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Cancers
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Triple Negative Breast Cancer: From Biology to Treatment
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Triple Negative Breast Cancer: From Biology to Treatment

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 October 2022) | Viewed by 21187

Special Issue Editor

Dr. Lucia Del Mastro

E-Mail Website
Guest Editor
UO Breast Unit, University of Genova - IRCCS Ospedale Policlinico San Martino, 10 - 16132 Genova, Italy
Interests: breast cancer; clinical trials; supportive care; fertility preservation; adjuvant treatment

Special Issue Information

Dear Colleagues,

Among breast cancer subtypes, triple negative is the less common and the most challenging to manage due to few treatment options and a worse prognosis compared to luminal and HER2-positive disease. In particular, neoadjuvant chemotherapy represents, at this point, the cornerstone of treatment of early stage in clinical practice, and the addition of immune checkpoint inhibitors targeting PD-L1 to chemotherapy has become the standard of care in first line for PD-L1 positive disease.

Translational and clinical research are now focusing on almost all aspects concerning triple negative breast cancer: the molecular characterization, the biological and clinical peculiarity of BRCA-associated cases, the role of immunotherapy in early-stage disease and of new antibody–drug conjugates in an advanced setting.

This Special Issue will highlight the current state of the art about triple negative breast cancer, moving from its biology to management in every setting of disease, and will explore future perspectives in terms of diagnosis, role of prognostic and predictive biomarkers, and therapeutic options potentially entering the next landscape of treatment.

Dr. Lucia Del Mastro
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • triple negative
  • breast cancer
  • chemotherapy
  • immunotherapy
  • BRCA
  • neoadjuvant chemotherapy
  • antibody–drug conjugate

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Published Papers (6 papers)

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Research

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34 pages, 9843 KiB  
Article
Novel Selenoesters as a Potential Tool in Triple-Negative Breast Cancer Treatment
by Dominika Radomska, Robert Czarnomysy, Anna Szymanowska, Dominik Radomski, Enrique Domínguez-Álvarez, Anna Bielawska and Krzysztof Bielawski
Cancers 2022, 14(17), 4304; https://doi.org/10.3390/cancers14174304 - 2 Sep 2022
Cited by 12 | Viewed by 2414
Abstract
Disturbing cancer statistics, especially for breast cancer, are becoming a rationale for the development of new anticancer therapies. For the past several years, studies have been proving a greater role of selenium in the chemoprevention of many cancers than previously considered; hence, a [...] Read more.
Disturbing cancer statistics, especially for breast cancer, are becoming a rationale for the development of new anticancer therapies. For the past several years, studies have been proving a greater role of selenium in the chemoprevention of many cancers than previously considered; hence, a trend to develop compounds containing this element as potential agents with anticancer activity has been set for some time. Therefore, our study aimed to evaluate the anticancer activity of novel selenoesters (EDA-71, E-NS-4) in MCF-7 and MDA-MB-231 human breast cancer cells. The assays evaluating proliferation and cell viability, and flow cytometer analysis of apoptosis/autophagy induction, changes in mitochondrial membrane potential, disruption of cell cycle phases, and protein activity of mTOR, NF-κB, cyclin E1/A2, and caspases 3/7, 8, 9, 10 were performed. The obtained results indicate that the tested selenoesters are highly cytotoxic and exhibit antiproliferative activity at low micromolar doses (<5 µM) compared with cisplatin. The most active compound—EDA-71—highly induces apoptosis, which proceeds via both pathways, as evidenced by the activation of all tested caspases. Furthermore, we observed the occurrence of autophagy (↓ mTOR levels) and cell cycle arrest in the S or G2/M phase (↓ cyclin E1, ↑ cyclin A2). Full article
(This article belongs to the Special Issue Triple Negative Breast Cancer: From Biology to Treatment)
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12 pages, 1648 KiB  
Article
CISH Expression Is Associated with Metastasis-Free Interval in Triple-Negative Breast Cancer and Refines the Prognostic Value of PDL1 Expression
by Laurys Boudin, Alexandre De Nonneville, Pascal Finetti, Geoffrey Guittard, Jacques A. Nunes, Daniel Birnbaum, Emilie Mamessier and François Bertucci
Cancers 2022, 14(14), 3356; https://doi.org/10.3390/cancers14143356 - 10 Jul 2022
Cited by 2 | Viewed by 2170
Abstract
Strategies are being explored to increase the efficiency of immune checkpoint inhibitors (ICIs) targeting PD1/PDL1 in triple-negative breast cancer (TNBC), including combination with therapies inhibiting intracellular immune checkpoints such as CISH (Cytokine-induced SH2 protein). Correlation between CISH expression and TNBC features is unknown. [...] Read more.
Strategies are being explored to increase the efficiency of immune checkpoint inhibitors (ICIs) targeting PD1/PDL1 in triple-negative breast cancer (TNBC), including combination with therapies inhibiting intracellular immune checkpoints such as CISH (Cytokine-induced SH2 protein). Correlation between CISH expression and TNBC features is unknown. We retrospectively analyzed CISH expression in 1936 clinical TNBC samples and searched for correlations with clinical variables, including metastasis-free interval (MFI). Among TNBCs, 44% were identified as “CISH-up” and 56% “CISH-down”. High expression was associated with pathological axillary lymph node involvement, more adjuvant chemotherapy, and Lehmann’s immunomodulatory and luminal AR subtypes. The “CISH-up” class showed longer 5-year MFI (72%) than the “CISH-down” class (60%; p = 2.8 × 10−2). CISH upregulation was associated with activation of IFNα and IFNγ pathways, antitumor cytotoxic immune response, and signatures predictive for ICI response. When CISH and PDL1 were upregulated together, the 5-year MFI was 81% versus 52% when not upregulated (p = 6.21 × 10−6). The two-gene model provided more prognostic information than each gene alone and maintained its prognostic value in multivariate analysis. CISH expression is associated with longer MFI in TNBC and refines the prognostic value of PDL1 expression. Such observation might reinforce the therapeutic relevance of combining CISH inhibition with an anti-PD1/PDL1 ICI. Full article
(This article belongs to the Special Issue Triple Negative Breast Cancer: From Biology to Treatment)
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19 pages, 1860 KiB  
Article
Unraveling the Role of Guanylate-Binding Proteins (GBPs) in Breast Cancer: A Comprehensive Literature Review and New Data on Prognosis in Breast Cancer Subtypes
by Erin N. Hunt, Jonathan P. Kopacz and Deborah J. Vestal
Cancers 2022, 14(11), 2794; https://doi.org/10.3390/cancers14112794 - 4 Jun 2022
Cited by 6 | Viewed by 3030
Abstract
At least one member of the Guanylate-Binding Protein (GBP) family of large interferon-induced GTPases has been classified as both a marker of good prognosis and as a potential drug target to treat breast cancers. However, the activity of individual GBPs appears to not [...] Read more.
At least one member of the Guanylate-Binding Protein (GBP) family of large interferon-induced GTPases has been classified as both a marker of good prognosis and as a potential drug target to treat breast cancers. However, the activity of individual GBPs appears to not just be tumor cell type–specific but dependent on the growth factor and/or cytokine environment in which the tumor cells reside. To clarify what we do and do not know about GBPs in breast cancer, the current literature on GBP-1, GBP-2, and GBP-5 in breast cancer has been assembled. In addition, we have analyzed the role of each of these GBPs in predicting recurrence-free survival (RFS), overall survival (OS), and distance metastasis-free survival (DMFS) as single gene products in different subtypes of breast cancers. When a large cohort of breast cancers of all types and stages were examined, GBP-1 correlated with poor RFS. However, it was the only GBP to do so. When smaller cohorts of breast cancer subtypes grouped into ER+, ER+/HER2−, and HER2+ tumors were analyzed, none of the GBPs influenced RFS, OS, or DMSF as single agents. The exception is GBP-5, which correlated with improved RFS in HER2+ breast cancers. All three GBPs individually predicted improved RFS, OS, and DMSF in ER− breast cancers, regardless of the PR or HER2 status, and TNBCs. Full article
(This article belongs to the Special Issue Triple Negative Breast Cancer: From Biology to Treatment)
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12 pages, 508 KiB  
Article
Prognostic Value of HER2-Low Expression in Non-Metastatic Triple-Negative Breast Cancer and Correlation with Other Biomarkers
by William Jacot, Aurélie Maran-Gonzalez, Océane Massol, Charlotte Sorbs, Caroline Mollevi, Séverine Guiu, Florence Boissière-Michot and Jeanne Ramos
Cancers 2021, 13(23), 6059; https://doi.org/10.3390/cancers13236059 - 1 Dec 2021
Cited by 74 | Viewed by 4623
Abstract
HER2-low breast cancer (i.e., HER 1+ or 2+, without gene amplification) is an emerging subtype for which very few data are available, especially within the triple-negative breast cancer (TNBC) group. Our aim was to evaluate HER2 expression and its prognostic value in a [...] Read more.
HER2-low breast cancer (i.e., HER 1+ or 2+, without gene amplification) is an emerging subtype for which very few data are available, especially within the triple-negative breast cancer (TNBC) group. Our aim was to evaluate HER2 expression and its prognostic value in a large retrospective series of patients with non-metastatic TNBC (median age: 57.7 years; range: 28.5–98.6). Among the 296 TNBC samples, 83.8% were HER2 0, 13.5% were HER2 1+, and 2.7% were HER2 2+ (HercepTestTM and 2018 ASCO/CAP guidelines for HER2 scoring). CK5/6 and/or EGFR-expressing androgen receptors and FOXA1-expressing tumors were classified as basal-like (63.8%) and molecular apocrine-like (MA, 40.2%), respectively. Compared with HER2 0 tumors, HER2 1+/2+ tumors exhibited a lower histological grade (1/2) (35.4% vs. 18.2%, p = 0.007) and MA profile (57.5% vs. 36.7%, p = 0.008). Moreover, patients with HER2 1+/2+ tumors were older (p = 0.047). After a median follow-up of 9.7 years, HER2 2+ tumors (compared with HER2 0/1+ tumors) were associated with worse relapse-free survival (RFS) (HR = 3.16, 95% CI [1.27; 7.85], p = 0.034) in a univariate analysis. Overall survival (OS) and RFS were not different in the HER2 0 and 1+/2+ groups. HER2 levels were not significantly associated with OS or RFS in a multivariate analysis. Full article
(This article belongs to the Special Issue Triple Negative Breast Cancer: From Biology to Treatment)
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Review

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31 pages, 756 KiB  
Review
Immune-Based Therapy in Triple-Negative Breast Cancer: From Molecular Biology to Clinical Practice
by Francesca Carlino, Anna Diana, Antonio Piccolo, Anna Ventriglia, Vincenzo Bruno, Irene De Santo, Ortensio Letizia, Ferdinando De Vita, Bruno Daniele, Fortunato Ciardiello and Michele Orditura
Cancers 2022, 14(9), 2102; https://doi.org/10.3390/cancers14092102 - 23 Apr 2022
Cited by 16 | Viewed by 4548
Abstract
Triple-negative breast cancer (TNBC) has been considered for many years an orphan disease in terms of therapeutic options, with conventional chemotherapy (CT) still representing the mainstay of treatment in the majority of patients. Although breast cancer (BC) has been historically considered a “cold [...] Read more.
Triple-negative breast cancer (TNBC) has been considered for many years an orphan disease in terms of therapeutic options, with conventional chemotherapy (CT) still representing the mainstay of treatment in the majority of patients. Although breast cancer (BC) has been historically considered a “cold tumor”, exciting progress in the genomic field leading to the characterization of the molecular portrait and the immune profile of TNBC has opened the door to novel therapeutic strategies, including Immune Checkpoint Inhibitors (ICIs), Poly ADP-Ribose Polymerase (PARP) inhibitors and Antibody Drug Conjugates (ADCs). In particular, compared to standard CT, the immune-based approach has been demonstrated to improve progression-free survival (PFS) and overall survival (OS) in metastatic PD-L1-positive TNBC and the pathological complete response rate in the early setting, regardless of PD-L1 expression. To date, PD-L1 has been widely used as a predictor of the response to ICIs; however, many patients do not benefit from the addition of immunotherapy. Therefore, PD-L1 is not a reliable predictive biomarker of the response, and its accuracy remains controversial due to the lack of a consensus about the assay, the antibody, and the scoring system to adopt, as well as the spatial and temporal heterogeneity of the PD-L1 status. In the precision medicine era, there is an urgent need to identify more sensitive biomarkers in the BC immune oncology field other than just PD-L1 expression. Through the characterization of the tumor microenvironment (TME), the analysis of peripheral blood and the evaluation of immune gene signatures, novel potential biomarkers have been explored, such as the Tumor Mutational Burden (TMB), Microsatellite Instability/Mismatch Repair Deficiency (MSI/dMMR) status, genomic and epigenomic alterations and tumor-infiltrating lymphocytes (TILs). This review aims to summarize the recent knowledge on BC immunograms and on the biomarkers proposed to support ICI-based therapy in TNBC, as well as to provide an overview of the potential strategies to enhance the immune response in order to overcome the mechanisms of resistance. Full article
(This article belongs to the Special Issue Triple Negative Breast Cancer: From Biology to Treatment)
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23 pages, 1073 KiB  
Review
Are Transcription Factors Plausible Oncotargets for Triple Negative Breast Cancers?
by Marta Marqués, Maria Alba Sorolla, Izaskun Urdanibia, Eva Parisi, Iván Hidalgo, Serafín Morales, Antonieta Salud and Anabel Sorolla
Cancers 2022, 14(5), 1101; https://doi.org/10.3390/cancers14051101 - 22 Feb 2022
Cited by 8 | Viewed by 3132
Abstract
Breast cancer (BC) is the most diagnosed cancer worldwide and one of the main causes of cancer deaths. BC is a heterogeneous disease composed of different BC intrinsic subtypes such as triple-negative BC (TNBC), which is one of the most aggressive subtypes and [...] Read more.
Breast cancer (BC) is the most diagnosed cancer worldwide and one of the main causes of cancer deaths. BC is a heterogeneous disease composed of different BC intrinsic subtypes such as triple-negative BC (TNBC), which is one of the most aggressive subtypes and which lacks a targeted therapy. Recent comprehensive analyses across cell types and cancer types have outlined a vast network of protein–protein associations between transcription factors (TFs). Not surprisingly, protein–protein networks central to oncogenesis and disease progression are highly altered during TNBC pathogenesis and are responsible for the activation of oncogenic programs, such as uncontrollable proliferation, epithelial-to-mesenchymal transition (EMT) and stemness. From the therapeutic viewpoint, inhibiting the interactions between TFs represents a very significant challenge, as the contact surfaces of TFs are relatively large and featureless. However, promising tools have emerged to offer a solution to the targeting problem. At the clinical level, some TF possess diagnostic and prognostic value in TNBC. In this review, we outline the recent advances in TFs relevant to TNBC growth and progression. Moreover, we highlight different targeting approaches to inhibit these TFs. Furthermore, the validity of such TFs as clinical biomarkers has been explored. Finally, we discuss how research is likely to evolve in the field. Full article
(This article belongs to the Special Issue Triple Negative Breast Cancer: From Biology to Treatment)
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