The molecular landscape of Asian breast cancers reveals clinically relevant population-specific differences

AbstractMolecular profiling of breast cancer has enabled the development of more robust molecular prognostic signatures and therapeutic options for breast cancer patients. However, non-Caucasian populations remain understudied. Here, we present the mutational, transcriptional, and copy number profiles of 560 Malaysian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to breast tumours in Caucasian women, we show an increased prevalence of HER2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. We also observe elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst HER2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations.

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The Molecular Landscape of Asian Breast Cancers Reveals Clinically Relevant Population-Specific Differences

10.1101/2020.04.09.035055 ◽

2020 ◽

Cited By ~ 1

Author(s):

Jia-Wern Pan ◽

Muhammad Mamduh Ahmad Zabidi ◽

Pei-Sze Ng ◽

Mei-Yee Meng ◽

Siti Norhidayu Hasan ◽

...

Keyword(s):

Breast Cancer ◽

Large Scale ◽

Somatic Mutations ◽

Checkpoint Inhibitors ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Breast Tumours ◽

Different Populations ◽

Molecular Profiles ◽

Caucasian Women

ABSTRACTMolecular profiles of breast cancer have contributed to an improved understanding of the disease, enabled development of molecular prognostic signatures to guide treatment decisions and unveiled new or more accurate therapeutic options for breast cancer patients. However, the extent to which differences in genetic, environmental and lifestyle factors influence molecular profiles in different populations remains poorly characterised, as relatively few large-scale molecular studies of breast tumours in non-Caucasian populations have hitherto been reported. Here, we present the molecular profiles of 560 Asian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to the breast tumours in predominantly Caucasian women reported in TCGA and METABRIC, we show an increased prevalence of Her2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. Using gene expression and immunohistochemistry, we observed elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst Her2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil new opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations.

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Integrative Analyses of Multilevel Omics Reveal Preneoplastic Breast to Possess a Molecular Landscape That is Globally Shared with Invasive Basal-Like Breast Cancer

Cancers ◽

10.3390/cancers12030722 ◽

2020 ◽

Vol 12 (3) ◽

pp. 722 ◽

Cited By ~ 3

Author(s):

Zhenlin Ju ◽

Anjana Bhardwaj ◽

Matthew Embury ◽

Harpreet Singh ◽

Preethi Gunaratne ◽

...

Keyword(s):

Breast Cancer ◽

Ductal Carcinoma ◽

Disease Free Survival ◽

Direct Result ◽

Mcf10a Cell ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Genomic Changes ◽

Basal Like Breast Cancer ◽

Molecular Landscape

To characterize molecular changes accompanying the stepwise progression to breast cancer and to identify functional target pathways, we performed miRNA and RNA sequencing using MCF10A cell lines based model system that replicates the multi-step progression involving normal, preneoplastic, ductal carcinoma in situ, and invasive carcinoma cells, where the carcinoma most resemble the basal-like subgroup of human breast cancers. These analyses suggest that 70% of miRNA alterations occurred during the initial progression from normal to a preneoplastic stage. Most of these early changes reflected a global upregulation of miRNAs. This was consistent with a global increase in the miRNA-processing enzyme DICER, which was upregulated as a direct result of loss of miRNA let-7b-5p. Several oncogenic and tumor suppressor pathways were also found to change early, prior to histologic stigmata of cancer. Our finding that most genomic changes in the progression to basal-like breast cancer occurred in the earliest stages of histologic progression has implications for breast cancer prevention and selection of appropriate control tissues in molecular studies. Furthermore, in support of a functional significance of let-7b-5p loss, we found its low levels to predict poor disease-free survival and overall survival in breast cancer patients.

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Determining Factors in the Therapeutic Success of Checkpoint Immunotherapies against PD-L1 in Breast Cancer: A Focus on Epithelial-Mesenchymal Transition Activation

Journal of Immunology Research ◽

10.1155/2021/6668573 ◽

2021 ◽

Vol 2021 ◽

pp. 1-18

Author(s):

Mariana Segovia-Mendoza ◽

Susana Romero-Garcia ◽

Cristina Lemini ◽

Heriberto Prado-Garcia

Keyword(s):

Breast Cancer ◽

Epithelial Mesenchymal Transition ◽

Checkpoint Inhibitors ◽

Death Receptor ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Therapeutic Success ◽

Mesenchymal Transition ◽

Determining Factors ◽

Triple Negative Phenotype

Breast cancer is the most common neoplasm diagnosed in women around the world. Checkpoint inhibitors, targeting the programmed death receptor-1 or ligand-1 (PD-1/PD-L1) axis, have dramatically changed the outcome of cancer treatment. These therapies have been recently considered as alternatives for treatment of breast cancers, in particular those with the triple-negative phenotype (TNBC). A further understanding of the regulatory mechanisms of PD-L1 expression is required to increase the benefit of PD-L1/PD-1 checkpoint immunotherapy in breast cancer patients. In this review, we will compile the most recent studies evaluating PD-1/PD-L1 checkpoint inhibitors in breast cancer. We review factors that determine the therapeutic success of PD-1/PD-L1 immunotherapies in this pathology. In particular, we focus on pathways that interconnect the epithelial-mesenchymal transition (EMT) with regulation of PD-L1 expression. We also discuss the relationship between cellular metabolic pathways and PD-L1 expression that are involved in the promotion of resistance in TNBC.

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The Current Status and Future Prospects of Oncolytic Viruses in Clinical Trials against Melanoma, Glioma, Pancreatic, and Breast Cancers

Cancers ◽

10.3390/cancers10100356 ◽

2018 ◽

Vol 10 (10) ◽

pp. 356 ◽

Cited By ~ 45

Author(s):

Ibrahim Eissa ◽

Itzel Bustos-Villalobos ◽

Toru Ichinose ◽

Shigeru Matsumura ◽

Yoshinori Naoe ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Checkpoint Inhibitors ◽

Oncolytic Viruses ◽

Current Status ◽

European Medicines Agency ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Future Prospects ◽

Phase I Clinical Trials

Oncolytic viral therapy has been accepted as a standard immunotherapy since talimogene laherparepvec (T-VEC, Imlygic®) was approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for melanoma treatment in 2015. Various oncolytic viruses (OVs), such as HF10 (Canerpaturev—C-REV) and CVA21 (CAVATAK), are now actively being developed in phase II as monotherapies, or in combination with immune checkpoint inhibitors against melanoma. Moreover, in glioma, several OVs have clearly demonstrated both safety and a promising efficacy in the phase I clinical trials. Additionally, the safety of several OVs, such as pelareorep (Reolysin®), proved their safety and efficacy in combination with paclitaxel in breast cancer patients, but the outcomes of OVs as monotherapy against breast cancer have not provided a clear therapeutic strategy for OVs. The clinical trials of OVs against pancreatic cancer have not yet demonstrated efficacy as either monotherapy or as part of combination therapy. However, there are several oncolytic viruses that have successfully proved their efficacy in different preclinical models. In this review, we mainly focused on the oncolytic viruses that transitioned into clinical trials against melanoma, glioma, pancreatic, and breast cancers. Hence, we described the current status and future prospects of OVs clinical trials against melanoma, glioma, pancreatic, and breast cancers.

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Prognostic Role of Hedgehog-GLI1 Signaling Pathway in Aggressive and Metastatic Breast Cancers

Current Drug Metabolism ◽

10.2174/1389200221666200122120625 ◽

2020 ◽

Vol 21 (1) ◽

pp. 33-43 ◽

Cited By ~ 1

Author(s):

Prasuja Rokkam ◽

Shailender Gugalavath ◽

Deepak Kakara Gift Kumar ◽

Rahul Kumar Vempati ◽

Rama Rao Malla

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Neural Development ◽

Splice Variants ◽

Metastatic Breast ◽

Basic Function ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Aberrant Expression ◽

Cellular Processes

Glioma-associated oncogene homolog 1 (GLI1) is reported as an amplified gene in human glioblastoma cells. It is a krupple like transcription factor, belonging to the zinc finger family. The basic function of GLI1 is normal neural development at various stages of human. The GLI1 gene was first mapped on the chromosome sub-bands 12q13.3-14.1. Further, single nucleotide polymorphism is mostly observed in translating a region of 5’ and 3’- UTR of GLI1 gene in addition to two post-transcriptional splice variants, GLIΔN and tGLI. Additionally, it also regulates a plethora of gene which mediates crucial cellular processes like proliferation, differentiation, oncogenesis, EMT, and metastasis. It also regulates tumor tolerance, chemoresistance, and radioresistance. Aberrant expression of GLI1 predicts the poor survival of breast cancer patients. GLI1 is an essential mediator of the SHH signaling pathway regulating self-renewal of stem cells, angiogenesis, and expression of FOXS1, CYR61. GLI1 mediated HH pathway can induce apoptosis. Hence, GLI1 can be a future diagnostic, prognostic marker, and as well as a potent target of therapeutics in breast cancer.

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Iodine Map Radiomics in Breast Cancer: Prediction of Metastatic Status

Cancers ◽

10.3390/cancers13102431 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2431

Author(s):

Lukas Lenga ◽

Simon Bernatz ◽

Simon S. Martin ◽

Christian Booz ◽

Christine Solbach ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast ◽

Principal Component ◽

Validation Dataset ◽

Dual Energy Ct ◽

Cancer Tissue ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Iodine Map ◽

Iodine Maps

Dual-energy CT (DECT) iodine maps enable quantification of iodine concentrations as a marker for tissue vascularization. We investigated whether iodine map radiomic features derived from staging DECT enable prediction of breast cancer metastatic status, and whether textural differences exist between primary breast cancers and metastases. Seventy-seven treatment-naïve patients with biopsy-proven breast cancers were included retrospectively (41 non-metastatic, 36 metastatic). Radiomic features including first-, second-, and higher-order metrics as well as shape descriptors were extracted from volumes of interest on iodine maps. Following principal component analysis, a multilayer perceptron artificial neural network (MLP-NN) was used for classification (70% of cases for training, 30% validation). Histopathology served as reference standard. MLP-NN predicted metastatic status with AUCs of up to 0.94, and accuracies of up to 92.6 in the training and 82.6 in the validation datasets. The separation of primary tumor and metastatic tissue yielded AUCs of up to 0.87, with accuracies of up to 82.8 in the training, and 85.7 in the validation dataset. DECT iodine map-based radiomic signatures may therefore predict metastatic status in breast cancer patients. In addition, microstructural differences between primary and metastatic breast cancer tissue may be reflected by differences in DECT radiomic features.

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

The American Surgeon ◽

10.1177/0003134820984877 ◽

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.

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

Cancers ◽

10.3390/cancers12030636 ◽

2020 ◽

Vol 12 (3) ◽

pp. 636 ◽

Cited By ~ 10

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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The Pattern of Proline, Glutamic Acid, and Leucine-Rich Protein 1 Expression in Chinese Women with Primary Breast Cancer

The International Journal of Biological Markers ◽

10.5301/jbm.5000078 ◽

2014 ◽

Vol 29 (1) ◽

pp. e1-e7 ◽

Cited By ~ 1

Author(s):

Yanzhi Zhang ◽

Peng Wang ◽

Mumu Shi ◽

Hironobu Sasano ◽

Monica S.M. Chan ◽

...

Keyword(s):

Breast Cancer ◽

Glutamic Acid ◽

Primary Breast Cancer ◽

Chinese Women ◽

Cancer Prognosis ◽

Clinicopathological Parameters ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Ki 67 ◽

Her 2

Background Disparities of biomarkers’ expression in breast cancer across different races and ethnicities have been well documented. Proline, glutamic acid, and leucine-rich protein 1 (PELP1), a novel ER coregulator, has been considered as a promising biomarker of breast cancer prognosis; however, the pattern of PELP1 expression in Chinese women with breast cancer has never been investigated. This study aims to provide useful reference on possible racial or ethnic differences of PELP1 expression in breast cancer by exploring the pattern of PELP1 expression in Chinese women with primary breast cancer. Methods The expression of PELP1 in primary breast cancer samples from 130 Chinese female patients was detected by immunohistochemistry and correlated to other clinicopathological parameters; for comparison, the expression of PELP1 in 26 benign breast fibroadenomas was also examined. Results The overall value of the PELP1 H-score in breast cancer was significantly higher than that in breast fibroadenoma (p<0.001). In our breast cancer patients, the ER/HER-2-positive group had significantly higher PELP1 H-scores than their negative counterparts (p=0.003 for ER and p=0.022 for HER-2); the Ki-67-high group also showed significantly higher PELP1 H-scores than the Ki-67-low group (p=0.008). No significant association between PELP1 H-scores and other clinicopathological parameters was found. Finally, the PELP1 H-score in breast cancers of the luminal B subtype was significantly higher than that in the triple negative subtype (p=0.002). Conclusion Overexpression of PELP1 in Chinese women with primary breast cancer appears to be associated with biomarkers of poor outcome; these results are similar to other reports based on Western populations.

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Predominance of RAD21 and ERBB2 amplification and progesterone receptor positivity in tumors of the right breast support breast cancer lateralization.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e12557 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e12557-e12557

Author(s):

Zachary Spigelman ◽

Jo-Ellen Murphy

Keyword(s):

Breast Cancer ◽

Progesterone Receptor ◽

Cancer Patients ◽

Breast Tumors ◽

Left Breast ◽

Breast Cancers ◽

Her2 Expression ◽

Breast Cancer Patients ◽

The Right ◽

Chi Square Analysis

e12557 Background: Biologic lateralization broadly impacts breast cancer. Malignancies originating in the left breast compared to the right breast tend to be more frequent, larger and of poorer prognosis. Left breast tumors respond differently to HER2-neu signaling and have lateralized Ki67 expression. In a prior study a right-left asymmetry in the neutrophil/lymphocyte ratio (NLR) of breast cancers was identified (ASCO 2018, e13094). As a follow-up, retrospective analysis of results from comprehensive genomic profiling (CGP) of right and left side breast cancer specimens was performed to determine a potential genomic etiology for the observed NLR lateralization. Methods: Tumors from 43 consecutive breast cancer patients underwent analysis for all classes of genomic alterations by hybrid capture-based CGP (Foundation Medicine). The CGP results from the 25 left- and 18 right-sided breast cancer samples were analyzed along with the histologic grade and status of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression. Results: In this cohort of advanced breast cancer patients (stage 3-4), no statistically significant differences in lateralization were identified based on patient age, tumor stage, or frequency of ER or Her2 expression (Table). A predominance of PR positivity (p=0.14 chi square analysis) and amplifications in the ERBB2 (p=0.37) and RAD21 (p=0.08) genes were detected in right side tumors. Conclusions: Together with the prior study, trends in asymmetry based on genomic, pathologic, and immunohistologic differences have been detected in breast cancers, including an increased incidence of ERBB2 and RAD21 amplification in right-side breast tumors in this cohort. The predominance of lower PR positivity in the left breast tumors may be due to preferential hypermethylation, consistent with reports that it mediates biologic lateralization changes, downregulates PR expression, and alters amplification rates. Epigenetic methylation, may contribute to asymmetric breast cancer biology and have implications for therapeutic strategy. Further study is warranted.[Table: see text]

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