markers. Follow-Up data might reveal whether DTC quantification and molecular subtypes at primary diagnosis can be used to stratify patients at elevated risk for recurrence.


2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22165-e22165
Author(s):  
Joseph A. Pinto ◽  
Claudio J. Flores ◽  
Priscila I. Valdiviezo ◽  
Rodolfo Velazco ◽  
MIguel Garay ◽  
...  

e22165 Background: To evaluate toll-like receptors (TLRs1-9) and IRAK 1,3 and 4 expression in a breast cancer patients dataset that were treated with NAC as prognostic factors in terms of recurrence-free survival (RFS). Methods: Weretrieved normalized gene expression data from a public database (GEO: GSE25066) that includes 253 samples of breast cancer patients treated with NAC (antracyclines/taxanes) profiled with the U133A microarray. The median of RFS was 3.2 years (52 relapses observed). Distribution of molecular subtypes was: Luminal A (31.2%), Luminal B (17.4%), HER2 (7.1%), Basal (36.4%) and Normal (7.9%). We build a ratio of target gene/reference gen (ATCB) with to obtain replicable cut-points in other datasets. Levels of Gene expression were divided in three cut-points (Q1, Q2, and Q3). A cox-model was used to select gene expression cut-points with significant effects in the RFS. Results: According to molecular subtypes, there were significant differences in expression of TLR5 (higher in basal and Luminal A), TLR6 and IRAK1 (higher in basal and HER2). There were not differences of expression according to the pathologic response. The multivariate analysis shown that genes associated with the RFS were: TLR5 (HR=2.1 for the lower quartile), TLR6 (HR=2.4 for upper Q2), IRAK1 (HR=2.0 for upper quartile) and IRAK 3 (HR=2.2 for upper Q2). A TLR-Score was constructed (1 point added for each unfavorable gene-group). Cases were grouped in two categories (score 0-1 as good prognostic and score ≥ 2 as poor prognostic). There were and overall significant differences in both score-groups (poor prognostic: HR=4.9). In Basal and luminal B tumors there were significant differences (logrank test: P<0.001 and P=0.014, respectively), in HER2 tumors there were differences although not significant (P=0.143). There were not differences in Luminal A tumors. Conclusions: These data support the exploration of a TLR expression-based score to predict for RFS in breast cancer treated with NAC.


Breast Care ◽  
2016 ◽  
Vol 11 (4) ◽  
pp. 248-252 ◽  
Author(s):  
Muhammet A. Kaplan ◽  
Ulku Y. Arslan ◽  
Abdurrahman Işıkdogan ◽  
Faysal Dane ◽  
Berna Oksuzoglu ◽  
...  

Purpose: The aim of the study was to investigate the association between the molecular subtypes and patterns of relapse in breast cancer patients who had undergone curative surgery. Methods: We retrospectively evaluated 1,350 breast cancer patients with relapses after curative surgery between 1998 and 2012 from referral centers in Turkey. Patients were divided into 4 biological subtypes according to immunohistochemistry and grade: triple negative, HER2 overexpressing, luminal A and luminal B. Results: The percentages of patients with luminal A, luminal B, HER2-overexpressing, and triple-negative breast cancer were 32.9% (n = 444), 34.9% (n = 471), 12.0% (n = 162), and 20.2% (n = 273), respectively. The distribution of metastases differed among the subgroups: bone (66.2% and 53.9% in luminal A and B vs. 38.9% in HER2-overexpressing and 45.1% in triple negative, p < 0.001), liver (40.1% in HER2-overexpressing vs. 24.5% in luminal A, 33.5% in luminal B, and 27.5% in triple negative, p < 0.001), lung (41.4% in triple negative and 35.2% in HER2-overexpressing vs. 30.2% and 30.6% in luminal A and B, p = 0.008) and brain (25.3% in HER2-overexpressing and 23.1% in triple negative vs. 10.1% and 15.1% in luminal A and B, p < 0.001). Conclusions: Organ-specific metastasis may depend on the molecular subtype of breast cancer. Tailored strategies against distant metastasis concerning the molecular subtypes in breast cancer should be considered.


2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Dongning Shi ◽  
Junwen Bai ◽  
Yibo Chen ◽  
Xia Wang ◽  
Yafeng Zhang ◽  
...  

Background. To determinate the association relationship of breast cancer bone metastasis and cancer characteristics and molecular subtype. Furthermore, to evaluate the impact of molecular subtype on prevalence and prognosis of bone metastasis from the breast cancer base on a large population real-word program, the Surveillance, Epidemiology, and End Results (SEER) database. Methods. We collected and analyzed the data obtained from SEER, which showed molecular subtype information for each patient. The prevalence and outcome of bone metastasis in breast cancer were estimated as per the different molecular subtypes. Results. Occurrence of bone metastasis in conformity with four different molecular subtypes in all 42684 breast cancer patients was 6.2, 9.4, 7.9, and 6.4%, respectively. The most unfavorable subtype was the triple-negative breast cancer (TNBC), followed by the luminal A, luminal B, and HER2 subtypes (hazard ratio [HR] of luminal A compared with TNBC, 0.533, 95% confidence interval, 0.444–0.641; HR of luminal B, 0.482, 95% CI 0.419–0.555; HR of HER2 subtype, 0.542, 95% CI 0.484–0.608). Brain metastasis impacts overall survival (OS) ( p < 0.001 ) fundamentally, and visceral metastases also significantly decreased OS ( p < 0.001 ). Conclusion. Bone metastasis patients present a more favorable oncological survival consequence than other metastases, and the TNBC subtype with bone metastasis showed the poorest tumor outcome compared with the other three molecular subtypes.


2020 ◽  
Vol 19 (1) ◽  
pp. 55-58
Author(s):  
Shafatujjahan ◽  
Ifatujjahan ◽  
Rajat Sanker Roy Biswas

Introduction: Breast cancer is a common malignancy among female in Bangladesh.But its molecular subtypes are not evaluated due to lack of expert investigationsupport. So objectives of the present study are to evaluate the molecular subtypesof breast cancer patients according to St Gallen classification in our contest. Materials and methods: It is retrospective study done among histopathologicallyproved 40 breast cancer patients visiting Medical Oncology and Radiotherapydepartment of Chattogram Maa-O-Shishu Hospital. Molecular subtypes wasevaluated by immunohistochemistry according to St Gallen Classification. Results: In this study a total of 40 cases of invasive female breast cancers wereincluded. Age of the patients ranged from 31-62 years, with a mean age of 41 ±13.5 years. ER expression was seen in 60% and PR in 55% of cases and Her-2/neupositivity in 16%. Majority (52.5%) of the tumors were located in the left breast. Thepercentage of ER but not PR positivity increased with age, though this differencewas not statistically significant. Majority of the cases were diagnosed at stage IIwith a percentage of 42.5%. Stage II tumors showed more ER and PR positivity.Among all 57.9% of ER positive and 49.5% of PR positive tumors were present while72.2% of tumors were negative for Her-2/neu. The triple-negative breast tumorswere more commonly found at grade 2. Regarding luminal status 14(35%) wasLuminal A, 5(12.5%) was Luminal B, 9(22.5%) was TNBC and 12(30%) was HER 2positive. Conclusion: In this study luminal A was the commonest molecular subtypes. LuminalA subtypes tumors had a long term risk of distant matastatic disease which can bereduced by hormonal treatment. Chatt Maa Shi Hosp Med Coll J; Vol.19 (1); January 2020; Page 55-58


2021 ◽  
Vol 10 (18) ◽  
pp. 4071
Author(s):  
Megha Lal ◽  
Asgar Hussain Ansari ◽  
Anurag Agrawal ◽  
Arijit Mukhopadhyay

Introduction: Breast cancer is the most frequently diagnosed cancer globally and is one of the most important contributors to cancer-related deaths. Earlier diagnosis is known to reduce mortality, and better biomarkers are needed. MiRNA clusters often co-express and target mRNAs in a coordinated fashion, perturbing entire pathways; they thus merit further exploration for diagnostic or prognostic use. MiR-379/656, at chromosome 14q32, is the second largest miRNA cluster in the human genome and implicated in various malignancies including glioblastoma, melanoma, gastrointestinal tumors and ovarian cancer highlighting its potential importance. In this study, we focus on the diagnostic and prognostic potentials of MiR-379/656 in breast cancer and its molecular subtypes. Materials and Methods: We analyzed miRNA and mRNA next generation sequencing data from 903 primary tumors and 90 normal controls (source: The Cancer Genome Atlas). The differential expression profile between tumor and normal was analyzed using DeSEQ2. Penalized logistic regression modelling (lasso regression) was used to assess the predictive potential of MiR-379/656 expression for tumor and normal samples. The association between MiR-379/656 expression and overall patient survival was studied using Cox Proportional-Hazard Model. The target mRNAs (validated) of MiR-379/656 were annotated via pathway enrichment analysis to understand the biological significance of the cluster in breast cancer. Results: The differential expression analysis for 1390 miRNAs (miRnome) revealed 310 upregulated (22.3%) and 176 downregulated (12.66%) miRNAs in breast cancer patients compared with controls. For MiR-379/656, 32 miRNAs (32/42; 76%) were downregulated. The MiR-379/656 cluster was found to be the most differentially expressed cluster in the human genome (p < 10−30). The Basal and Luminal B subtypes showed at least 83% (35/42) of the miRNAs to be downregulated. The binomial model prioritized 15 miRNAs, which distinguished breast cancer patients from controls with 99.15 ± 0.58% sensitivity and 77.78 ± 5.24% specificity. Overall, the Basal and Luminal B showed the most effective predictive power with respect to the 15 prioritized miRNAs at MiR-379/656 cluster. The decreased expression of MiR-379/656 was found to be associated with poorer clinical outcome in Basal and Luminal B subtypes, increasing tumor stage and tumor size/extent, and overall patient survival. Pathway enrichment for the validated targets of MiR-379/656 was significant for cancer-related pathways, especially DNA repair, transcriptional regulation by p53 and cell cycle checkpoints (adjusted p-value < 0.05). Conclusions: Genome informatics analysis of high throughput data for MiR-379/656 cluster has shown that a subset of 15 miRNAs from MiR-379/656 cluster can be used for the diagnostic and prognostic purpose of breast cancer and its subtypes—especially in Basal and Luminal B.


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