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The Molecular Predictive and Prognostic Biomarkers in Breast Cancer
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The Molecular Predictive and Prognostic Biomarkers in Breast Cancer

A topical collection in Cancers (ISSN 2072-6694). This collection belongs to the section "Cancer Biomarkers".

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Editors

Prof. Dr. Daniele Generali

E-Mail Website
Guest Editor
Department of Medical, Surgery and Health Sciences, University of Trieste, Piazza Ospitale 1, 34129 Trieste, Italy
Interests: breast cancer; molecular oncology
Special Issues, Collections and Topics in MDPI journals
Dr. Ida Paris

E-Mail Website
Guest Editor
Department of Woman's and Child Health and Public Health Sciences, Gynecologic Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
Interests: breast cancer; precision medicine; targeted therapy
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues, 

Personalized oncology depends on the effects of germline and somatic differences on the way cancer patients respond to treatments. Routinely, through the genomic profiling of the tumors, the molecular signature would help clinicians in providing information relevant for personalization of the therapeutical program. Moreover, due to the molecular approaches, the interception of prognostic and/or predictive biomarkers would support the optimization of cancer diagnosis and the address of therapy decisions for any single patients, with a higher probability of responding or not to a specific treatment.

Several biomarkers are currently widely employed in breast cancers: from the routine pathology test of ER, PgR, Ki67 and HER2 to the new molecular tools as the status of BRCA 1 and 2, Pi3KCa, etc.

This review would provide an update of the known molecular or the potential new biomarkers in breast cancers that are or might be used in the evaluation of the benefits that can be achieved through targeted therapy or in the evaluation of toxic effects of treatments used in cancer patients.

Prof. Dr. Daniele Generali
Dr. Ida Paris
Guest Editors

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Keywords

  • biomarkers
  • immuno-related markers
  • BRCA
  • mutation
  • genomic signature
  • pharmacogenomics
  • NGS

Published Papers (22 papers)

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2023

Jump to: 2022

13 pages, 701 KiB  
Article
The Contribution of Germline Pathogenic Variants in Breast Cancer Genes to Contralateral Breast Cancer Risk in BRCA1/BRCA2/PALB2-Negative Women
by Alexey Larionov, Eleanor Fewings, James Redman, Mae Goldgraben, Graeme Clark, John Boice, Patrick Concannon, Jonine Bernstein, David V. Conti, the WECARE Study Collaborative Group and Marc Tischkowitz
Cancers 2023, 15(2), 415; https://doi.org/10.3390/cancers15020415 - 8 Jan 2023
Viewed by 2013
Abstract
Background: Contralateral breast cancer (CBC) is associated with younger age at first diagnosis, family history and pathogenic germline variants (PGVs) in genes such as BRCA1, BRCA2 and PALB2. However, data regarding genetic factors predisposing to CBC among younger women who are BRCA1/2/PALB2-negative [...] Read more.
Background: Contralateral breast cancer (CBC) is associated with younger age at first diagnosis, family history and pathogenic germline variants (PGVs) in genes such as BRCA1, BRCA2 and PALB2. However, data regarding genetic factors predisposing to CBC among younger women who are BRCA1/2/PALB2-negative remain limited. Methods: In this nested case-control study, participants negative for BRCA1/2/PALB2 PGVs were selected from the WECARE Study. The burden of PGVs in established breast cancer risk genes was compared in 357 cases with CBC and 366 matched controls with unilateral breast cancer (UBC). The samples were sequenced in two phases. Whole exome sequencing was used in Group 1, 162 CBC and 172 UBC (mean age at diagnosis: 42 years). A targeted panel of genes was used in Group 2, 195 CBC and 194 UBC (mean age at diagnosis: 50 years). Comparisons of PGVs burdens between CBC and UBC were made in these groups, and additional stratified sub-analysis was performed within each group according to the age at diagnosis and the time from first breast cancer (BC). Results: The PGVs burden in Group 1 was significantly higher in CBC than in UBC (p = 0.002, OR = 2.5, 95CI: 1.2–5.6), driven mainly by variants in CHEK2 and ATM. The proportions of PGVs carriers in CBC and UBC in this group were 14.8% and 5.8%, respectively. There was no significant difference in PGVs burden between CBC and UBC in Group 2 (p = 0.4, OR = 1.4, 95CI: 0.7–2.8), with proportions of carriers being 8.7% and 8.2%, respectively. There was a significant association of PGVs in CBC with younger age. Metanalysis combining both groups confirmed the significant association between the burden of PGVs and the risk of CBC (p = 0.006) with the significance driven by the younger cases (Group 1). Conclusion: In younger BRCA1/BRCA2/PALB2-negative women, the aggregated burden of PGVs in breast cancer risk genes was associated with the increased risk of CBC and was inversely proportional to the age at onset. Full article
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18 pages, 3106 KiB  
Article
Transcriptomic Analysis of Subtype-Specific Tyrosine Kinases as Triple Negative Breast Cancer Biomarkers
by Praopim Limsakul, Pongsakorn Choochuen, Gorn Charupanit and Krit Charupanit
Cancers 2023, 15(2), 403; https://doi.org/10.3390/cancers15020403 - 7 Jan 2023
Cited by 3 | Viewed by 1911
Abstract
Triple negative breast cancer (TNBC) shows impediment to the development of targeted therapies due to the absence of specific molecular targets. The high heterogeneity across TNBC subtypes, which can be classified to be at least four subtypes, including two basal-like (BL1, BL2), a [...] Read more.
Triple negative breast cancer (TNBC) shows impediment to the development of targeted therapies due to the absence of specific molecular targets. The high heterogeneity across TNBC subtypes, which can be classified to be at least four subtypes, including two basal-like (BL1, BL2), a mesenchymal (M), and a luminal androgen receptor (LAR) subtype, limits the response to cancer therapies. Despite many attempts to identify TNBC biomarkers, there are currently no effective targeted therapies against this malignancy. In this study, thus, we identified the potential tyrosine kinase (TK) genes that are uniquely expressed in each TNBC subtype, since TKs have been typically used as drug targets. Differentially expressed TK genes were analyzed from The Cancer Genome Atlas (TCGA) database and were confirmed with the other datasets of both TNBC patients and cell lines. The results revealed that each TNBC subtype expressed distinct TK genes that were specific to the TNBC subtype. The identified subtype-specific TK genes of BL1, BL2, M, and LAR are LYN, CSF1R, FGRF2, and SRMS, respectively. These findings could serve as a potential biomarker of specific TNBC subtypes, which could lead to an effective treatment for TNBC patients. Full article
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2022

Jump to: 2023

11 pages, 661 KiB  
Review
Controversies and Opportunities in the Clinical Daily Use of the 21-Gene Assay for Prognostication and Prediction of Chemotherapy Benefit in HR+/HER2- Early Breast Cancer
by Flavia Jacobs, Mariangela Gaudio, Chiara Benvenuti, Rita De Sanctis, Armando Santoro and Alberto Zambelli
Cancers 2023, 15(1), 148; https://doi.org/10.3390/cancers15010148 - 27 Dec 2022
Cited by 3 | Viewed by 2449
Abstract
Several multigene assays have been developed to help clinicians in defining adjuvant treatment for patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor-2 (HER2)–negative early breast cancer. Despite the 21-gene assay having been available for decades, it has only recently been included in [...] Read more.
Several multigene assays have been developed to help clinicians in defining adjuvant treatment for patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor-2 (HER2)–negative early breast cancer. Despite the 21-gene assay having been available for decades, it has only recently been included in the healthcare systems of several countries. Clinical optimisation of the test remains of critical interest to achieve a greater impact of genomic information in HR+/HER2- early breast cancer. Although current guidelines recommend the use of the 21-gene assay in early breast cancer at intermediate risk of relapse, the implication of the Recurrence Score (RS) in some grey areas still remains uncertain. Our aim is to critically discuss the role of RS in peculiar circumstances. In particular, we focus on the complex integration of genomic data with clinicopathological factors; the potential clinical impact of RS in node-positive premenopausal women and in the neoadjuvant setting; the significance of RS in special histologies and in male patients; and the management and time-optimisation of test ordering. In the absence of robust evidence in these areas, we provide perspectives for improving the use of the 21-gene assay in the decision-making process and guide adjuvant treatment decisions even in challenging cases. Full article
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23 pages, 1488 KiB  
Review
Potential Impact of Preoperative Circulating Biomarkers on Individual Escalating/de-Escalating Strategies in Early Breast Cancer
by Caterina Gianni, Michela Palleschi, Filippo Merloni, Sara Bleve, Chiara Casadei, Marianna Sirico, Giandomenico Di Menna, Samanta Sarti, Lorenzo Cecconetto, Marita Mariotti and Ugo De Giorgi
Cancers 2023, 15(1), 96; https://doi.org/10.3390/cancers15010096 - 23 Dec 2022
Cited by 2 | Viewed by 2005
Abstract
The research on non-invasive circulating biomarkers to guide clinical decision is in wide expansion, including the earliest disease settings. Several new intensification/de-intensification strategies are approaching clinical practice, personalizing the treatment for each patient. Moreover, liquid biopsy is revealing its potential with multiple techniques [...] Read more.
The research on non-invasive circulating biomarkers to guide clinical decision is in wide expansion, including the earliest disease settings. Several new intensification/de-intensification strategies are approaching clinical practice, personalizing the treatment for each patient. Moreover, liquid biopsy is revealing its potential with multiple techniques and studies available on circulating biomarkers in the preoperative phase. Inflammatory circulating cells, circulating tumor cells (CTCs), cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), and other biological biomarkers are improving the armamentarium for treatment selection. Defining the escalation and de-escalation of treatments is a mainstay of personalized medicine in early breast cancer. In this review, we delineate the studies investigating the possible application of these non-invasive tools to give a more enlightened approach to escalating/de-escalating strategies in early breast cancer. Full article
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11 pages, 2244 KiB  
Article
Predicting the Early Response to Neoadjuvant Therapy with Breast MR Morphological, Functional and Relaxometry Features—A Pilot Study
by Roxana Pintican, Radu Fechete, Bianca Boca, Madalina Cambrea, Tiberiu Leonte, Oana Camuescu, Diana Gherman, Ioana Bene, Larisa Dorina Ciule, Cristiana Augusta Ciortea, Sorin Marian Dudea and Anca Ileana Ciurea
Cancers 2022, 14(23), 5866; https://doi.org/10.3390/cancers14235866 - 28 Nov 2022
Cited by 1 | Viewed by 1129
Abstract
Aim: To evaluate the role of MR relaxometry and derived proton density analysis in the prediction of early treatment response after two cycles of neoadjuvant therapy (NAT), in patients with breast cancer. Methods: This was a prospective study that included 59 [...] Read more.
Aim: To evaluate the role of MR relaxometry and derived proton density analysis in the prediction of early treatment response after two cycles of neoadjuvant therapy (NAT), in patients with breast cancer. Methods: This was a prospective study that included 59 patients with breast cancer, who underwent breast MRI prior (MRI1) and after two cycles of NAT (MRI2). The MRI1 included a sequential acquisition with five different TE’s (50, 100, 150, 200 and 250 ms) and a TR of 5000 ms. Post-processing was used to obtain the T2 relaxometry map from the MR acquisition. The tumor was delineated and seven relaxometry and proton density parameters were extracted. Additional histopathology data, T2 features and ADC were included. The response to NAT was reported based on the MRI2 as responders: partial response (>30% decreased size) and complete response (no visible tumor stable disease (SD); and non-responders: stable disease or progression (>20% increased size). Statistics was done using Medcalc software. Results: There were 50 (79.3%) patients with response and 13 (20.7%) non-responders to NAT. Age, histologic type, “in situ” component, tumor grade, estrogen and progesterone receptors, ki67% proliferation index and HER2 status were not associated with NAT response (all p > 0.05). The nodal status (N) 0 was associated with early response, while N2 was associated with non-response (p = 0.005). The tumor (T) and metastatic (M) stage were not statistically significant associated with response (p > 0.05). The margins, size and ADC values were not associated with NAT response (p-value > 0.05). The T2 min relaxometry value was associated with response (p = 0.017); a cut-off value of 53.58 obtained 86% sensitivity (95% CI 73.3–94.2), 69.23 specificity (95% CI 38.6–90.9), with an AUC = 0.715 (p = 0.038). The combined model (T2 min and N stage) achieved an AUC of 0.826 [95% CI: 0.66–0.90, p-value < 0.001]. Conclusions: MR relaxometry may be a useful tool in predicting early treatment response to NAT in breast cancer patients. Full article
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16 pages, 7024 KiB  
Article
Integrated Analysis of Single-Cell and Bulk RNA-Sequencing Reveals a Tissue-Resident Macrophage-Related Signature for Predicting Immunotherapy Response in Breast Cancer Patients
by Zi-An Xia, You Zhou, Jun Li and Jiang He
Cancers 2022, 14(22), 5506; https://doi.org/10.3390/cancers14225506 - 9 Nov 2022
Cited by 4 | Viewed by 2604
Abstract
Immune checkpoint therapy (ICT) is among the widely used treatments for breast cancer (BC), but most patients do not respond to ICT and the availability of the predictive biomarkers is limited. Emerging evidence indicates that tissue-resident macrophages (RTMs) inhibit BC progression, suggesting that [...] Read more.
Immune checkpoint therapy (ICT) is among the widely used treatments for breast cancer (BC), but most patients do not respond to ICT and the availability of the predictive biomarkers is limited. Emerging evidence indicates that tissue-resident macrophages (RTMs) inhibit BC progression, suggesting that their presence may predict immunotherapy response. A single-cell RNA-sequencing analysis of BC samples was performed to identify five RTM clusters with a mixed phenotype of M1-M2 macrophages. The comprehensive results showed that a high score of each RTM cluster was associated with a high infiltration of CD8+ T cells, M1 macrophages, and dendritic cells, and improved overall survival. In addition, a low score of each RTM cluster was associated with a high infiltration of M0 macrophages, naïve B cells and Tregs, and poor overall survival. Gene signatures from each RTM cluster were significantly enriched in responders compared with nonresponders. Each RTM cluster expression was significantly higher in responders than in nonresponders. The analyses of bulk RNA-seq datasets of BC samples led to identification and validation of a gene expression signature, named RTM.Sig, which contained the related genes of RTM clusters for predicting response to immunotherapy. This study highlights RTM.Sig could provide a valuable tool for clinical decisions in administering ICT. Full article
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31 pages, 3272 KiB  
Review
The Predictive and Prognostic Role of RAS–RAF–MEK–ERK Pathway Alterations in Breast Cancer: Revision of the Literature and Comparison with the Analysis of Cancer Genomic Datasets
by Andrea Rocca, Luca Braga, Maria Concetta Volpe, Serena Maiocchi and Daniele Generali
Cancers 2022, 14(21), 5306; https://doi.org/10.3390/cancers14215306 - 28 Oct 2022
Cited by 13 | Viewed by 2486
Abstract
Although gene alterations of the RAS/RAF/MEK/ERK pathway are uncommon in breast cancer, this pathway is frequently activated in breast tumors, implying its role in tumor progression. We describe, after a revision of the literature, the frequency and types of gene alterations affecting this [...] Read more.
Although gene alterations of the RAS/RAF/MEK/ERK pathway are uncommon in breast cancer, this pathway is frequently activated in breast tumors, implying its role in tumor progression. We describe, after a revision of the literature, the frequency and types of gene alterations affecting this pathway in breast cancer by analyzing some public datasets from cBioPortal. Moreover, we consider their prognostic and predictive impact on treatment response, along with the role of transcriptomic predictors of RAS pathway activation. Our analysis shows that the driver alterations in RAS/RAF/MEK/ERK pathway-related genes are detected in 11% of primary breast cancers. The most frequently mutated genes are NF1 and KRAS, while copy number alterations mainly affect KRAS and BRAF, especially in basal-like tumors. The subgroup of patients carrying these alterations shows a worse prognosis; alterations in NF1 and RAF1 are associated with significantly reduced breast-cancer-specific survival in multivariate analysis. The literature review shows that the pathway is implicated, either by genetic or epigenetic alterations or by signaling network adaptations, in the mechanisms of sensitivity and resistance to a wide range of drugs used in the treatment of breast cancer. A thorough understanding of these alterations is critical for developing combination therapies that can delay or overcome drug resistance. Full article
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32 pages, 1825 KiB  
Review
Multiplexed In Situ Spatial Protein Profiling in the Pursuit of Precision Immuno-Oncology for Patients with Breast Cancer
by Davide Massa, Anna Tosi, Antonio Rosato, Valentina Guarneri and Maria Vittoria Dieci
Cancers 2022, 14(19), 4885; https://doi.org/10.3390/cancers14194885 - 6 Oct 2022
Cited by 5 | Viewed by 4538
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many solid tumors. In breast cancer (BC), immunotherapy is currently approved in combination with chemotherapy, albeit only in triple-negative breast cancer. Unfortunately, most patients only derive limited benefit from ICIs, progressing either upfront or [...] Read more.
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many solid tumors. In breast cancer (BC), immunotherapy is currently approved in combination with chemotherapy, albeit only in triple-negative breast cancer. Unfortunately, most patients only derive limited benefit from ICIs, progressing either upfront or after an initial response. Therapeutics must engage with a heterogeneous network of complex stromal–cancer interactions that can fail at imposing cancer immune control in multiple domains, such as in the genomic, epigenomic, transcriptomic, proteomic, and metabolomic domains. To overcome these types of heterogeneous resistance phenotypes, several combinatorial strategies are underway. Still, they can be predicted to be effective only in the subgroups of patients in which those specific resistance mechanisms are effectively in place. As single biomarker predictive performances are necessarily suboptimal at capturing the complexity of this articulate network, precision immune-oncology calls for multi-omics tumor microenvironment profiling in order to identify unique predictive patterns and to proactively tailor combinatorial treatments. Multiplexed single-cell spatially resolved tissue analysis, through precise epitope colocalization, allows one to infer cellular functional states in view of their spatial organization. In this review, we discuss—through the lens of the cancer-immunity cycle—selected, established, and emerging markers that may be evaluated in multiplexed spatial protein panels to help identify prognostic and predictive patterns in BC. Full article
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22 pages, 5422 KiB  
Article
The Impact of the Hippo Pathway and Cell Metabolism on Pathological Complete Response in Locally Advanced Her2+ Breast Cancer: The TRISKELE Multicenter Prospective Study
by Eriseld Krasniqi, Francesca Sofia Di Lisa, Anna Di Benedetto, Maddalena Barba, Laura Pizzuti, Lorena Filomeno, Cristiana Ercolani, Nicola Tinari, Antonino Grassadonia, Daniele Santini, Mauro Minelli, Filippo Montemurro, Maria Agnese Fabbri, Marco Mazzotta, Teresa Gamucci, Giuliana D’Auria, Claudio Botti, Fabio Pelle, Flavia Cavicchi, Sonia Cappelli, Federico Cappuzzo, Giuseppe Sanguineti, Silverio Tomao, Andrea Botticelli, Paolo Marchetti, Marcello Maugeri-Saccà, Ruggero De Maria, Gennaro Ciliberto, Francesca Sperati and Patrizia Viciadd Show full author list remove Hide full author list
Cancers 2022, 14(19), 4835; https://doi.org/10.3390/cancers14194835 - 3 Oct 2022
Cited by 1 | Viewed by 1952
Abstract
The Hippo pathway and its two key effectors, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), are consistently altered in breast cancer. Pivotal regulators of cell metabolism such as the AMP-activated protein kinase (AMPK), Stearoyl-CoA-desaturase 1 (SCD1), and HMG-CoA reductase (HMGCR) [...] Read more.
The Hippo pathway and its two key effectors, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), are consistently altered in breast cancer. Pivotal regulators of cell metabolism such as the AMP-activated protein kinase (AMPK), Stearoyl-CoA-desaturase 1 (SCD1), and HMG-CoA reductase (HMGCR) are relevant modulators of TAZ/YAP activity. In this prospective study, we measured the tumor expression of TAZ, YAP, AMPK, SCD1, and HMGCR by immunohistochemistry in 65 Her2+ breast cancer patients who underwent trastuzumab-based neoadjuvant treatment. The aim of the study was to assess the impact of the immunohistochemical expression of the Hippo pathway transducers and cell metabolism regulators on pathological complete response. Low expression of cytoplasmic TAZ, both alone and in the context of a composite signature identified by machine learning including also low nuclear levels of YAP and HMGCR and high cytoplasmic levels of SCD1, was a predictor of residual disease in the univariate logistic regression. This finding was not confirmed in the multivariate model including estrogen receptor > 70% and body mass index > 20. However, our findings were concordant with overall survival data from the TCGA cohort. Our results, possibly affected by the relatively small sample size of this study population, deserve further investigation in adequately sized, ad hoc prospective studies. Full article
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10 pages, 768 KiB  
Commentary
FOXA1 in Breast Cancer: A Luminal Marker with Promising Prognostic and Predictive Impact
by Jasna Metovic, Fulvio Borella, Marta D’Alonzo, Nicoletta Biglia, Luca Mangherini, Cristian Tampieri, Luca Bertero, Paola Cassoni and Isabella Castellano
Cancers 2022, 14(19), 4699; https://doi.org/10.3390/cancers14194699 - 27 Sep 2022
Cited by 4 | Viewed by 2564
Abstract
The present review focuses on the function of the forkhead protein FOXA1 in breast cancer (BC) in relation to steroid hormone receptors. We explored the currently available analytic approaches for FOXA1 assessment both at gene and protein levels, comparing the differences between the [...] Read more.
The present review focuses on the function of the forkhead protein FOXA1 in breast cancer (BC) in relation to steroid hormone receptors. We explored the currently available analytic approaches for FOXA1 assessment both at gene and protein levels, comparing the differences between the available techniques used for its diagnostic assessment. In addition, we elaborated on data regarding the prognostic and predictive role of this marker in BC based on several studies that evaluated its expression in relation to the outcome and/or response to therapy. FOXA1, similar to the androgen receptor (AR), may have a dual role in BC according to hormonal status. In luminal cancers, its expression contributes to a better prognosis, while in triple-negative breast cancers (TNBC), it implies an adverse outcome. Consequently, we observed that FOXA1-positive expression in a neoadjuvant setting may predict a lack of response in luminal BC as opposed to TNBC, in which FOXA1 allegedly increases its chemosensitivity. In conclusion, considering its accessible and convenient identification by immunohistochemistry, its important impact on prognosis, and its suitability to identify patients with different responses to chemotherapy, we propose that FOXA1 could be tested in routine diagnostics as an additional prognostic and predictive marker in BC. Full article
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14 pages, 635 KiB  
Article
BRCA Mutation Status in Triple-Negative Breast Cancer Patients Treated with Neoadjuvant Chemotherapy: A Pivotal Role for Treatment Decision-Making
by Francesco Pavese, Ettore Domenico Capoluongo, Margherita Muratore, Angelo Minucci, Concetta Santonocito, Paola Fuso, Paola Concolino, Enrico Di Stasio, Luisa Carbognin, Giordana Tiberi, Giorgia Garganese, Giacomo Corrado, Alba Di Leone, Daniele Generali, Simona Maria Fragomeni, Tatiana D’Angelo, Gianluca Franceschini, Riccardo Masetti, Alessandra Fabi, Antonino Mulè, Angela Santoro, Paolo Belli, Giampaolo Tortora, Giovanni Scambia and Ida Parisadd Show full author list remove Hide full author list
Cancers 2022, 14(19), 4571; https://doi.org/10.3390/cancers14194571 - 21 Sep 2022
Cited by 7 | Viewed by 2683
Abstract
Triple-negative breast cancer (TNBC) is characterized by earlier recurrence and shorter survival compared with other types of breast cancer. Moreover, approximately 15 to 25% of all TNBC patients harbor germline BRCA (gBRCA) 1/2 mutations, which confer a more aggressive phenotype. However, TNBC seems [...] Read more.
Triple-negative breast cancer (TNBC) is characterized by earlier recurrence and shorter survival compared with other types of breast cancer. Moreover, approximately 15 to 25% of all TNBC patients harbor germline BRCA (gBRCA) 1/2 mutations, which confer a more aggressive phenotype. However, TNBC seems to be particularly sensitive to chemotherapy, the so-called ‘triple negative paradox’. Therefore, Neoadjuvant chemotherapy (NACT) is currently considered the preferred approach for early-stage TNBC. BRCA status has also been studied as a predictive biomarker of response to platinum compounds. Although several randomized trials investigated the addition of carboplatin to standard NACT in early-stage TNBC, the role of BRCA status remains unclear. In this retrospective analysis, we evaluated data from 136 consecutive patients with Stage I-III TNBC who received standard NACT with or without the addition of carboplatin, in order to define clinical features and outcomes in BRCA 1/2 mutation carriers and non-carrier controls. Between January 2013 and February 2021, 67 (51.3%) out of 136 patients received a standard anthracyclines/taxane regimen and 69 (50.7%) patients received a platinum-containing chemotherapy regimen. Deleterious germline BRCA1 or BRCA2 mutations were identified in 39 (28.7%) patients. Overall, patients with deleterious gBRCA1/2 mutation have significantly higher pCR rate than non-carrier patients (23 [59%] of 39 vs. 33 [34%] of 97; p = 0.008). The benefit of harboring a gBRCA mutation was confirmed only in the subset of patients who received a platinum-based NACT (17 [65.4%] of 26 vs. 13 [30.2%] of 43; p = 0.005) while no differences were found in the platinum-free subgroup. Patients who achieved pCR after NACT had significantly better EFS (OR 4.5; 95% CI 1.9–10.7; p = 0.001) and OS (OR 3.3; 95% CI 1.3–8.9; p = 0.01) than patients who did not, regardless of BRCA1/2 mutation status and type of NACT received. Our results based on real-world evidence show that TNBC patients with the gBRCA1/2 mutation who received platinum-based NACT have a higher pCR rate than non-carrier patients, supporting the use of this chemotherapy regimen in this patient population. Long-term follow-up analyses are needed to further define the role of gBRCA mutation status on clinical outcomes in patients with early-TNBC. Full article
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17 pages, 5950 KiB  
Article
Prognostic Relevance of Nuclear Receptors in Relation to Peritumoral Inflammation and Tumor Infiltration by Lymphocytes in Breast Cancer
by Melitta B. Köpke, Marie-Christine Chateau, Florence Boissière-Michot, Mariella Schneider, Fabian Garrido, Alaleh Zati-Zehni, Theresa Vilsmaier, Mirjana Kessler, Nina Ditsch, Vincent Cavaillès and Udo Jeschke
Cancers 2022, 14(19), 4561; https://doi.org/10.3390/cancers14194561 - 20 Sep 2022
Cited by 1 | Viewed by 1527
Abstract
The prognostic impact of tumor-infiltrating lymphocytes (TILs) is intensively investigated in breast cancer (BC). It is already known that triple-negative breast cancer (TNBC), the most aggressive type of BC, has the highest percentage of TILs. In addition, there is an influence of steroid [...] Read more.
The prognostic impact of tumor-infiltrating lymphocytes (TILs) is intensively investigated in breast cancer (BC). It is already known that triple-negative breast cancer (TNBC), the most aggressive type of BC, has the highest percentage of TILs. In addition, there is an influence of steroid hormone receptor expression (type I nuclear receptors) on TIL subpopulations in breast cancer tissue. The link between type II nuclear receptors and the level of TILs is unclear. Therefore, the aim of this study was to quantify TILs in a panel of 264 sporadic breast cancers and investigate the correlation of TIL levels with type I and II nuclear receptors expression. TIL levels were significantly increased in the subgroup of TNBC. By contrast, they decreased in estrogen (ER)- or progesterone receptor (PR)-positive cases. Moreover, TIL levels were correlated with type II nuclear receptors, including PPARγ, with a significant inverse correlation of the nuclear form (r = −0.727, p < 0.001) and a weak positive correlation of the cytoplasmic form (r = 0.202, p < 0.002). Surprisingly, BC cases with a TIL Salgado score of >15% showed a significantly decreased overall survival. In addition, peritumoral inflammation was also quantified in BC tissue samples. In our cohort, although the level of peritumoral inflammation was not correlated with OS, it determined the prognostic value of ER, PR, and PPARγ in BC. Altogether, the present study provides a differentiated overview of the relations between nuclear receptor expression, TIL levels, peritumoral inflammation, and prognosis in BC. Full article
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16 pages, 1832 KiB  
Systematic Review
Prognostic Value of the Serum HER2 Extracellular Domain Level in Breast Cancer: A Systematic Review and Meta-Analysis
by Yun Wu, Lixi Li, Di Zhang and Fei Ma
Cancers 2022, 14(19), 4551; https://doi.org/10.3390/cancers14194551 - 20 Sep 2022
Cited by 3 | Viewed by 1835
Abstract
An elevated serum HER2 extracellular domain is associated with poor prognosis in breast cancer, but the relationship between sHER2 and the efficacy of different modalities remains controversial. Herein, we aimed to evaluate the prognostic value of serum HER2 extracellular domain (sHER2 ECD) in [...] Read more.
An elevated serum HER2 extracellular domain is associated with poor prognosis in breast cancer, but the relationship between sHER2 and the efficacy of different modalities remains controversial. Herein, we aimed to evaluate the prognostic value of serum HER2 extracellular domain (sHER2 ECD) in breast cancer and to identify its correlation with the efficacy of different treatment regimens. A systematic search of the PubMed, Embase, Cochrane Library, Web of Science, and Scopus databases was conducted to identify studies exploring the association between HER2 ECD level and clinical outcomes among patients with breast cancer. Using the random effects models, pooled hazard ratios (HRs), and odds ratios (ORs) with 95% confidence intervals (CI), were calculated for progression-free survival (PFS), overall survival (OS), disease-free survival (DFS), and the objective response rate (ORR). Heterogeneity was further evaluated by subgroup and sensitivity analysis. Overall, 40 studies comprising 12,229 patients were included in this systematic review and meta-analysis. Elevated HER2 ECD levels were associated with worse PFS (HR 1.74, 95% CI 1.40–2.17; p < 0.001), and this effect was observed in patients treated with chemotherapy (HR 1.81, 95% CI 1.37–2.39; p < 0.001), endocrine therapy (HR 1.91, 95% CI 1.57–2.32; p < 0.001), and trastuzumab (HR 1.74, 95% CI 1.31–2.30; p < 0.001). However, this association was not present in patients treated with tyrosine kinase inhibitors (TKIs) (HR 1.44, 95% CI 0.85–2.43, p = 0.17). The HRs/ORs for an elevated HER2 ECD level for DFS, OS, and ORR were 2.73 (95% CI 2.17–3.42; p < 0.001), 2.13 (95% CI 1.77–2.57; p < 0.001), and 0.80 (95% CI 0.49–1.31; p = 0.381), respectively. An elevated sHER2 ECD was an unfavorable prognostic factor in breast cancer but did not affect the efficacy of tyrosine kinase inhibitors such as lapatinib. Detection of sHER2 ECD may be helpful for clinicians selecting the appropriate anti-HER2 therapy for patients with HER2-positive breast cancer. Full article
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21 pages, 351 KiB  
Article
NBN, RAD51 and XRCC3 Polymorphisms as Potential Predictive Biomarkers of Adjuvant Radiotherapy Toxicity in Early HER2-Positive Breast Cancer
by Katja Goričar, Franja Dugar, Vita Dolžan and Tanja Marinko
Cancers 2022, 14(18), 4365; https://doi.org/10.3390/cancers14184365 - 8 Sep 2022
Cited by 2 | Viewed by 1551
Abstract
Radiotherapy (RT) for breast cancer significantly impacts patient survival and causes adverse events. Double-strand breaks are the most harmful type of DNA damage associated with RT, which is repaired through homologous recombination (HRR). As genetic variability of DNA repair genes could affect response [...] Read more.
Radiotherapy (RT) for breast cancer significantly impacts patient survival and causes adverse events. Double-strand breaks are the most harmful type of DNA damage associated with RT, which is repaired through homologous recombination (HRR). As genetic variability of DNA repair genes could affect response to RT, we aimed to evaluate the association of polymorphisms in HRR genes with tumor characteristics and the occurrence of RT adverse events in early HER2-positive breast cancer. Our study included 101 breast cancer patients treated with adjuvant RT and trastuzumab. All patients were genotyped for eight single nucleotide polymorphisms in NBN, RAD51 and XRCC3 using competitive allele-specific PCR. Carriers of XRCC3 rs1799794 GG genotype were less likely to have higher tumor differentiation grade (OR = 0.05, 95% CI = 0.01–0.44, p = 0.007). Carriers of RAD51 rs1801321 TT genotype were more likely to have higher NYHA class in univariable (OR = 10.0; 95% CI = 1.63–61.33; p = 0.013) and multivariable (OR = 9.27; 95% CI = 1.28–67.02; p = 0.027) analysis. Carriers of RAD51 rs12593359 GG genotype were less likely to have higher NYHA class in univariable (OR = 0.09; 95% CI = 0.01–0.79; p = 0.030) and multivariable (OR = 0.07; 95% CI = 0.01–0.81; p = 0.034) analysis. Carriers of XRCC3 rs1799794 GG genotypes experienced more skin adverse events based on LENT-SOMA scale in univariable (OR = 5.83; 95% CI = 1.22–28.00; p = 0.028) and multivariable (OR = 10.90; 95% CI = 1.61–73.72; p = 0.014) analysis. In conclusion, XRCC3 and RAD51 polymorphisms might contribute to RT adverse events in early HER2-positive breast cancer patients. Full article
12 pages, 502 KiB  
Review
The Molecular Predictive and Prognostic Biomarkers in Metastatic Breast Cancer: The Contribution of Molecular Profiling
by Benjamin Verret, Michele Bottosso, Sofia Hervais and Barbara Pistilli
Cancers 2022, 14(17), 4203; https://doi.org/10.3390/cancers14174203 - 30 Aug 2022
Cited by 5 | Viewed by 2472
Abstract
The past decade was marked by several important studies deciphering the molecular landscape of metastatic breast cancer. Although the initial goal of these studies was to find driver oncogenic events to explain cancer progression and metastatic spreading, they have also permitted the identification [...] Read more.
The past decade was marked by several important studies deciphering the molecular landscape of metastatic breast cancer. Although the initial goal of these studies was to find driver oncogenic events to explain cancer progression and metastatic spreading, they have also permitted the identification of several molecular alterations associated with treatment response or resistance. Herein, we review validated (PI3KCA, ESR1, MSI, NTRK translocation) and emergent molecular biomarkers (ERBB2, AKT, PTEN, HRR gene, CD274 amplification RB1, NF1, mutational process) in metastatic breast cancer, on the bases of the largest molecular profiling studies. These biomarkers will be classed according the level of evidence and, if possible, the ESCAT (ESMO) classification. Finally, we will provide some perspective on development in clinical practice for the main biomarkers. Full article
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20 pages, 745 KiB  
Review
Altered Adipokine Expression in Tumor Microenvironment Promotes Development of Triple Negative Breast Cancer
by Efthymia Papakonstantinou, Zoi Piperigkou, Nikos K. Karamanos and Vasiliki Zolota
Cancers 2022, 14(17), 4139; https://doi.org/10.3390/cancers14174139 - 26 Aug 2022
Cited by 8 | Viewed by 2721
Abstract
Obesity is a remarkably important factor for breast carcinogenesis and aggressiveness. The implication of increased BMI in triple negative breast cancer (TNBC) development is also well established. A malignancy-promoting role of the adipose tissue has been supposed, where the adipocytes that constitute the [...] Read more.
Obesity is a remarkably important factor for breast carcinogenesis and aggressiveness. The implication of increased BMI in triple negative breast cancer (TNBC) development is also well established. A malignancy-promoting role of the adipose tissue has been supposed, where the adipocytes that constitute the majority of stromal cells release pro-inflammatory cytokines and growth factors. Alterations in adipokines and their receptors play significant roles in breast cancer initiation, progression, metastasis, and drug response. Classic adipokines, such as leptin, adiponectin, and resistin, have been extensively studied in breast cancer and connected with breast cancer risk and progression. Notably, new molecules are constantly being discovered and the list is continuously growing. Additionally, substantial progress has been made concerning their differential expression in association with clinical and pathological parameters of tumors and the prognostic and predictive value of their dysregulation in breast cancer carcinogenesis. However, evidence regarding the mechanisms by which adipose tissue is involved in the development of TNBC is lacking. In the present article we comment on current data on the suggested involvement of these mediators in breast cancer development and progression, with particular emphasis on TNBC, to draw attention to the design of novel targeted therapies and biomarkers. Full article
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18 pages, 7453 KiB  
Article
Interleukin-3-Receptor-α in Triple-Negative Breast Cancer (TNBC): An Additional Novel Biomarker of TNBC Aggressiveness and a Therapeutic Target
by Malvina Koni, Isabella Castellano, Emilio Venturelli, Alessandro Sarcinella, Tatiana Lopatina, Cristina Grange, Massimo Cedrino, Saveria Femminò, Paolo Cossu-Rocca, Sandra Orrù, Fabrizio D’Ascenzo, Ilaria Cotellessa, Cristian Tampieri, Carla Debernardi, Giovanni Cugliari, Giuseppe Matullo, Giovanni Camussi, Maria Rosaria De Miglio and Maria Felice Brizzi
Cancers 2022, 14(16), 3918; https://doi.org/10.3390/cancers14163918 - 13 Aug 2022
Cited by 6 | Viewed by 2372
Abstract
Tumour molecular annotation is mandatory for biomarker discovery and personalised approaches, particularly in triple-negative breast cancer (TNBC) lacking effective treatment options. In this study, the interleukin-3 receptor α (IL-3Rα) was investigated as a prognostic biomarker and therapeutic target in TNBC. IL-3Rα expression and [...] Read more.
Tumour molecular annotation is mandatory for biomarker discovery and personalised approaches, particularly in triple-negative breast cancer (TNBC) lacking effective treatment options. In this study, the interleukin-3 receptor α (IL-3Rα) was investigated as a prognostic biomarker and therapeutic target in TNBC. IL-3Rα expression and patients’ clinical and pathological features were retrospectively analysed in 421 TNBC patients. IL-3Rα was expressed in 69% human TNBC samples, and its expression was associated with nodal metastases (p = 0.026) and poor overall survival (hazard ratio = 1.50; 95% CI = 1.01–2.2; p = 0.04). The bioinformatics analysis on the Breast Invasive Carcinoma dataset of The Cancer Genome Atlas (TCGA) proved that IL-3Rα was highly expressed in TNBC compared with luminal breast cancers (p = 0.017, padj = 0.026). Functional studies demonstrated that IL-3Rα activation induced epithelial-to-endothelial and epithelial-to-mesenchymal transition, promoted large blood lacunae and lung metastasis formation, and increased programmed-cell death ligand-1 (PD-L1) in primary tumours and metastases. Based on the TCGA data, IL-3Rα, PD-L1, and EMT coding genes were proposed to discriminate against TNBC aggressiveness (AUC = 0.86 95% CI = 0.82–0.89). Overall, this study identified IL-3Rα as an additional novel biomarker of TNBC aggressiveness and provided the rationale to further investigate its relevance as a therapeutic target. Full article
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35 pages, 2199 KiB  
Review
Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells, Obesity and the Tumor Microenvironment of Breast Cancer
by Andreas Ritter, Nina-Naomi Kreis, Samira Catharina Hoock, Christine Solbach, Frank Louwen and Juping Yuan
Cancers 2022, 14(16), 3908; https://doi.org/10.3390/cancers14163908 - 12 Aug 2022
Cited by 18 | Viewed by 3968
Abstract
Breast cancer is the most frequently diagnosed cancer and a common cause of cancer-related death in women. It is well recognized that obesity is associated with an enhanced risk of more aggressive breast cancer as well as reduced patient survival. Adipose tissue is [...] Read more.
Breast cancer is the most frequently diagnosed cancer and a common cause of cancer-related death in women. It is well recognized that obesity is associated with an enhanced risk of more aggressive breast cancer as well as reduced patient survival. Adipose tissue is the major microenvironment of breast cancer. Obesity changes the composition, structure, and function of adipose tissue, which is associated with inflammation and metabolic dysfunction. Interestingly, adipose tissue is rich in ASCs/MSCs, and obesity alters the properties and functions of these cells. As a key component of the mammary stroma, ASCs play essential roles in the breast cancer microenvironment. The crosstalk between ASCs and breast cancer cells is multilateral and can occur both directly through cell–cell contact and indirectly via the secretome released by ASC/MSC, which is considered to be the main effector of their supportive, angiogenic, and immunomodulatory functions. In this narrative review, we aim to address the impact of obesity on ASCs/MSCs, summarize the current knowledge regarding the potential pathological roles of ASCs/MSCs in the development of breast cancer, discuss related molecular mechanisms, underline the possible clinical significance, and highlight related research perspectives. In particular, we underscore the roles of ASCs/MSCs in breast cancer cell progression, including proliferation and survival, angiogenesis, migration and invasion, the epithelial–mesenchymal transition, cancer stem cell development, immune evasion, therapy resistance, and the potential impact of breast cancer cells on ASCS/MSCs by educating them to become cancer-associated fibroblasts. We conclude that ASCs/MSCs, especially obese ASCs/MSCs, may be key players in the breast cancer microenvironment. Targeting these cells may provide a new path of effective breast cancer treatment. Full article
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32 pages, 6621 KiB  
Article
Knockdown of CKAP2 Inhibits Proliferation, Migration, and Aggregate Formation in Aggressive Breast Cancer
by Alexsandro dos Santos, Geneviève Ouellete, Caroline Diorio, Sabine Elowe and Francine Durocher
Cancers 2022, 14(15), 3759; https://doi.org/10.3390/cancers14153759 - 2 Aug 2022
Cited by 2 | Viewed by 2228
Abstract
Loss of mitotic regulation is commonly observed in cancer and is a major cause of whole-chromosome aneuploidy. The identification of genes that play a role in the proper progression of mitosis can help us to understand the development and evolution of this disease. [...] Read more.
Loss of mitotic regulation is commonly observed in cancer and is a major cause of whole-chromosome aneuploidy. The identification of genes that play a role in the proper progression of mitosis can help us to understand the development and evolution of this disease. Here, we generated a list of proteins implicated in mitosis that we used to probe a patient-derived breast cancer (BC) continuum gene-expression dataset generated by our group by human transcriptome analysis of breast lesions of varying aggressiveness (from normal to invasive). We identified cytoskeleton-associated protein 2 (CKAP2) as an important mitotic regulator in invasive BC. The results showed that CKAP2 is overexpressed in invasive BC tumors when compared with normal tissues, and highly expressed in all BC subtypes. Higher expression of CKAP2 is also related to a worse prognosis in overall survival and relapse-free survival in estrogen receptor (ER)-positive and human epidermal growth factor receptor type 2 (HER2)-negative BC patients. Knockdown of CKAP2 in SKBR3 cells impaired cell proliferation and cell migration and reduced aggregate formation in a 3D culture. Our results show the important role of CKAP2 in BC tumorigenesis, and its potential utility as a prognostic marker in BC. Full article
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28 pages, 707 KiB  
Review
Personalised Therapies for Metastatic Triple-Negative Breast Cancer: When Target Is Not Everything
by Serena Capici, Luca Carlofrancesco Ammoni, Nicole Meli, Viola Cogliati, Francesca Fulvia Pepe, Francesca Piazza and Marina Elena Cazzaniga
Cancers 2022, 14(15), 3729; https://doi.org/10.3390/cancers14153729 - 31 Jul 2022
Cited by 6 | Viewed by 2309
Abstract
Triple-negative breast cancer—defined by the absence of oestrogen/progesterone receptors and human epidermal growth factor receptor 2 expression—is a complex and heterogeneous type of tumour characterised by poor prognosis, aggressive behaviour and lack of effective therapeutic strategies. The identification of new biomarkers and molecular [...] Read more.
Triple-negative breast cancer—defined by the absence of oestrogen/progesterone receptors and human epidermal growth factor receptor 2 expression—is a complex and heterogeneous type of tumour characterised by poor prognosis, aggressive behaviour and lack of effective therapeutic strategies. The identification of new biomarkers and molecular signatures is leading to development of new therapeutic strategies including immunotherapy, targeted therapy and antibody-drug conjugates (ADCs). Against a background where chemotherapy has always been considered the standard of care, evolution towards a precision medicine approach could improve TNBC clinical practice in a complex scenario, with many therapeutic options and new drugs. The aim of this review was to focus on emerging therapeutic targets and their related specific therapy, discussing available and emerging drugs, underlining differences in approval by American and European regulatory authorities and showing the future perspective in the large number of ongoing clinical trials. Full article
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14 pages, 283 KiB  
Article
Anthracycline-Free Neoadjuvant Treatment in Patients with HER2-Positive Breast Cancer: Real-Life Use of Pertuzumab, Trastuzumab and Taxanes Association with an Exploratory Analysis of PIK3CA Mutational Status
by Azzurra Irelli, Alessandro Parisi, Carla D’Orazio, Tina Sidoni, Silvia Rotondaro, Leonardo Patruno, Francesco Pavese, Alberto Bafile, Valter Resta, Laura Pizzorno, Virginia Ciuffetelli, Antonella Dal Mas, Giuseppe Calvisi, Alessandra Di Sibio, Anna Marzullo, Veronica Zelli, Chiara Compagnoni, Alessandra Tessitore, Edoardo Alesse, Corrado Ficorella, Alessio Cortellini and Katia Cannitaadd Show full author list remove Hide full author list
Cancers 2022, 14(12), 3003; https://doi.org/10.3390/cancers14123003 - 18 Jun 2022
Cited by 4 | Viewed by 1902
Abstract
HER2 is considered one of the most traditional prognostic and predictive biomarkers in breast cancer. Literature data confirmed that the addition of pertuzumab to a standard neoadjuvant chemotherapy backbone (either with or without anthracyclines), in patients with human epidermal growth factor receptor 2 [...] Read more.
HER2 is considered one of the most traditional prognostic and predictive biomarkers in breast cancer. Literature data confirmed that the addition of pertuzumab to a standard neoadjuvant chemotherapy backbone (either with or without anthracyclines), in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC), leads to a higher pathological complete response (pCR) rate, which is known to correlate with a better prognosis. In this retrospective analysis, 47 consecutive patients with HER2-positive EBC received sequential anthracyclines and taxanes plus trastuzumab (ATH) or pertuzumab, trastuzumab and docetaxel (THP). Despite the limited sample size, this monocentric experience highlights the efficacy (in terms of pCR) and safety of THP in the neoadjuvant setting of HER2-positive EBC as an anthracycline-free approach. Given the role of PIK3CA as a prognostic and therapeutic target in breast cancer, tumors were also analyzed to assess the PIK3CA mutational status. Thirty-eight out of forty-seven patients were evaluated, and PIK3CA variants were identified in 21% of tumor samples: overall, one mutation was detected in exon 4 (2.6%), two in exon 9 (5.3%) and four in exon 20 (10.5%). Of note, one sample showed concurrent mutations in exons 9 (codon 545) and 20 (codon 1047). Among patients reaching pCR (n = 13), 38.5% were PIK3CA mutants; on the other hand, among those lacking pCR (n = 25), just 12% showed PIK3CA variants. Regarding THP-treated mutant patients (n = 5), 80% reached pCR (three hormone-receptor-negative, one hormone-receptor-positive). Interestingly, the only patient not achieving pCR had a tumor with two co-occurring PIK3CA mutations. In conclusion, this study provides new evidence about the efficacy and good safety profile of THP, compared to the ATH regimen, as an anthracycline-free neoadjuvant treatment of HER2-positive EBC. Further studies on larger/multicentric cohorts are planned for more in-depth analysis to confirm our molecular and clinical results. Full article
44 pages, 2081 KiB  
Review
Predictive and Prognostic Value of Non-Coding RNA in Breast Cancer
by Navid Sobhani, Richard Chahwan, Raheleh Roudi, Rachel Morris, Stefano Volinia, Dafei Chai, Alberto D’Angelo and Daniele Generali
Cancers 2022, 14(12), 2952; https://doi.org/10.3390/cancers14122952 - 15 Jun 2022
Cited by 9 | Viewed by 3036
Abstract
For decades since the central dogma, cancer biology research has been focusing on the involvement of genes encoding proteins. It has been not until more recent times that a new molecular class has been discovered, named non-coding RNA (ncRNA), which has been shown [...] Read more.
For decades since the central dogma, cancer biology research has been focusing on the involvement of genes encoding proteins. It has been not until more recent times that a new molecular class has been discovered, named non-coding RNA (ncRNA), which has been shown to play crucial roles in shaping the activity of cells. An extraordinary number of studies has shown that ncRNAs represent an extensive and prevalent group of RNAs, including both oncogenic or tumor suppressive molecules. Henceforth, various clinical trials involving ncRNAs as extraordinary biomarkers or therapies have started to emerge. In this review, we will focus on the prognostic and diagnostic role of ncRNAs for breast cancer. Full article
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