Variability in metabolic cross-feeding behaviors in breast cancer and response to neoadjuvant chemotherapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12645-e12645
Author(s):  
Joseph R Peterson ◽  
John A Cole ◽  
Tyler M Earnest ◽  
Micahel J Hallock ◽  
Tushar Pandey ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Density Lipoprotein ◽  
In Silico Analysis ◽  
Primary Energy ◽  
Intrinsic Subtype ◽  
Breast Cancers ◽  
Luminal A ◽  
Feeding Behaviors ◽  
Cancer Subtypes

e12645 Background: Success of neoadjuvant chemotherapy (NACT) varies by intrinsic subtype of a patient’s breast cancer (e.g., Normal-like, Luminal A/B, HER2-enriched, Triple Negative). The metabolic rate of a given tumor is implicated in response to chemotherapies, as many act by killing rapidly dividing cells. Metabolic dis-regulation opens avenues for cancer cells to exploit environmental niches arising in the tumor microenvironment (TME). Focusing on the role the TME plays in defining cancer behavior, we undertook a theoretical investigation to uncover how metabolic cross-feeding affects subtype behavior and patient response. Methods: An in silico analysis of cross-feeding variability arising from metabolic differences breast cancers was undertaken. TME community models consisting of fatty, glandular, and cancerous tissues’ metabolic behaviors were created. Expression levels of metabolic enzymes for 1222 community patients in TCGA BRCA were used to create models. Models were used in 3D simulations of tumors for 300 patients from the TCIA (Clark et al., J. Digital Imaging, 2013). Cross-feeding trends within each intrinsic subtype were analyzed. Results: Predicted TME metabolic capabilities were compared to literature: LA/LB had lower amino acid consumption than TNBC/HER2+ for asparagine, glutamine (Glu), tryptophan, phenylalanine (van Geldermolsen et al. Oncogone 2016; Furuya et al. Cancer Sci. 2012). Additionally, TNBC tumors produced Glu which was consumed by adipose tissue ( Cao et al. BMC Cancer, 2014), TNBC produced methionine and proline (Kanaan et al. Can. Gen. Prot. 2014), and TNBC/HER2+ cancers consumed high density lipoprotein produced by adipose (Balabum et al. Cancer Met. 2017). The simulations revealed novel cross-feeding behaviors. In general, TNBC/HER2+ relied on glucose as the primary energy source, while LA/LB relied on the amino acids alanine, glycine and Glu. TNBC/HER2+ cancers produced high levels of lactate which was consumed by adipose tissues. Uniquely, glycine produced by cancer was consumed by fat in TNBC cancers Several environmental niches were induced in the healthy tissue by the presence of the cancer; for example, ornithine was predicted to be cross-fed from fatty to glandular tissues in TNBC/HER2+ cancers, and glutamate and inosine from glandular to fatty tissues in HER2+ cancers. Conclusions: Metabolic niches provide opportunities for cancer subtypes. These results suggest that metabolic pathway usage can lead to difference in growth, cross-feeding, and drug efficacy.

scholarly journals Genomic Signatures in Luminal Breast Cancer

Breast Care ◽  
2020 ◽  
Vol 15 (4) ◽  
pp. 355-365
Author(s):  
Julian Puppe ◽  
Tabea Seifert ◽  
Christian Eichler ◽  
Henryk Pilch ◽  
Peter Mallmann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Throughput Sequencing ◽  
Early Stage ◽  
Intrinsic Subtype ◽  
Luminal Breast Cancer ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Cancer Subtypes ◽  
Molecular Tests ◽  
Immunohistochemical Markers

Background: Breast cancer is a very heterogeneous disease and luminal breast carcinomas represent the hormone receptor-positive tumors among all breast cancer subtypes. In this context, multigene signatures were developed to gain further prognostic and predictive information beyond clinical parameters and traditional immunohistochemical markers. Summary: For early breast cancer patients these molecular tools can guide clinicians to decide on the extension of endocrine therapy to avoid over- and undertreatment by adjuvant chemotherapy. Beside the predictive and prognostic value, a few genomic tests are also able to provide intrinsic subtype classification. In this review, we compare the most frequently used and commercially available molecular tests (OncotypeDX®, MammaPrint®, Prosigna®, EndoPredict®, and Breast Cancer IndexSM). Moreover, we discuss the clinical utility of molecular profiling for advanced breast cancer of the luminal subtype. Key Messages: Multigene assays can help to de-escalate systemic therapy in early-stage breast cancer. Only the Oncotype DX® and MammaPrint®test are validated by entirely prospective and randomized phase 3 trials. More clinical evidence is needed to support the use of genomic tests in node-positive disease. Recent developments in high-throughput sequencing technology will provide further insights to understand the heterogeneity of luminal breast cancers in early-stage and metastatic disease.

scholarly journals Identification of Long Noncoding RNAs as Predictors of Survival in Triple-Negative Breast Cancer Based on Network Analysis

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Xiao-Xiao Li ◽  
Li-Juan Wang ◽  
Jie Hou ◽  
Hong-Yang Liu ◽  
Rui Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Network Analysis ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Breast Cancers ◽  
Luminal A ◽  
Her2 Positive ◽  
Cancer Subtypes

Breast cancer is the most common cancer observed in adult females, worldwide. Due to the heterogeneity and varied molecular subtypes of breast cancer, the molecular mechanisms underlying carcinogenesis in different subtypes of breast cancer are distinct. Recently, long noncoding RNAs (lncRNAs) have been shown to be oncogenic or play important roles in cancer suppression and are used as biomarkers for diagnosis and therapy. In this study, we identified 134 lncRNAs and 6,414 coding genes were differentially expressed in triple-negative (TN), human epidermal growth factor receptor 2- (HER2-) positive, luminal A-positive, and luminal B-positive breast cancer. Of these, 37 lncRNAs were found to be dysregulated in all four subtypes of breast cancers. Subtypes of breast cancer special modules and lncRNA-mRNA interaction networks were constructed through weighted gene coexpression network analysis (WGCNA). Survival analysis of another public datasets was used to verify the identified lncRNAs exhibiting potential indicative roles in TN prognosis. Results from heat map analysis of the identified lncRNAs revealed that five blocks were significantly displayed. High expressions of lncRNAs, including LINC00911, CSMD2-AS1, LINC01192, SNHG19, DSCAM-AS1, PCAT4, ACVR28-AS1, and CNTFR-AS1, and low expressions of THAP9-AS1, MALAT1, TUG1, CAHM, FAM2011, NNT-AS1, COX10-AS1, and RPARP-AS1 were associated with low survival possibility in TN breast cancers. This study provides novel lncRNAs as potential biomarkers for the therapeutic and prognostic classification of different breast cancer subtypes.

Response to neoadjuvant chemotherapy and outcome based on breast cancer subtype

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e11516-e11516
Author(s):  
A. Guerrero-Zotano ◽  
J. Gavila ◽  
M. A. Climent ◽  
M. J. Juan ◽  
V. Guillem ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Breast Cancer Subtypes ◽  
Nuclear Staining ◽  
Luminal A ◽  
Long Term Outcome ◽  
Cancer Subtypes ◽  
Luminal B ◽  
Her 2

e11516 Background: Gene expression profiling identifies several breast cancer subtypes with different chemosensitivity and outcome. We used immunohistochemistry surrogate markers to classify tumors according to known breast cancer subtypes and examined the relationship between neoadjuvant chemotherapy (NAC) response and long-term end points, including distant disease-free survival (DDFS) and overall survival (OS). Methods: Review of clinical and pathological data from 271 breast cancer patients treated in our institution with NAC between 1991–2008. Breast cancer subtypes were defined as follows: Luminal A: Estrogen receptor positive (ER+) and/or progesterone peceptor positive (PR+), human epidermal growth factor receptor 2-positive (Her-2+); Luminal B: ER+ and/or PR+,Her-2+; Basal: ER-,PR-,Her-2-;HER2: ER-,PR-,Her-2 +. ER and PR positive scored as positive if tumor cell nuclear staining was at least 2+. Her-2 scored as positive if test DAKO scored 3+ or FISH ratio Her-2/CEP-17>2.2. Results: 121 (45.8%) patients were classifed as Luminal A; 22 (8.1%) as Luminal B; 75 (27.7%) as Basal, and 50 (18.5%) as HER2. Most patients (63%) received NAC based on anthracyclines and taxanes. 36% Her-2+ patients were treated with NAC based on trastuzumab, and 43% received trastuzumab as adjuvant treatment. Response and outcome results are shown below (Table). Independently from subtype, only four patients out of 58 with pCR relapsed. Among patients who didn´t achieved pathologic complete response (pCR), basal and HER2 subtypes have the worst outcome (4 years SG 80% and 72% respectevely) compared with Luminal A (4 years SG: 94.7%), (log-rank p=0.009). Conclusions: Basal and HER2 tumor despite high chemosensitivity have worst long term outcome, particularly if pCR is not achieved after NAC. [Table: see text] No significant financial relationships to disclose.

scholarly journals Evaluation of FGFR targeting in breast cancer through interrogation of patient-derived models

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Nicole J. Chew ◽  
Terry C. C. Lim Kam Sian ◽  
Elizabeth V. Nguyen ◽  
Sung-Young Shin ◽  
Jessica Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Therapeutic Target ◽  
Breast Cancer Subtype ◽  
Breast Cancer Subtypes ◽  
Cancer Tissue ◽  
Breast Cancers ◽  
Luminal A ◽  
Tissue Samples ◽  
Cancer Subtypes ◽  
Luminal B

Abstract Background Particular breast cancer subtypes pose a clinical challenge due to limited targeted therapeutic options and/or poor responses to the existing targeted therapies. While cell lines provide useful pre-clinical models, patient-derived xenografts (PDX) and organoids (PDO) provide significant advantages, including maintenance of genetic and phenotypic heterogeneity, 3D architecture and for PDX, tumor–stroma interactions. In this study, we applied an integrated multi-omic approach across panels of breast cancer PDXs and PDOs in order to identify candidate therapeutic targets, with a major focus on specific FGFRs. Methods MS-based phosphoproteomics, RNAseq, WES and Western blotting were used to characterize aberrantly activated protein kinases and effects of specific FGFR inhibitors. PDX and PDO were treated with the selective tyrosine kinase inhibitors AZD4547 (FGFR1-3) and BLU9931 (FGFR4). FGFR4 expression in cancer tissue samples and PDOs was assessed by immunohistochemistry. METABRIC and TCGA datasets were interrogated to identify specific FGFR alterations and their association with breast cancer subtype and patient survival. Results Phosphoproteomic profiling across 18 triple-negative breast cancers (TNBC) and 1 luminal B PDX revealed considerable heterogeneity in kinase activation, but 1/3 of PDX exhibited enhanced phosphorylation of FGFR1, FGFR2 or FGFR4. One TNBC PDX with high FGFR2 activation was exquisitely sensitive to AZD4547. Integrated ‘omic analysis revealed a novel FGFR2-SKI fusion that comprised the majority of FGFR2 joined to the C-terminal region of SKI containing the coiled-coil domains. High FGFR4 phosphorylation characterized a luminal B PDX model and treatment with BLU9931 significantly decreased tumor growth. Phosphoproteomic and transcriptomic analyses confirmed on-target action of the two anti-FGFR drugs and also revealed novel effects on the spliceosome, metabolism and extracellular matrix (AZD4547) and RIG-I-like and NOD-like receptor signaling (BLU9931). Interrogation of public datasets revealed FGFR2 amplification, fusion or mutation in TNBC and other breast cancer subtypes, while FGFR4 overexpression and amplification occurred in all breast cancer subtypes and were associated with poor prognosis. Characterization of a PDO panel identified a luminal A PDO with high FGFR4 expression that was sensitive to BLU9931 treatment, further highlighting FGFR4 as a potential therapeutic target. Conclusions This work highlights how patient-derived models of human breast cancer provide powerful platforms for therapeutic target identification and analysis of drug action, and also the potential of specific FGFRs, including FGFR4, as targets for precision treatment.

scholarly journals Circadian Oscillations Persist in Low Malignancy Breast Cancer Cells

2019 ◽  
Author(s):  
Sujeewa S. Lellupitiyage Don ◽  
Hui-Hsien Lin ◽  
Jessica J. Furtado ◽  
Maan Qraitem ◽  
Stephanie R. Taylor ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Circadian Rhythms ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Clock Genes ◽  
Luciferase Reporter ◽  
Low Grade ◽  
Breast Cancers ◽  
Luminal A ◽  
Cancer Subtypes

AbstractEpidemiological studies have shown that humans with altered circadian rhythms have higher cancer incidence, with breast cancer being one of the most cited examples. To uncover how circadian disruptions may be correlated with breast cancer and its development, prior studies have assessed the expression of BMAL1 and PER2 core clock genes via RT-qPCR and western blot analyses. These and our own low-resolution data show that BMAL1 and PER2 expression are suppressed and arrhythmic. We hypothesized that oscillations persist in breast cancer cells, but due to limitations of protocols utilized, cannot be observed. This is especially true where dynamic changes may be subtle. In the present work, we generated luciferase reporter cell lines representing high- and low-grade breast cancers to assess circadian rhythms. We tracked signals for BMAL1 and PER2 to determine whether and to what extent oscillations exist and provide initial correlations of circadian rhythm alterations with breast cancer aggression. In contrast to previous studies, where the clock was deemed to be “broken” in breast cancer, our luminometry data reveal that circadian oscillations of BMAL1 and PER2 do in fact exist in the low-grade, luminal A cell line, MCF7 but are not apparent in high-grade, basal MDA-MB-231 cells. To our knowledge, this is the first evidence of core circadian clock oscillations in breast cancer cells. This work also suggests that circadian rhythms are increasingly disrupted with breast cancer tumor grade/aggressiveness, and that use of real time luminometry to study additional representatives of breast and other cancer subtypes is highly merited.

scholarly journals Quantitative Mammographic Density Measurements and Molecular Subtypes in Chinese Women with Breast Cancer

2020 ◽  
Author(s):  
Yuan Tian ◽  
Jennifer L Guida ◽  
Hela Koka ◽  
Er-Ni Li ◽  
Bin Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Mammographic Density ◽  
Chinese Women ◽  
Statistical Tests ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Luminal A ◽  
Cancer Subtypes ◽  
Luminal B

Abstract Background Studies investigating associations between mammographic density (MD) and breast cancer subtypes have generated mixed results. We previously showed that having extremely dense breasts was associated with the HER2-enriched subtype in Chinese breast cancer patients. Methods In this study, we re-evaluated the MD-subtype association in 1,549 Chinese breast cancer patients, using VolparaDensity software to obtain quantitative MD measures. All statistical tests were two-sided. Results Compared to women with luminal A tumors, women with luminal B/HER2- (odds ratio [OR]=1.20, 95% confidence interval [CI]: 1.04-1.38, p = 0.01), luminal B/HER2 + (OR = 1.22, 95% CI: 1.03-1.46, p = 0.03), and HER2-enriched tumors (OR = 1.30, 95% CI: 1.06-1.59, p = 0.01) had higher fibroglandular dense volume. These associations were stronger in patients with smaller tumors (<2cm). In contrast, the triple negative subtype was associated with lower non-dense volume (OR = 0.82, 95% CI: 0.68-0.99, p = 0.04), and the association was only seen among older women (>50 years old). Conclusion Although biological mechanisms remain to be investigated, the associations for the HER2-enriched and luminal B subtypes with increasing MD may partially explain the higher prevalence of luminal B and HER2+ breast cancers previously reported in Asian women.

In situ Imaging for Multiplex Tumor Microbiome Interactions via Imaging Mass Cytometry on Single-Cell Level

2021 ◽  
Author(s):  
Zijian Feng ◽  
Xianting Ding ◽  
Guangxia Shen ◽  
Yuli Hu ◽  
Xin Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gram Negative Bacteria ◽  
Breast Cancers ◽  
Cell Level ◽  
Luminal A ◽  
Gram Negative ◽  
Cancer Subtypes ◽  
Luminal B ◽  
Gram Positive Bacteria

Abstract Background: Co-detection of multiplex cancer subtypes and bacteria subtypes in situ is crucial for understanding tumor microbiome interactions in tumor microenvironment. Current standard techniques such as immunohistochemical staining and immunofluorescence staining are limited for their multiplicity. Simultaneously visualizing detailed cell subtypes and bacteria distribution across the same pathological section remains a major technical challenge. Results: Herein, we developed a rapid semi-quantitative method for in situ imaging of bacteria and multiplex cell phenotypes on the same solid tumor tissue sections. We designed a panel of antibody probes labeled with mass tags, namely prokaryotic and eukaryotic cell hybrid probes for in situ imaging (PEHPSI). For application demonstration, PEHPSI stained two bacteria subtypes (lipopolysaccharides (LPS) for Gram-negative bacteria and lipoteichoic acid (LTA) for Gram-positive bacteria) simultaneously with four types of immune cells (leukocytes, CD8+T-cells, B-cells and macrophages) and four breast cancer subtypes (classified by a panel of 12 human proteins) on the same tissue section. Conclusions: We unveiled that breast cancer cells are commonly enriched with Gram-negative bacteria and almost absent of Gram-positive bacteria, regardless of the cancer subtypes (triple-negative breast cancer (TNBC), HER2+, Luminal A and Luminal B). Further analysis revealed that on the single-cell level, Gram-negative bacteria have a significant correlation with CD8+T-cells only in HER2+ breast cancer, while PKCD, ER, PR and Ki67 are correlated with Gram-negative bacteria in the other three subtypes of breast cancers. On the cell population level, in TNBC, CD19 expression intensity is up-regulated by approximately 25% in bacteria-enriched cells, while for HER2+, Luminal A and Luminal B breast cancers, the intensity of biomarkers associated with the malignancy, metastasis and proliferation of cancer cells (PKCD, ISG15 and IFI6) is down-regulated by 29-38%. The flexible and expandable PEHPSI system permits intuitive multiplex co-visualization of bacteria and mammalian cells, which facilitates future research on tumor microbiome and tumor pathogenesis.

Is There a Bias Against Obese Patients in the Treatment of Breast Cancer?

2020 ◽  
pp. 000313482098487
Author(s):  
Melinda Wang ◽  
Julian Huang ◽  
Anees B. Chagpar
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Patients ◽  
Prophylactic Mastectomy ◽  
Implicit Bias ◽  
Treatment Decision ◽  
Obese Patients ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Immediate Reconstruction

Background Patient and tumor characteristics often coincide with obesity, potentially affecting treatment decision-making in obese breast cancer patients. Independent of all of these factors, however, it is unclear whether obesity itself impacts the decision to offer patients undergoing mastectomy breast reconstruction, postmastectomy radiation therapy (PMRT), or neoadjuvant chemotherapy. We sought to determine whether implicit bias against obese breast cancer patients undergoing mastectomy plays a role in their treatment. Methods Medical records of breast cancer patients undergoing mastectomy from January 2010 to April 2018 from a single institution were retrospectively reviewed, separated into obese (BMI ≥30) and nonobese (BMI <30) categories, and compared using nonparametric statistical analyses. Results Of 972 patients, 291 (31.2%) were obese. Obese patients were more likely to have node-positive, triple-negative breast cancers ( P = .026) and were also more likely to have other comorbidities such as a history of smoking ( P = .026), hypertension ( P < .001), and diabetes ( P < .001). Receipt of immediate reconstruction and contralateral prophylactic mastectomy did not vary between obese and nonobese patients. While obese patients were more likely to undergo neoadjuvant chemotherapy (26.5% vs. 18.1%, P = .004) and PMRT (33.0% vs. 23.4%, P = .003), this did not remain significant when controlling for comorbidities and clinicopathologic confounders. Conclusion Obese patients present with more aggressive tumors and often have concomitant comorbidities. Independent of these factors, however, differences in the treatment of patients undergoing mastectomy do not seem to be affected by an implicit bias against obese patients.

Recent progress in immunotherapy of breast cancer targeting the human epidermal growth factor receptor 2 (HER2)

2021 ◽  
pp. 107815522199163
Author(s):  
Homa Seyedmirzaei ◽  
Mahsa Keshavarz-Fathi ◽  
Sepideh Razi ◽  
Masoumeh Gity ◽  
Nima Rezaei
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
New Drugs ◽  
Breast Cancers ◽  
Cancer Subtypes ◽  
Drug Conjugates ◽  
Heavy Burden ◽  
Epidermal Growth

Objective Breast cancer is responsible for most of the cancer-induced deaths in women around the world. The current review will discuss different approaches of targeting HER2, an epidermal growth factor overexpressed in 30% of breast cancer cases. Data sources We conducted a search on Pubmed and Scopus databases to find studies relevant to HER2+ breast cancers and targeting HER2 as means of immunotherapy. Out of 1043 articles, 105 studies were included in this review. Data summary As well as the introduction of HER2 and breast cancer subtypes, we discussed various aspects of HER2-targeting immunotherapy including monoclonal antibodies, Antibody-drug conjugates (ADCs), Chimeric Antigen Receptor (CAR) T-cells and vaccines. Conclusions Despite several ways of controlling breast cancer, the need to investigate new drugs and approaches seems to be much significant as this cancer still has a heavy burden on people’s health and survival.

scholarly journals Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 636 ◽  
Author(s):  
Regina Padmanabhan ◽  
Hadeel Shafeeq Kheraldine ◽  
Nader Meskin ◽  
Semir Vranic ◽  
Ala-Eddin Al Moustafa
Keyword(s):  
Breast Cancer ◽  
Mathematical Models ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Breast Cancers ◽  
Treatment Protocols ◽  
Cancer Subtypes ◽  
Cancer Management ◽  
Her2 Breast Cancer ◽  
Programmed Death

Breast cancer is one of the major causes of mortality in women worldwide. The most aggressive breast cancer subtypes are human epidermal growth factor receptor-positive (HER2+) and triple-negative breast cancers. Therapies targeting HER2 receptors have significantly improved HER2+ breast cancer patient outcomes. However, several recent studies have pointed out the deficiency of existing treatment protocols in combatting disease relapse and improving response rates to treatment. Overriding the inherent actions of the immune system to detect and annihilate cancer via the immune checkpoint pathways is one of the important hallmarks of cancer. Thus, restoration of these pathways by various means of immunomodulation has shown beneficial effects in the management of various types of cancers, including breast. We herein review the recent progress in the management of HER2+ breast cancer via HER2-targeted therapies, and its association with the programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) axis. In order to link research in the areas of medicine and mathematics and point out specific opportunities for providing efficient theoretical analysis related to HER2+ breast cancer management, we also review mathematical models pertaining to the dynamics of HER2+ breast cancer and immune checkpoint inhibitors.

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