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10 pages, 561 KiB

Open AccessArticle

Which Patients Do We Need to Test for BRCA1/2 Mutation? Feasibility of Adjuvant Olaparib Treatment in Early Breast Cancer–Real-World Data from Two Large German Breast Centers

by Dominik Dannehl, Tobias Engler, Léa Louise Volmer, Christian Martin Tegeler, Julia Fusshoeller, Emma Gabrysch, Kenneth Eissler, Anna Seller, Eva-Maria Grischke, Markus Hahn, Ines Gruber, Fabienne Schochter, Kerstin Pfister, Kristina Veselinovic, Elena Leinert, Brigitte Rack, Visnja Fink, Wolfgang Janni, Sara Yvonne Brucker, Andreas Daniel Hartkopf and Henning Schäffler Show full author list Hide full author list

Cancers 2023, 15(15), 3847; https://doi.org/10.3390/cancers15153847 - 28 Jul 2023

Cited by 2 | Viewed by 1272

Abstract

Background: Approximately 6% of women with breast cancer carry pathogenic germline variants in predisposition genes such as BRCA1 and BRCA2. Depending on personal and family cancer history, it is therefore recommended to test for hereditary breast cancer. Moreover, as shown by the phase [...] Read more.

Background: Approximately 6% of women with breast cancer carry pathogenic germline variants in predisposition genes such as BRCA1 and BRCA2. Depending on personal and family cancer history, it is therefore recommended to test for hereditary breast cancer. Moreover, as shown by the phase III OlympiA trial, olaparib significantly improves overall survival in patients with HER2 negative (HER2−) early breast cancer who (1) carry a BRCA1 or BRCA2 germline mutation (gBRCA1/2-positive), (2) have received (neo)adjuvant chemotherapy and (3) are at high clinical risk. The objective of the current analysis was to determine the number of patients with early HER2− breast cancer who are at high clinical risk, according to the inclusion criteria of OlympiA, and to estimate how many of these patients would meet the criteria for hereditary cancer testing in a real-world analysis. Methods: All patients included in this retrospective analysis were treated for early breast cancer (eBC) at the Department of Gynecology and Obstetrics, Ulm University Hospital, Germany, and the Department of Women’s Health at Tuebingen University Hospital, Germany, between January 2018 and December 2020. Patients were identified as high risk, in line with the clinicopathological determiners used in the OlympiA trial. The criteria of the German Consortium for Hereditary Breast and Ovarian Cancer were used to identify patients who qualify for hereditary cancer testing. Results: Of 2384 eligible patients, 1738 patients (72.9%) showed a hormone receptor positive (HR+)/HER2− tumor biology, 345 patients (14.5%) displayed HER2+ breast cancer and 301 patients (12.6%) suffered from HR-/HER2− breast cancer (TNBC). Of 2039 HER2− breast cancer patients, 271 patients (13.3%) were at high clinical risk. This cohort encompassed 130 of the 1738 patients with HR+/HER2− breast cancer (7.5%) and 141 of 301 patients with TNBC (46.8%). A total of 121 of 271 patients (44.6%) with high clinical risk met the criteria for hereditary cancer testing (34 of 130 (26.2%) HR+/HER2− patients and 87 of 141 (61.7%) patients with TNBC). Conclusion: Approximately one in ten patients with HR+/HER2−, and half of the patients with TNBC, meet the high-risk criteria according to OlympiA. Half of these patients do not meet the criteria for hereditary cancer testing and should therefore be tested for the presence of gBRCA1/2 mutations, irrespective of their own or family cancer history. The overall number of patients with early breast cancer benefiting from olaparib needs to be investigated in future studies. Full article

(This article belongs to the Special Issue New Insights into Targeted Drugs for Breast Cancer)

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22 pages, 3035 KiB

Open AccessArticle

Efficacy of a HER2-Targeted Thorium-227 Conjugate in a HER2-Positive Breast Cancer Bone Metastasis Model

by Jenny Karlsson, Urs B. Hagemann, Véronique Cruciani, Christoph A. Schatz, Derek Grant, Christine Ellingsen, Alexander Kristian, Shirin Katoozi, Dessislava Mihaylova, Steinar R. Uran, Mari Suominen, Roger M. Bjerke, Olav B. Ryan and Alan Cuthbertson

Cancers 2023, 15(13), 3419; https://doi.org/10.3390/cancers15133419 - 29 Jun 2023

Viewed by 1866

Abstract

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 15–30% of breast cancers but has low expression in normal tissue, making it attractive for targeted alpha therapy (TAT). HER2-positive breast cancer typically metastasizes to bone, resulting in incurable disease and significant morbidity [...] Read more.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 15–30% of breast cancers but has low expression in normal tissue, making it attractive for targeted alpha therapy (TAT). HER2-positive breast cancer typically metastasizes to bone, resulting in incurable disease and significant morbidity and mortality. Therefore, new strategies for HER2-targeting therapy are needed. Here, we present the preclinical in vitro and in vivo characterization of the HER2-targeted thorium-227 conjugate (HER2-TTC) TAT in various HER2-positive cancer models. In vitro, HER2-TTC showed potent cytotoxicity in various HER2-expressing cancer cell lines and increased DNA double strand break formation and the induction of cell cycle arrest in BT-474 cells. In vivo, HER2-TTC demonstrated dose-dependent antitumor efficacy in subcutaneous xenograft models. Notably, HER2-TTC also inhibited intratibial tumor growth and tumor-induced abnormal bone formation in an intratibial BT-474 mouse model that mimics breast cancer metastasized to bone. Furthermore, a match in HER2 expression levels between primary breast tumor and matched bone metastases samples from breast cancer patients was observed. These results demonstrate proof-of-concept for TAT in the treatment of patients with HER2-positive breast cancer, including cases where the tumor has metastasized to bone. Full article

(This article belongs to the Special Issue New Insights into Targeted Drugs for Breast Cancer)

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16 pages, 6145 KiB

Open AccessArticle

Cytotoxic Activity, Anti-Migration and In Silico Study of Black Ginger (Kaempferia parviflora) Extract against Breast Cancer Cell

by Indah Hairunisa, Mohd Fadzelly Abu Bakar, Muhammad Da’i, Fazleen Izzany Abu Bakar and Eka Siswanto Syamsul

Cancers 2023, 15(10), 2785; https://doi.org/10.3390/cancers15102785 - 17 May 2023

Cited by 5 | Viewed by 2287

Abstract

Metastatic breast cancer remains the leading cause of death in women worldwide. This condition necessitates extensive research to find an effective treatment, one of which is the natural medicine approach. Kaempferia parviflora (KP) is a plant believed to possess anticancer properties. Therefore, this [...] Read more.

Metastatic breast cancer remains the leading cause of death in women worldwide. This condition necessitates extensive research to find an effective treatment, one of which is the natural medicine approach. Kaempferia parviflora (KP) is a plant believed to possess anticancer properties. Therefore, this study aims to determine KP’s bioactive compound, cytotoxic, and anti-migration activity in the highly metastatic breast cancer cell line model 4T1, also in the breast cancer cell model MCF-7 and noncancerous cell line NIH-3T3. Maceration with ethanol (EEKP) and infusion with distilled water (EWKP) was used for extraction. The MTT assay was used to test for cytotoxicity, and the scratch wound healing assay was used to test for the inhibition of migration. Phytochemical profiling of EEKP was performed using UHPLC-MS, and the results were studied for in silico molecular docking. Result showed that EEKP had a better cytotoxic activity than EWKP with an IC₅₀ value of 128.33 µg/mL (24 h) and 115.09 µg/mL (48 h) on 4T1 cell line, and 138.43 µg/mL (24 h) and 124.81 µg/mL (48 h) on MCF-7 cell line. Meanwhile, no cytotoxic activity was observed at concentrations ranging from 3–250 µg/mL in NIH-3T3. EEKP also showed anti-migration activity in a concentration of 65 µg/mL. Mass Spectrophotometer (MS) structures from EEKP are 5-Hydroxy-7,4′-dimethoxyflavanone (HDMF), 5-Hydro-7,8,2′-trimethoxyflavanone (HTMF), Retusine, and Denbinobin. The in silico docking was investigated for receptors Bcl-2, Bcl-XL, ERK2, and FAK, as well as their activities. In silico result indicates that HTMF and denbinobin are bioactive compounds responsible for EEKP’s cytotoxic and anti-migration activity. These two compounds and standardized plant extract can be further studied as potential breast cancer treatment candidates. Full article

(This article belongs to the Special Issue New Insights into Targeted Drugs for Breast Cancer)

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14 pages, 2339 KiB

Open AccessArticle

Androgen Receptor Is Expressed in the Majority of Breast Cancer Brain Metastases and Is Subtype-Dependent

by Kevin Yijun Fan, Rania Chehade, Maleeha Qazi, Veronika Moravan, Sharon Nofech-Mozes and Katarzyna J. Jerzak

Cancers 2023, 15(10), 2748; https://doi.org/10.3390/cancers15102748 - 13 May 2023

Viewed by 1263

Abstract

We aimed to evaluate the expression of the “targetable” androgen receptor (AR) in breast cancer brain metastases (BrM). An established, retrospective 57-patient cohort with metastatic breast cancer who underwent surgery for BrM at the Sunnybrook Odette Cancer Centre between 1999–2013 was studied. AR [...] Read more.

We aimed to evaluate the expression of the “targetable” androgen receptor (AR) in breast cancer brain metastases (BrM). An established, retrospective 57-patient cohort with metastatic breast cancer who underwent surgery for BrM at the Sunnybrook Odette Cancer Centre between 1999–2013 was studied. AR expression in BrM samples was assessed in triplicate using immunohistochemistry (IHC). AR positive status was defined as nuclear AR expression ≥ 10% by IHC using the SP107 antibody. The median age of patients was 52 years (range 32–85 years). 28 (49%) of BrM were HER2+, 17 (30%) were hormone receptor positive (HR+)/HER2−, and 12 (21%) were triple negative breast cancers (TNBCs). 56% (n = 32/57) of BrM were AR positive, and median AR expression was 20% (CI 1.6–38.3%). AR expression was different across breast cancer subtypes; AR was most frequently expressed in HER2+ (n = 21/28), followed by HR+/HER2− (n = 9/17), and lowest in TNBC (n = 2/12) BrM (p = 0.003). Patients with AR positive versus AR negative BrM had similar overall survival (12.5 vs. 7.9 months, p = 0.6), brain-specific progression-free survival (8.0 vs. 5.1 months, p = 0.95), and time from breast cancer diagnosis to BrM diagnosis (51 vs. 29 months, p = 0.16). AR is expressed in the majority of breast cancer BrM and represents a potential therapeutic target. Full article

(This article belongs to the Special Issue New Insights into Targeted Drugs for Breast Cancer)

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14 pages, 2285 KiB

Open AccessArticle

Sensitization of Resistant Cells with a BET Bromodomain Inhibitor in a Cell Culture Model of Deep Intrinsic Resistance in Breast Cancer

by Balraj Singh, Vanessa N. Sarli, Ryan D. Milligan, Hannah E. Kinne, Anna Shamsnia, Laura J. Washburn, Sridevi Addanki and Anthony Lucci

Cancers 2023, 15(7), 2036; https://doi.org/10.3390/cancers15072036 - 29 Mar 2023

Viewed by 1295

Abstract

We treated highly metabolically adaptable (SUM149-MA) triple-negative inflammatory breast cancer cells and their control parental SUM149-Luc cell line with JQ1 for long periods to determine its efficacy at inhibiting therapy-resistant cells. After 20 days of treatment with 1–2 µM of JQ1, which killed [...] Read more.

We treated highly metabolically adaptable (SUM149-MA) triple-negative inflammatory breast cancer cells and their control parental SUM149-Luc cell line with JQ1 for long periods to determine its efficacy at inhibiting therapy-resistant cells. After 20 days of treatment with 1–2 µM of JQ1, which killed majority of cells in the parental cell line, a large number of SUM149-MA cells survived, consistent with their pan-resistant nature. Interestingly, though, the JQ1 treatment sensitized resistant cancer cells in both the SUM149-MA and SUM149-Luc cell lines to subsequent treatment with doxorubicin and paclitaxel. To measure JQ1-mediated sensitization of resistant cancer cells, we first eradicated approximately 99% of relatively chemotherapy-sensitive cancer cells in culture dishes by long treatments with doxorubicin or paclitaxel, and then analyzed the remaining resistant cells for survival and growth into colonies. In addition, combination, rather than sequential, treatment with JQ1 and doxorubicin was also effective in overcoming resistance. Notably, Western blotting showed that JQ1-treated cancer cells had significantly lower levels of PD-L1 protein than did untreated cells, indicating that JQ1 treatment may reduce tumor-mediated immune suppression and improve the response to immunotherapy targeting PD-L1. Finally, JQ1 treatment with a low 62.5 nM dose sensitized another resistant cell line, FC-IBC02-MA, to treatment with doxorubicin and paclitaxel. Full article

(This article belongs to the Special Issue New Insights into Targeted Drugs for Breast Cancer)

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21 pages, 3043 KiB

Open AccessArticle

Antigens Expressed by Breast Cancer Cells Undergoing EMT Stimulate Cytotoxic CD8⁺ T Cell Immunity

by Faye A. Camp, Tonya M. Brunetti, Michelle M. Williams, Jessica L. Christenson, Varsha Sreekanth, James C. Costello, Zachary L. Z. Hay, Ross M. Kedl, Jennifer K. Richer and Jill E. Slansky

Cancers 2022, 14(18), 4397; https://doi.org/10.3390/cancers14184397 - 09 Sep 2022

Cited by 2 | Viewed by 2995

Abstract

Antigenic differences formed by alterations in gene expression and alternative splicing are predicted in breast cancer cells undergoing epithelial to mesenchymal transition (EMT) and the reverse plasticity known as MET. How these antigenic differences impact immune interactions and the degree to which they [...] Read more.

Antigenic differences formed by alterations in gene expression and alternative splicing are predicted in breast cancer cells undergoing epithelial to mesenchymal transition (EMT) and the reverse plasticity known as MET. How these antigenic differences impact immune interactions and the degree to which they can be exploited to enhance immune responses against mesenchymal cells is not fully understood. We utilized a master microRNA regulator of EMT to alter mesenchymal-like EO771 mammary carcinoma cells to a more epithelial phenotype. A computational approach was used to identify neoantigens derived from the resultant differentially expressed somatic variants (SNV) and alternative splicing events (neojunctions). Using whole cell vaccines and peptide-based vaccines, we find superior cytotoxicity against the more-epithelial cells and explore the potential of neojunction-derived antigens to elicit T cell responses through experiments designed to validate the computationally predicted neoantigens. Overall, results identify EMT-associated splicing factors common to both mouse and human breast cancer cells as well as immunogenic SNV- and neojunction-derived neoantigens in mammary carcinoma cells. Full article

(This article belongs to the Special Issue New Insights into Targeted Drugs for Breast Cancer)

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20 pages, 3173 KiB

Open AccessArticle

NPC1 Confers Metabolic Flexibility in Triple Negative Breast Cancer

by Kathleen I. O’Neill, Li-Wei Kuo, Michelle M. Williams, Hanne Lind, Lyndsey S. Crump, Nia G. Hammond, Nicole S. Spoelstra, M. Cecilia Caino and Jennifer K. Richer

Cancers 2022, 14(14), 3543; https://doi.org/10.3390/cancers14143543 - 21 Jul 2022

Cited by 8 | Viewed by 3049

Abstract

Triple-negative breast cancer (TNBC) often undergoes at least partial epithelial-to-mesenchymal transition (EMT) to facilitate metastasis. Identifying EMT-associated characteristics can reveal novel dependencies that may serve as therapeutic vulnerabilities in this aggressive breast cancer subtype. We found that NPC1, which encodes the lysosomal [...] Read more.

Triple-negative breast cancer (TNBC) often undergoes at least partial epithelial-to-mesenchymal transition (EMT) to facilitate metastasis. Identifying EMT-associated characteristics can reveal novel dependencies that may serve as therapeutic vulnerabilities in this aggressive breast cancer subtype. We found that NPC1, which encodes the lysosomal cholesterol transporter Niemann–Pick type C1 is highly expressed in TNBC as compared to estrogen receptor-positive (ER+) breast cancer, and is significantly elevated in high-grade disease. We demonstrated that NPC1 is directly targeted by microRNA-200c (miR-200c), a potent suppressor of EMT, providing a mechanism for its differential expression in breast cancer subtypes. The silencing of NPC1 in TNBC causes an accumulation of cholesterol-filled lysosomes, and drives decreased growth in soft agar and invasive capacity. Conversely, overexpression of NPC1 in an ER+ cell line increases invasion and growth in soft agar. We further identified TNBC cell lines as cholesterol auxotrophs, however, they do not solely depend on NPC1 for adequate cholesterol supply. The silencing of NPC1 in TNBC cell lines led to altered mitochondrial function and morphology, suppression of mTOR signaling, and accumulation of autophagosomes. A small molecule inhibitor of NPC1, U18666A, decreased TNBC proliferation and synergized with the chemotherapeutic drug, paclitaxel. This work suggests that NPC1 promotes aggressive characteristics in TNBC, and identifies NPC1 as a potential therapeutic target. Full article

(This article belongs to the Special Issue New Insights into Targeted Drugs for Breast Cancer)

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19 pages, 3427 KiB

Open AccessArticle

Focal Adhesion Kinase Provides a Collateral Vulnerability That Can Be Leveraged to Improve mTORC1 Inhibitor Efficacy

by Leslie Cuellar-Vite, Kristen L. Weber-Bonk, Fadi W. Abdul-Karim, Christine N. Booth and Ruth A. Keri

Cancers 2022, 14(14), 3374; https://doi.org/10.3390/cancers14143374 - 11 Jul 2022

Cited by 2 | Viewed by 2315

Abstract

The PI3K/AKT/mTORC1 pathway is a major therapeutic target for many cancers, particularly breast cancer. Everolimus is an mTORC1 inhibitor used in metastatic estrogen receptor-positive (ER+) and epidermal growth factor receptor 2-negative (HER2-) breast cancer. However, mTORC1 inhibitors have limited efficacy in other breast [...] Read more.

The PI3K/AKT/mTORC1 pathway is a major therapeutic target for many cancers, particularly breast cancer. Everolimus is an mTORC1 inhibitor used in metastatic estrogen receptor-positive (ER+) and epidermal growth factor receptor 2-negative (HER2-) breast cancer. However, mTORC1 inhibitors have limited efficacy in other breast cancer subtypes. We sought to discover collateral sensitivities to mTORC1 inhibition that could be exploited to improve therapeutic response. Using a mouse model of breast cancer that is intrinsically resistant to mTORC1 inhibition, we found that rapamycin alters the expression of numerous extracellular matrix genes, suggesting a potential role for integrins/FAK in controlling mTORC1-inhibitor efficacy. FAK activation was also inversely correlated with rapamycin response in breast cancer cell lines. Supporting its potential utility in patients, FAK activation was observed in >50% of human breast cancers. While blocking FAK in mouse models of breast cancer that are highly responsive to rapamycin had no impact on tumor growth, FAK inhibition sensitized rapamycin-resistant tumors to mTORC1 inhibition. These data reveal an innate dependency on FAK when mTORC1 signaling is lost in tumors that are resistant to mTORC1 inhibitors. They also suggest a precision medicine approach to improving mTORC1 inhibitor efficacy in resistant cancers by suppressing FAK signaling. Full article

(This article belongs to the Special Issue New Insights into Targeted Drugs for Breast Cancer)

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19 pages, 3284 KiB

Open AccessArticle

Targeting MUC1-C Suppresses Chronic Activation of Cytosolic Nucleotide Receptors and STING in Triple-Negative Breast Cancer

by Nami Yamashita, Atsushi Fushimi, Yoshihiro Morimoto, Atrayee Bhattacharya, Masayuki Hagiwara, Masaaki Yamamoto, Tsuyoshi Hata, Geoffrey I. Shapiro, Mark D. Long, Song Liu and Donald Kufe

Cancers 2022, 14(11), 2580; https://doi.org/10.3390/cancers14112580 - 24 May 2022

Cited by 14 | Viewed by 2345

Abstract

The MUC1-C apical transmembrane protein is activated in the acute response of epithelial cells to inflammation. However, chronic MUC1-C activation promotes cancer progression, emphasizing the importance of MUC1-C as a target for treatment. We report here that MUC1-C is necessary for intrinsic expression [...] Read more.

The MUC1-C apical transmembrane protein is activated in the acute response of epithelial cells to inflammation. However, chronic MUC1-C activation promotes cancer progression, emphasizing the importance of MUC1-C as a target for treatment. We report here that MUC1-C is necessary for intrinsic expression of the RIG-I, MDA5 and cGAS cytosolic nucleotide pattern recognition receptors (PRRs) and the cGAS-stimulator of IFN genes (STING) in triple-negative breast cancer (TNBC) cells. Consistent with inducing the PRR/STING axis, MUC1-C drives chronic IFN-

β

production and activation of the type I interferon (IFN) pathway. MUC1-C thereby induces the IFN-related DNA damage resistance gene signature (IRDS), which includes ISG15, in linking chronic inflammation with DNA damage resistance. Targeting MUC1-C in TNBC cells treated with carboplatin or the PARP inhibitor olaparib further demonstrated that MUC1-C is necessary for expression of PRRs, STING and ISG15 and for intrinsic DNA damage resistance. Of translational relevance, MUC1 significantly associates with upregulation of STING and ISG15 in TNBC tumors and is a target for treatment with CAR T cells, antibody–drug conjugates (ADCs) and direct inhibitors that are under preclinical and clinical development. Full article

(This article belongs to the Special Issue New Insights into Targeted Drugs for Breast Cancer)

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15 pages, 2055 KiB

Open AccessArticle

Endocrine Therapy-Resistant Breast Cancer Cells Are More Sensitive to Ceramide Kinase Inhibition and Elevated Ceramide Levels Than Therapy-Sensitive Breast Cancer Cells

by Purab Pal, Alec Millner, Svetlana E. Semina, Rosemary J. Huggins, Logan Running, Diana S. Aga, Debra A. Tonetti, Rachel Schiff, Geoffrey L. Greene, G. Ekin Atilla-Gokcumen and Jonna Frasor

Cancers 2022, 14(10), 2380; https://doi.org/10.3390/cancers14102380 - 12 May 2022

Cited by 5 | Viewed by 2528

Abstract

ET resistance is a critical problem for estrogen receptor-positive (ER+) breast cancer. In this study, we have investigated how alterations in sphingolipids promote cell survival in ET-resistant breast cancer. We have performed LC-MS-based targeted sphingolipidomics of tamoxifen-sensitive and -resistant MCF-7 breast cancer cell [...] Read more.

ET resistance is a critical problem for estrogen receptor-positive (ER+) breast cancer. In this study, we have investigated how alterations in sphingolipids promote cell survival in ET-resistant breast cancer. We have performed LC-MS-based targeted sphingolipidomics of tamoxifen-sensitive and -resistant MCF-7 breast cancer cell lines. Follow-up studies included treatments of cell lines and patient-derived xenograft organoids (PDxO) with small molecule inhibitors; cytometric analyses to measure cell death, proliferation, and apoptosis; siRNA-mediated knockdown; RT-qPCR and Western blot for gene and protein expression; targeted lipid analysis; and lipid addback experiments. We found that tamoxifen-resistant cells have lower levels of ceramides and hexosylceramides compared to their tamoxifen-sensitive counterpart. Upon perturbing the sphingolipid pathway with small molecule inhibitors of key enzymes, we identified that CERK is essential for tamoxifen-resistant breast cancer cell survival, as well as a fulvestrant-resistant PDxO. CERK inhibition induces ceramide-mediated cell death in tamoxifen-resistant cells. Ceramide-1-phosphate (C1P) partially reverses CERK inhibition-induced cell death in tamoxifen-resistant cells, likely through lowering endogenous ceramide levels. Our findings suggest that ET-resistant breast cancer cells maintain lower ceramide levels as an essential pro-survival mechanism. Consequently, ET-resistant breast cancer models have a unique dependence on CERK as its activity can inhibit de novo ceramide production. Full article

(This article belongs to the Special Issue New Insights into Targeted Drugs for Breast Cancer)

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Review

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12 pages, 816 KiB

Open AccessReview

Modern Management and Diagnostics in HER2+ Breast Cancer with CNS Metastasis

by Surbhi Warrior, Adam Cohen-Nowak and Priya Kumthekar

Cancers 2023, 15(11), 2908; https://doi.org/10.3390/cancers15112908 - 25 May 2023

Cited by 1 | Viewed by 1453

Abstract

Patients with HER2-positive breast cancer have seen improved survival and outcomes over the past two decades. As patients live longer, the incidence of CNS metastases has increased in this population. The authors’ review outlines the most current data in HER2-positive brain and leptomeningeal [...] Read more.

Patients with HER2-positive breast cancer have seen improved survival and outcomes over the past two decades. As patients live longer, the incidence of CNS metastases has increased in this population. The authors’ review outlines the most current data in HER2-positive brain and leptomeningeal metastases and discuss the current treatment paradigm in this disease. Up to 55% of HER2-positive breast cancer patients go on to experience CNS metastases. They may present with a variety of focal neurologic symptoms, such as speech changes or weakness, and may also have more diffuse symptoms related to high intracranial pressure, such as headaches, nausea, or vomiting. Treatment can include focal treatments, such as surgical resection or radiation (focal or whole-brain radiation), as well as systemic therapy options or even intrathecal therapy in the case of leptomeningeal disease. There have been multiple advancements in systemic therapy for these patients over the past few years, including the availability of tucatinib and trastuzumab-deruxtecan. Hope remains high as clinical trials for CNS metastases receive greater attention and as other HER2-directed methods are being studied in clinical trials with the goal of better outcomes for these patients. Full article

(This article belongs to the Special Issue New Insights into Targeted Drugs for Breast Cancer)

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21 pages, 596 KiB

Open AccessReview

Triple Negative Breast Cancer: Updates on Classification and Treatment in 2021

by Maroun Bou Zerdan, Tala Ghorayeb, Fares Saliba, Sabine Allam, Morgan Bou Zerdan, Marita Yaghi, Nadeem Bilani, Rola Jaafar and Zeina Nahleh

Cancers 2022, 14(5), 1253; https://doi.org/10.3390/cancers14051253 - 28 Feb 2022

Cited by 69 | Viewed by 7681

Abstract

Breast cancer (BC) is the most common malignancy affecting women. It is a highly heterogeneous disease broadly defined by the differential expression of cell surface receptors. In the United States, triple negative breast cancer (TNBC) represents 15 to 20% of all BC. When [...] Read more.

Breast cancer (BC) is the most common malignancy affecting women. It is a highly heterogeneous disease broadly defined by the differential expression of cell surface receptors. In the United States, triple negative breast cancer (TNBC) represents 15 to 20% of all BC. When compared with other subtypes of BC, TNBC tends to present in younger women, and has a higher mortality rate of 40% in advanced stages within the first 5 years after diagnosis. TNBC has historically had limited treatment options when compared to other types of BC. The mainstay of treatment for TNBC remains cytotoxic chemotherapy despite the emergence of new biologic and targeted agents. Defining the specific tumor molecular profile including PDL-1 and androgen receptor testing is expanding treatment options in the clinical setting. Identifying more targetable, novel biomarkers that may better define therapeutic targets or prognostic markers is currently underway. TNBC nomenclature is expected to be updated in favor of other nomenclature which would help direct therapy, and further redefine TNBC’s heterogeneity. Given the continuous advances in the field of TNBC, this review assesses the latest developments in basic characterization, subtyping, and treatment of TNBC, including novel drug developments with antibody-drug conjugates, immune checkpoint inhibitors, PARP inhibitors and androgen receptor targeted agents. Future trials are necessary in the face of these innovations to further support the use of new therapies in TNBC and the detection of the appropriate biomarkers. Full article

(This article belongs to the Special Issue New Insights into Targeted Drugs for Breast Cancer)

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