scholarly journals AKT Inhibitors: New Weapons in the Fight Against Breast Cancer?

2021 ◽  
Vol 12 ◽  
Author(s):  
Federica Martorana ◽  
Gianmarco Motta ◽  
Giuliana Pavone ◽  
Lucia Motta ◽  
Stefania Stella ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
New Combination ◽  
Cancer Subtypes ◽  
Combination Strategies

The serine/threonine kinase AKT is a key component of the PI3K/AKT/mTOR signaling pathway as it exerts a pivotal role in cell growth, proliferation, survival, and metabolism. Deregulation of this pathway is a common event in breast cancer including hormone receptor-positive (HR+) disease, HER2-amplified, and triple negative tumors. Hence, targeting AKT represents an attractive treatment option for many breast cancer subtypes, especially those resistant to conventional treatments. Several AKT inhibitors have been recently developed and two ATP-competitive compounds, capivasertib and ipatasertib, have been extensively tested in phase I and II clinical trials either alone, with chemotherapy, or with hormonal agents. Additionally, phase III trials of capivasertib and ipatasertib are already under way in HR+ and triple-negative breast cancer. While the identification of predictive biomarkers of response and resistance to AKT inhibition represents an unmet need, new combination strategies are under investigation aiming to boost the therapeutic efficacy of these drugs. As such, trials combining capivasertib and ipatasertib with CDK4/6 inhibitors, immune checkpoint inhibitors, and PARP inhibitors are currently ongoing. This review summarizes the available evidence on AKT inhibition in breast cancer, reporting both efficacy and toxicity data from clinical trials along with the available translational correlates and then focusing on the potential use of these drugs in new combination strategies.

scholarly journals Immune Check-Point Inhibitors in Breast Cancer: Current Evidence and Future Directions

2021 ◽  
Vol 8 (3) ◽  
Author(s):  
Mosteiro M ◽  
◽  
Cejuela M ◽  
Pernas S ◽  
◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Triple Negative ◽  
New Combination ◽  
Current Evidence ◽  
Check Point ◽  
Future Directions ◽  
Combination Strategies ◽  
Check Point Inhibitors

Check-point inhibitors have erupted as a treatment option for numerous kinds of neoplasms. Although there have been some achievements, the evidence supporting their use in breast cancer is scarce. Combinations with chemotherapy seem to provide better outcomes, and triple negative is the subtype most likely to benefit from them. New combination strategies are undergoing research to improve these results. Other approaches to determining biomarkers that identify which populations clearly benefit from these therapies are needed. Here, we review the clinical data of the role of immune check-point inhibitors in early and advanced breast cancer and present emerging strategies.

scholarly journals Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4139
Author(s):  
Pere Llinàs-Arias ◽  
Sandra Íñiguez-Muñoz ◽  
Kelly McCann ◽  
Leonie Voorwerk ◽  
Javier I. J. Orozco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Regulatory Elements ◽  
Her2 Overexpression ◽  
Breast Cancers ◽  
Cancer Subtypes

Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15–20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher intrinsic aggressiveness, and worse outcomes than other breast cancer subtypes. Immune checkpoint inhibitors have shown promising efficacy for early-stage and advanced TNBC, but this seems limited to a subgroup of patients. Understanding the underlying mechanisms that determine immunotherapy efficiency is essential to identifying which TNBC patients will respond to immunotherapy-based treatments and help to develop new therapeutic strategies. Emerging evidence supports that epigenetic alterations, including aberrant chromatin architecture conformation and the modulation of gene regulatory elements, are critical mechanisms for immune escape. These alterations are particularly interesting since they can be reverted through the inhibition of epigenetic regulators. For that reason, several recent studies suggest that the combination of epigenetic drugs and immunotherapeutic agents can boost anticancer immune responses. In this review, we focused on the contribution of epigenetics to the crosstalk between immune and cancer cells, its relevance on immunotherapy response in TNBC, and the potential benefits of combined treatments.

scholarly journals Immunotherapy in Triple-Negative Breast Cancer: Present and Future

2019 ◽  
Vol 11 (4) ◽  
pp. 259-271 ◽  
Author(s):  
Isaac Kim ◽  
Katherine Sanchez ◽  
Heather L. McArthur ◽  
David Page
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Survival Benefit ◽  
Triple Negative ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Immune Checkpoint Blockade ◽  
Phase Iii ◽  
Breast Cancers ◽  
Effective Treatment Option

Abstract Purpose of Review Immunotherapy is emerging as an effective treatment option for metastatic triple-negative breast cancer. In this review, we summarize clinical data of immunotherapy in triple-negative breast cancer and comment on future directions in the field. Recent Findings IMpassion130 was a phase III trial that demonstrated progression-free survival benefit, and potentially overall survival benefit, of first-line chemotherapy (nab-paclitaxel) plus anti-programmed death ligand 1 (PD-L1) atezolizumab, among PD-L1-positive metastatic triple-negative breast cancers. Studies are ongoing to evaluate other combination therapies with immune checkpoint blockade in TNBC, and to evaluate efficacy in PD-L1-negative tumors and in later lines of therapy. Summary Immunotherapy is now a standard option in the treatment of triple-negative breast cancer. Ongoing trials may expand the degree of clinical benefit. Further work is ongoing to identify novel predictive biomarkers, which in the future may enable a personalized approach of combination immunotherapy.

scholarly journals Breast Cancer Immunotherapy: From Biology to Current Clinical Applications

2020 ◽  
pp. 113-124
Author(s):  
Jorge Henrique Santos Leal ◽  
Heather McArthur
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Immune Checkpoint ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Metastatic Breast ◽  
Response Rates ◽  
Phase Iii

Therapeutic strategies for the treatment of breast cancer have historically been determined by the presence or absence of hormone receptors and HER2 amplification and/or protein expression. For patients with breast cancer that lack these biomarkers, the so-called ‘triple-negative’ subtype, chemotherapy has been the cornerstone of cure and palliation. However, with the recent successful development of immune checkpoint molecules that target cytotoxic T-lymphocyte antigen-4, programmed cell death-1 (PD-1), and PD-ligand 1 (PD-L1), improved survival has been reported across a range of tumour types including melanoma, lung, and bladder cancer. In metastatic breast cancer, trials of single-agent immune checkpoint inhibitors (ICI) have resulted in limited overall response rates; however, strategies that combine local or systemic therapies with ICI have improved response rates and, in some cases, improved survival. For example, the addition of an anti-PD-L1 inhibitor, atezolizumab, to nab-paclitaxel chemotherapy for newly diagnosed metastatic triple-negative breast cancer demonstrated an improvement in overall survival in an informal analysis of the PD-L1-positive subset in a recently reported Phase III clinical trial. These results ultimately led to U.S. Food and Drug Administration (FDA) approval for an ICI for the treatment of breast cancer, with numerous other health authorities following suit. Herein, the authors describe the biology behind ICI, the rationale for ICI administration in breast cancer, the related clinical trial data reported to date, and promising future strategies.

BRCA Mutational Status is a Promising Predictive Biomarker for Platinum- based Chemotherapy in Triple-Negative Breast Cancer

2020 ◽  
Vol 21 (10) ◽  
pp. 962-973 ◽  
Author(s):  
Amal Tazzite ◽  
Hassan Jouhadi ◽  
Abdellatif Benider ◽  
Sellama Nadifi
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Susceptibility Gene ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Breast Cancer Susceptibility Gene ◽  
Mutational Status ◽  
Platinum Based Chemotherapy

Triple-negative breast cancer (TNBC) can be distinguished from other breast malignancies by the lack of expression of estrogen receptors (ER), progesterone receptors (PR) as well as human epidermal growth factor receptor 2 (HER2). TNBC is associated with adverse clinical outcomes and high risk of metastasis. Currently, several clinical and translational reports are focusing on developing targeted therapies for this aggressive cancer. In addition to approved targeted drugs such as poly(ADP-ribose) polymerase inhibitors (PARPi) and immune-checkpoint inhibitors, platinum-based chemotherapy is still a cornerstone therapeutic option in TNBC. However, despite the observed improved outcomes with platinum- based chemotherapy in TNBC, there is still a large proportion of patients who do not respond to this treatment, hence, the need for predictive biomarkers to stratify TNBC patients and therefore, avoiding unwanted toxicities of these agents. With the emergence of genetic testing, several recent studies suggested mutations in breast cancer susceptibility gene (BRCA) in TNBC patients as important predictors of outcomes. These mutations alter the homologous recombination repair (HRR) mechanisms leading to genomic instability. Consequently, sensitivity to platinum-based treatments in this subpopulation of TNBC patients may be explained by cell death enhanced by deoxyribonucleic acid (DNA) damage induced by these potent anticancer drugs. Through this paper, we review several recent studies on this topic to better understand the mechanisms and discuss the potential of BRCA mutational status as a predictive biomarker of platinum-based chemotherapy in TNBC.

scholarly journals Clinical Data on Immunotherapy in Breast Cancer

Breast Care ◽  
2020 ◽  
Vol 15 (5) ◽  
pp. 450-469
Author(s):  
Julia Caroline Radosa ◽  
Lisa Stotz ◽  
Carolin Müller ◽  
Askin Canguel Kaya ◽  
Erich-Franz Solomayer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
First Line ◽  
Metastatic Setting ◽  
Epidermal Growth

<b><i>Background:</i></b> Breast cancer has traditionally been considered to have a low immunogenic potential compared to other tumor entities. <b><i>Summary:</i></b> The most extensively studied immunotherapeutic agents for breast cancer to date are immune checkpoint inhibitors, with the results of the IMpassion130 trial leading to the approval of atezolizumab plus nab-paclitaxel for first-line treatment of programmed cell death ligand 1-positive, metastatic, triple-negative breast cancer, and studies in earlier stages have yielded promising results. Other immunotherapeutic options being assessed in phases 2 and 3 trials include vaccine-based therapies and treatment with anti-human epidermal growth factor receptor 2 (H-directed immune-linked antibodies) and substances evaluated in early clinical trials as cellular therapies (adoptive cell therapy and chimeric antigen receptor T cells). <b><i>Key Messages:</i></b> Immunotherapy is an emerging modality for the treatment of breast cancer, as evidenced by the plethora of preclinical and clinical concepts and ongoing trials. Early studies established the role of immunotherapeutic agents in the metastatic setting. Ongoing studies will expand our knowledge about the timing of administration, best partners for combination therapy, and predictive biomarkers to guide immunotherapy for breast cancer.

scholarly journals Emerging Therapeutic Drugs in Metastatic Triple-Negative Breast Cancer

2021 ◽  
Vol 15 ◽  
pp. 117822342110024
Author(s):  
Élia Cipriano ◽  
Alexandra Mesquita
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Triple Negative Breast Cancer ◽  
Systemic Chemotherapy ◽  
Triple Negative ◽  
Treatment Options ◽  
Phase Iii ◽  
Molecular Testing ◽  
Targeted Drugs ◽  
Metastatic Setting

Metastatic triple-negative breast cancer (TNBC) is a heterogeneous disease with a poor prognosis and currently with few treatment options. Treatment of these patients is highly based on systemic chemotherapy. Some targeted drugs were recently approved for these patients: two poly(ADP-ribose) polymerase inhibitors in patients with germline BRCA1/2 mutations (olaparib and talazoparib), immune checkpoint inhibitors in association with chemotherapy if programmed death-ligand 1 positive (atezolizumab plus nabpaclitaxel and pembrolizumab plus chemotherapy [nabpaclitaxel, paclitaxel, and carboplatin plus gemcitabine]), and an antibody-drug conjugate sacituzumab-govitecan in heavily pretreated patients (at least 2 previous lines for the metastatic setting). Combinations using these and other targeted treatment options are under investigation in early and late clinical trials, and we will probably have some practice-changing results in the new future. Other targeted drugs explored in phase II and phase III clinical trials are PI3K/AKT pathway inhibitors and androgen receptor antagonists in patients with alterations in these signaling pathways. The definition of molecular subtypes has been essential for the development of these treatment strategies. Soon, the treatment of metastatic TNBC could be based on personalized medicine using molecular testing for targeted drugs instead of only systemic chemotherapy. The authors present a review of emerging treatment options in metastatic TNBC, focusing on targeted drugs, including the recent data published in 2020.

scholarly journals CSCs in Breast Cancer—One Size Does Not Fit All: Therapeutic Advances in Targeting Heterogeneous Epithelial and Mesenchymal CSCs

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1128 ◽  
Author(s):  
Andrew Sulaiman ◽  
Sarah McGarry ◽  
Xianghui Han ◽  
Sheng Liu ◽  
Lisheng Wang
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Triple Negative ◽  
Signal Pathway ◽  
Future Research ◽  
Research Needs ◽  
Disease Relapse ◽  
Differential Signal ◽  
Cancer Subtypes ◽  
Potential Inhibitors

Unlike other breast cancer subtypes, triple-negative breast cancer (TNBC) has no specific targets and is characterized as one of the most aggressive subtypes of breast cancer that disproportionately accounts for the majority of breast cancer-related deaths. Current conventional chemotherapeutics target the bulk tumor population, but not the cancer stem cells (CSCs) that are capable of initiating new tumors to cause disease relapse. Recent studies have identified distinct epithelial-like (E) ALDH+ CSCs, mesenchymal-like (M) CD44+/CD24− CSCs, and hybrid E/M ALDH+/CD44+/CD24− CSCs. These subtypes of CSCs exhibit differential signal pathway regulations, possess plasticity, and respond differently to treatment. As such, co-inhibition of different subtypes of CSCs is key to viable therapy. This review serves to highlight different pathway regulations in E and M CSCs in TNBC, and to further describe their role in disease progression. Potential inhibitors targeting E and/or M CSCs based on clinical trials are summarized for further investigation. Since future research needs to adopt suitable tumor models and take into account the divergence of E and M CSCs for the development of effective treatments, TNBC models for clinically translatable studies are further discussed.

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