Immunotherapy and Targeted Therapy in Breast Cancer

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biology biology	3.6	5.7	2012	16.4 Days	CHF 2700
Cancers cancers	4.5	8.0	2009	17.4 Days	CHF 2900
Current Oncology curroncol	2.8	3.3	1994	19.8 Days	CHF 2200
Diseases diseases	2.9	0.8	2013	21.4 Days	CHF 1800
Onco onco	-	-	2021	27.8 Days	CHF 1000

21 pages, 1649 KiB

Open AccessReview

Therapeutic Delivery of Tumor Suppressor miRNAs for Breast Cancer Treatment

by Sonali S. Shinde, Sakeel Ahmed, Jonaid Ahmad Malik, Umme Hani, Afreen Khanam, Faisal Ashraf Bhat, Suhail Ahmad Mir, Mohammed Ghazwani, Shadma Wahab, Nazima Haider and Abdulrahman A. Almehizia

Biology 2023, 12(3), 467; https://doi.org/10.3390/biology12030467 - 19 Mar 2023

Cited by 22 | Viewed by 4891

Abstract

The death rate from breast cancer (BC) has dropped due to early detection and sophisticated therapeutic options, yet drug resistance and relapse remain barriers to effective, systematic treatment. Multiple mechanisms underlying miRNAs appear crucial in practically every aspect of cancer progression, including carcinogenesis, [...] Read more.

The death rate from breast cancer (BC) has dropped due to early detection and sophisticated therapeutic options, yet drug resistance and relapse remain barriers to effective, systematic treatment. Multiple mechanisms underlying miRNAs appear crucial in practically every aspect of cancer progression, including carcinogenesis, metastasis, and drug resistance, as evidenced by the elucidation of drug resistance. Non-coding RNAs called microRNAs (miRNAs) attach to complementary messenger RNAs and degrade them to inhibit the expression and translation to proteins. Evidence suggests that miRNAs play a vital role in developing numerous diseases, including cancer. They affect genes critical for cellular differentiation, proliferation, apoptosis, and metabolism. Recently studies have demonstrated that miRNAs serve as valuable biomarkers for BC. The contrast in the expression of miRNAs in normal tissue cells and tumors suggest that miRNAs are involved in breast cancer. The important aspect behind cancer etiology is the deregulation of miRNAs that can specifically influence cellular physiology. The main objective of this review is to emphasize the role and therapeutic capacity of tumor suppressor miRNAs in BC and the advancement in the delivery system that can deliver miRNAs specifically to cancerous cells. Various approaches are used to deliver these miRNAs to the cancer cells with the help of carrier molecules, like nanoparticles, poly D, L-lactic-co-glycolic acid (PLGA) particles, PEI polymers, modified extracellular vesicles, dendrimers, and liposomes. Additionally, we discuss advanced strategies of TS miRNA delivery techniques such as viral delivery, self-assembled RNA-triple-helix hydrogel drug delivery systems, and hyaluronic acid/protamine sulfate inter-polyelectrolyte complexes. Subsequently, we discuss challenges and prospects on TS miRNA therapeutic delivery in BC management so that miRNAs will become a routine technique in developing individualized patient profiles. Full article

(This article belongs to the Topic Immunotherapy and Targeted Therapy in Breast Cancer)

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15 pages, 1977 KiB

Open AccessArticle

The Value of Tucatinib in Metastatic HER2-Positive Breast Cancer Patients: An Italian Cost-Effectiveness Analysis

by Ippazio Cosimo Antonazzo, Paolo Angelo Cortesi, Gerardo Miceli Sopo, Giampiero Mazzaglia, Pierfranco Conte and Lorenzo Giovanni Mantovani

Cancers 2023, 15(4), 1175; https://doi.org/10.3390/cancers15041175 - 12 Feb 2023

Cited by 1 | Viewed by 2557

Abstract

Background: This study was aimed at estimating the appropriate price of tucatinib plus trastuzumab and capecitabine (TXC), as third-line treatment, in HER2⁺ breast cancer (BC) patients from the Italian National Health System (NHS) perspective. Methods: A partitioned survival model with three mutually [...] Read more.

Background: This study was aimed at estimating the appropriate price of tucatinib plus trastuzumab and capecitabine (TXC), as third-line treatment, in HER2⁺ breast cancer (BC) patients from the Italian National Health System (NHS) perspective. Methods: A partitioned survival model with three mutually exclusive health states (i.e., progression-free survival (PFS), progressive disease (PD), and death) was used to estimate the price of tucatinib vs trastuzumab emtansine (TDM-1), considering a willingness to pay (WTP) of 60,000 EUR. Data from the HER2CLIMB trial, the Italian population, and the literature were used as input. The model also estimated the total costs and the life-years (LY) of TXC and TDM1. Deterministic and probabilistic (PSA) sensitivity analyses were conducted to evaluate the robustness of the model. Results: In the base case scenario, the appropriate price of tucatinib was 4828.44 EUR per cycle. The TXC resulted in +0.28 LYs and +16,628 EUR compared with TDM-1. Results were mainly sensitive to therapy intensity variation. In PSA analysis, TXC resulted cost-effective in 53% of the simulations. Assuming a WTP ranging 20,000–80,000 EUR, the tucatinib price ranged from 4090.60 to 5197.41 EUR. Conclusions: This study estimated the appropriate price for tucatinib according to different WTP in order to help healthcare decision makers to better understand the treatment value. Full article

(This article belongs to the Topic Immunotherapy and Targeted Therapy in Breast Cancer)

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9 pages, 1356 KiB

Open AccessSystematic Review

Optimal Choice as First-Line Therapy for Patients with Triple-Negative Breast Cancer: A Bayesian Network Meta-Analysis

by Yiqun Han, Jiayu Wang, Yun Wu, Hangcheng Xu, Yan Wang and Binghe Xu

Curr. Oncol. 2022, 29(12), 9172-9180; https://doi.org/10.3390/curroncol29120718 - 25 Nov 2022

Cited by 1 | Viewed by 2611

Abstract

To identify the advantageous therapy as the first-line treatment for patients with triple-negative breast cancer (TNBC). Randomized controlled trials were searched for on Medline, Embase, ClinicalTrials.gov, and the Cochrane Library between January 2001 and December 2021. The primary endpoint was progression-free survival (PFS) [...] Read more.

To identify the advantageous therapy as the first-line treatment for patients with triple-negative breast cancer (TNBC). Randomized controlled trials were searched for on Medline, Embase, ClinicalTrials.gov, and the Cochrane Library between January 2001 and December 2021. The primary endpoint was progression-free survival (PFS) and secondary endpoints were overall survival (OS) and treatment-related adverse events (TRAEs). A Bayesian framework was applied to facilitate indirect comparisons, of which the outcomes were presented using cumulative ranking curve (SUCRA) values, synthesized hazard ratio, risk ratio, and 95% credible interval. A total of 3140 patients were identified. Pooled results of PFS revealed that chemotherapy plus AKT inhibitors (AKTi) was likely the most effective therapy among enrolled therapies (SUCRA = 91.6%), of which the result remained consistent in comparative analysis for OS. In addition, no significant difference was detected between PD-1/PD-L1 antibodies in patients, whereas the PD-1 inhibitors (PD-1i) regimen was advantageous over PD-L1 inhibitor (PD-L1i) therapy for PD-L1 positive TNBC. Concerning TRAEs, an apparent heterogeneity associated with safety profiles were denoted among enrolled agents. Chemotherapy plus AKTi was the most effective therapy with comparable safety profiles. Chemotherapy plus the anti-PD-1 regimen was advantageous over the combination therapy based on the PD-L1 blockade. Full article

(This article belongs to the Topic Immunotherapy and Targeted Therapy in Breast Cancer)

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17 pages, 3246 KiB

Open AccessArticle

Upregulation of Receptor Tyrosine Kinase Activity and Stemness as Resistance Mechanisms to Akt Inhibitors in Breast Cancer

by Tiffany Tsang, Qingling He, Emily B. Cohen, Casey Stottrup, Evan C. Lien, Huiqi Zhang, C. Geoffrey Lau and Y. Rebecca Chin

Cancers 2022, 14(20), 5006; https://doi.org/10.3390/cancers14205006 - 13 Oct 2022

Cited by 4 | Viewed by 2538

Abstract

The PI3K/Akt pathway is frequently deregulated in human cancers, and multiple Akt inhibitors are currently under clinical evaluation. Based on the experience from other molecular targeted therapies, however, it is likely that acquired resistance will be developed in patients treated with Akt inhibitors. [...] Read more.

The PI3K/Akt pathway is frequently deregulated in human cancers, and multiple Akt inhibitors are currently under clinical evaluation. Based on the experience from other molecular targeted therapies, however, it is likely that acquired resistance will be developed in patients treated with Akt inhibitors. We established breast cancer models of acquired resistance by prolonged treatment of cells with allosteric or ATP-competitive Akt inhibitors. Phospho-Receptor tyrosine kinase (Phospho-RTK) arrays revealed hyper-phosphorylation of multiple RTKS, including EGFR, Her2, HFGR, EhpB3 and ROR1, in Akt-inhibitor-resistant cells. Importantly, resistance can be overcome by treatment with an EGFR inhibitor. We further showed that cancer stem cells (CSCs) are enriched in breast tumor cells that have developed resistance to Akt inhibitors. Several candidates of CSC regulators, such as ID4, are identified by RNA sequencing. Cosmic analysis indicated that sensitivity of tumor cells to Akt inhibitors can be predicted by ID4 and stem cell/epithelial–mesenchymal transition pathway targets. These findings indicate the potential of targeting the EGFR pathway and CSC program to circumvent Akt inhibitor resistance in breast cancer. Full article

(This article belongs to the Topic Immunotherapy and Targeted Therapy in Breast Cancer)

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10 pages, 891 KiB

Open AccessArticle

Phase II Study Combining Pembrolizumab with Aromatase Inhibitor in Patients with Metastatic Hormone Receptor Positive Breast Cancer

by Xuan Ge, Susan E. Yost, Jin Sun Lee, Paul H. Frankel, Christopher Ruel, Yujie Cui, Mireya Murga, Aileen Tang, Norma Martinez, Samuel Chung, Christina Yeon, Daphne Stewart, Daneng Li, Swapnil Rajurkar, George Somlo, Joanne Mortimer, James Waisman and Yuan Yuan

Cancers 2022, 14(17), 4279; https://doi.org/10.3390/cancers14174279 - 1 Sep 2022

Cited by 5 | Viewed by 2571

Abstract

This study investigated the safety and antitumor activity of aromatase inhibitors (AI) with immune checkpoint inhibitor (ICI) pembrolizumab in patients with hormone receptor positive (HR⁺) human epidermal growth factor receptor 2-negative (HER2⁻) metastatic breast cancer (MBC) in a phase [...] Read more.

This study investigated the safety and antitumor activity of aromatase inhibitors (AI) with immune checkpoint inhibitor (ICI) pembrolizumab in patients with hormone receptor positive (HR⁺) human epidermal growth factor receptor 2-negative (HER2⁻) metastatic breast cancer (MBC) in a phase II study with a safety lead-in (NCT 02648477). Patients received pembrolizumab plus AI up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria were HR⁺ HER2⁻ MBC; RECIST v1.1 measurable disease; adequate organ function; and ECOG 0-1. Primary endpoints were safety and overall response rate. A 3-at-risk design was used for the safety lead-in with a targeted accrual of 20 patients. Grade 2 adverse events (AEs) included 35% fatigue, 20% rash, and 10% hot flashes. Grade 3 immune-related AEs (irAEs) related to pembrolizumab included 5% elevated AST/ALT, 5% rash, and 5% lymphopenia. Two (10%) patients had partial responses, three (15%) had stable disease, and 15 (75%) had progression of disease. Median progression-free survival was 1.8 months (95% CI 1.6, 2.6), median overall survival was 17.2 months (95% CI 9.4, NA), and median follow-up time was 40.1 months (range 31.3–46.8 months). The combination was well tolerated, but clinical activity was comparable to AI alone. Full article

(This article belongs to the Topic Immunotherapy and Targeted Therapy in Breast Cancer)

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17 pages, 3265 KiB

Open AccessArticle

HER2-Displaying M13 Bacteriophages induce Therapeutic Immunity against Breast Cancer

by Junbiao Wang, Alessia Lamolinara, Laura Conti, Mara Giangrossi, Lishan Cui, Maria Beatrice Morelli, Consuelo Amantini, Maurizio Falconi, Caterina Bartolacci, Cristina Andreani, Fiorenza Orlando, Mauro Provinciali, Francesco Domenico Del Pizzo, Francesca Russo, Barbara Belletti, Federica Riccardo, Elisabetta Bolli, Elena Quaglino, Federica Cavallo, Augusto Amici, Manuela Iezzi and Cristina Marchini Show full author list Hide full author list

Cancers 2022, 14(16), 4054; https://doi.org/10.3390/cancers14164054 - 22 Aug 2022

Cited by 18 | Viewed by 4228

Abstract

The advent of trastuzumab has significantly improved the prognosis of HER2-positive (HER2+) breast cancer patients; nevertheless, drug resistance limits its clinical benefit. Anti-HER2 active immunotherapy represents an attractive alternative strategy, but effective immunization needs to overcome the patient’s immune tolerance against the self-HER2. [...] Read more.

The advent of trastuzumab has significantly improved the prognosis of HER2-positive (HER2+) breast cancer patients; nevertheless, drug resistance limits its clinical benefit. Anti-HER2 active immunotherapy represents an attractive alternative strategy, but effective immunization needs to overcome the patient’s immune tolerance against the self-HER2. Phage display technology, taking advantage of phage intrinsic immunogenicity, permits one to generate effective cancer vaccines able to break immune tolerance to self-antigens. In this study, we demonstrate that both preventive and therapeutic vaccination with M13 bacteriophages, displaying the extracellular (EC) and transmembrane (TM) domains of human HER2 or its Δ16HER2 splice variant on their surface (ECTM and Δ16ECTM phages), delayed mammary tumor onset and reduced tumor growth rate and multiplicity in ∆16HER2 transgenic mice, which are tolerant to human ∆16HER2. This antitumor protection correlated with anti-HER2 antibody production. The molecular mechanisms underlying the anticancer effect of vaccine-elicited anti-HER2 antibodies were analyzed in vitro against BT-474 human breast cancer cells, sensitive or resistant to trastuzumab. Immunoglobulins (IgG) purified from immune sera reduced cell viability mainly by impairing ERK phosphorylation and reactivating retinoblastoma protein function in both trastuzumab-sensitive and -resistant BT-474 cells. In conclusion, we demonstrated that phage-based HER2 vaccines impair mammary cancer onset and progression, opening new perspectives for HER2+ breast cancer treatment. Full article

(This article belongs to the Topic Immunotherapy and Targeted Therapy in Breast Cancer)

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22 pages, 1815 KiB

Open AccessReview

The Effects of Tamoxifen on Tolerogenic Cells in Cancer

by Ros Akmal Mohd Idris, Ali Mussa, Suhana Ahmad, Mohammad A. I. Al-Hatamleh, Rosline Hassan, Tengku Ahmad Damitri Al Astani Tengku Din, Wan Faiziah Wan Abdul Rahman, Norhafiza Mat Lazim, Jennifer C. Boer, Magdalena Plebanski and Rohimah Mohamud

Biology 2022, 11(8), 1225; https://doi.org/10.3390/biology11081225 - 17 Aug 2022

Cited by 9 | Viewed by 4521

Abstract

Tamoxifen (TAM) is the most prescribed selective estrogen receptor modulator (SERM) to treat hormone-receptor-positive breast cancer patients and has been used for more than 20 years. Its role as a hormone therapy is well established; however, the potential role in modulating tolerogenic cells [...] Read more.

Tamoxifen (TAM) is the most prescribed selective estrogen receptor modulator (SERM) to treat hormone-receptor-positive breast cancer patients and has been used for more than 20 years. Its role as a hormone therapy is well established; however, the potential role in modulating tolerogenic cells needs to be better clarified. Infiltrating tumor-microenvironment-regulatory T cells (TME-Tregs) are important as they serve a suppressive function through the transcription factor Forkhead box P3 (Foxp3). Abundant studies have suggested that Foxp3 regulates the expression of several genes (CTLA-4, PD-1, LAG-3, TIM-3, TIGIT, TNFR2) involved in carcinogenesis to utilize its tumor suppressor function through knockout models. TAM is indirectly concomitant via the Cre/loxP system by allowing nuclear translocation of the fusion protein, excision of the floxed STOP cassette and heritable expression of encoding fluorescent protein in a cohort of cells that express Foxp3. Moreover, TAM administration in breast cancer treatment has shown its effects directly through MDSCs by the enrichment of its leukocyte populations, such as NK and NKT cells, while it impairs the differentiation and activation of DCs. However, the fundamental mechanisms of the reduction of this pool by TAM are unknown. Here, we review the vital effects of TAM on Tregs for a precise mechanistic understanding of cancer immunotherapies. Full article

(This article belongs to the Topic Immunotherapy and Targeted Therapy in Breast Cancer)

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15 pages, 11043 KiB

Open AccessArticle

Identification and Characterization of Tunneling Nanotubes Involved in Human Mast Cell FcεRI-Mediated Apoptosis of Cancer Cells

by Elnaz Ahani, Mohammad Fereydouni, Mona Motaghed and Christopher L. Kepley

Cancers 2022, 14(12), 2944; https://doi.org/10.3390/cancers14122944 - 14 Jun 2022

Cited by 8 | Viewed by 2469

Abstract

Mast cells (MCs) are found in practically all tissues where they participate in innate and adaptive immune responses. They are also found in and around tumors, yet their interactions with cancer cells and the resulting impact on cancer cell growth and metastasis are [...] Read more.

Mast cells (MCs) are found in practically all tissues where they participate in innate and adaptive immune responses. They are also found in and around tumors, yet their interactions with cancer cells and the resulting impact on cancer cell growth and metastasis are not well understood. In this study, we examined a novel mechanism of IgE-FcεRI-mediated, intercellular communication between human adipose-derived mast cells (ADMC) and cancer cells. The formation of heterotypic tunneling nanotubes (TnT) and membrane structures between MCs and tumor cells in vitro was examined using microscopy and a diverse array of molecule-specific indicator dyes. We show that several MC-specific structures are dependent on the specific interactions between human tumor IgE-sensitized MCs and antigens on the tumor cell surface. The formation of TnT, membrane blebs and other MC-specific structures paralleled FcεRI-degranulation occurring within 30 min and persisting for up to 24 h. The TnT-specific adhesion of FcεRI-activated MCs to tumor cells was characterized by the transport of the MC granule content into the tumor cells, including tryptase and TNF-α. This interaction led to apoptosis of the tumor cells, which differs from previous studies examining tissue cells within the cancer microenvironment. The formation of heterotypic TnT results in stimulation of an invasive tumor cell phenotype and increased tumor cell invasion and chemoresistance of the cancer cells. These studies describe a heretofore-unrecognized mechanism underlying IgE-mediated interactions and FcεRI-activated MC-mediated killing of tumor cells through the formation of TnT. Full article

(This article belongs to the Topic Immunotherapy and Targeted Therapy in Breast Cancer)

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24 pages, 5398 KiB

Open AccessArticle

Low-Salt Diet Reduces Anti-CTLA4 Mediated Systemic Immune-Related Adverse Events while Retaining Therapeutic Efficacy against Breast Cancer

by Durga Khandekar, Debolanle O. Dahunsi, Isaac V. Manzanera Esteve, Sonya Reid, Jeffrey C. Rathmell, Jens Titze and Venkataswarup Tiriveedhi

Biology 2022, 11(6), 810; https://doi.org/10.3390/biology11060810 - 25 May 2022

Cited by 6 | Viewed by 3207

Abstract

Immune checkpoint inhibitor (ICI) therapy has revolutionized the breast cancer treatment landscape. However, ICI-induced systemic inflammatory immune-related adverse events (irAE) remain a major clinical challenge. Previous studies in our laboratory and others have demonstrated that a high-salt (HS) diet induces inflammatory activation of [...] Read more.

Immune checkpoint inhibitor (ICI) therapy has revolutionized the breast cancer treatment landscape. However, ICI-induced systemic inflammatory immune-related adverse events (irAE) remain a major clinical challenge. Previous studies in our laboratory and others have demonstrated that a high-salt (HS) diet induces inflammatory activation of CD4+T cells leading to anti-tumor responses. In our current communication, we analyzed the impact of dietary salt modification on therapeutic and systemic outcomes in breast-tumor-bearing mice following anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibody (mAb) based ICI therapy. As HS diet and anti-CTLA4 mAb both exert pro-inflammatory activation of CD4+T cells, we hypothesized that a combination of these would lead to enhanced irAE response, while low-salt (LS) diet through blunting peripheral inflammatory action of CD4+T cells would reduce irAE response. We utilized an orthotopic murine breast tumor model by injecting Py230 murine breast cancer cells into syngeneic C57Bl/6 mice. In an LS diet cohort, anti-CTLA4 mAb treatment significantly reduced tumor progression (day 35, 339 ± 121 mm³), as compared to isotype mAb (639 ± 163 mm³, p < 0.05). In an HS diet cohort, treatment with anti-CTLA4 reduced the survival rate (day 80, 2/15) compared to respective normal/regular salt (NS) diet cohort (8/15, p < 0.05). Further, HS plus anti-CTLA4 mAb caused an increased expression of inflammatory cytokines (IFNγ and IL-1β) in lung infiltrating and peripheral circulating CD4+T cells. This inflammatory activation of CD4+T cells in the HS plus anti-CTLA4 cohort was associated with the upregulation of inflammasome complex activity. However, an LS diet did not induce any significant irAE response in breast-tumor-bearing mice upon treatment with anti-CTLA4 mAb, thus suggesting the role of high-salt diet in irAE response. Importantly, CD4-specific knock out of osmosensitive transcription factor NFAT5 using CD4cre/creNFAT5flox/flox transgenic mice caused a downregulation of high-salt-mediated inflammatory activation of CD4+T cells and irAE response. Taken together, our data suggest that LS diet inhibits the anti-CTLA4 mAb-induced irAE response while retaining its anti-tumor efficacy. Full article

(This article belongs to the Topic Immunotherapy and Targeted Therapy in Breast Cancer)

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17 pages, 696 KiB

Open AccessReview

Definition of High-Risk Early Hormone-Positive HER2−Negative Breast Cancer: A Consensus Review

by Mattia Garutti, Gaia Griguolo, Andrea Botticelli, Giulia Buzzatti, Carmine De Angelis, Lorenzo Gerratana, Chiara Molinelli, Vincenzo Adamo, Giampaolo Bianchini, Laura Biganzoli, Giuseppe Curigliano, Michelino De Laurentiis, Alessandra Fabi, Antonio Frassoldati, Alessandra Gennari, Caterina Marchiò, Francesco Perrone, Giuseppe Viale, Claudio Zamagni, Alberto Zambelli, Lucia Del Mastro, Sabino De Placido, Valentina Guarneri, Paolo Marchetti and Fabio Puglisi Show full author list Hide full author list

Cancers 2022, 14(8), 1898; https://doi.org/10.3390/cancers14081898 - 9 Apr 2022

Cited by 34 | Viewed by 6166

Abstract

Breast cancer is one of the major causes of cancer-related morbidity and mortality in women worldwide. During the past three decades, several improvements in the adjuvant treatment of hormone receptor-positive/HER2−negative breast cancer have been achieved with the introduction of optimized adjuvant chemotherapy and [...] Read more.

Breast cancer is one of the major causes of cancer-related morbidity and mortality in women worldwide. During the past three decades, several improvements in the adjuvant treatment of hormone receptor-positive/HER2−negative breast cancer have been achieved with the introduction of optimized adjuvant chemotherapy and endocrine treatment. However, estimating the risk of relapse of breast cancer on an individual basis is still challenging. The IRIDE (hIGh Risk DEfinition in breast cancer) working group was established with the aim of reviewing evidence from the literature to synthesize the current relevant features that predict hormone-positive/HER2−negative early breast cancer relapse. A panel of experts in breast cancer was involved in identifying clinical, pathological, morphological, and genetic factors. A RAND consensus method was used to define the relevance of each risk factor. Among the 21 features included, 12 were considered relevant risk factors for relapse. For each of these, we provided a consensus statement and relevant comments on the supporting scientific evidence. This work may guide clinicians in the practical management of hormone-positive/HER2−negative early breast cancers. Full article

(This article belongs to the Topic Immunotherapy and Targeted Therapy in Breast Cancer)

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12 pages, 3275 KiB

Open AccessCase Report

Management of HER2-Positive Breast Cancer for a Young Patient with Visceral Crisis—The Adjuvant Role of Lifestyle Changes

by Larisa Maria Badau, Andrei Dorin Ciocoiu, Cristina Marinela Oprean, Nusa Alina Segarceanu, Adelina Gheju and Brigitha Vlaicu

Curr. Oncol. 2022, 29(3), 1890-1901; https://doi.org/10.3390/curroncol29030154 - 10 Mar 2022

Cited by 2 | Viewed by 5391

Abstract

The safety profile and effectiveness of existing anti-HER2-targeted therapies have not been evaluated in patients with breast cancer and visceral crisis. We report the case of a 26-year-old woman who was diagnosed with advanced HER2-positive breast cancer and initially treated with curative intent [...] Read more.

The safety profile and effectiveness of existing anti-HER2-targeted therapies have not been evaluated in patients with breast cancer and visceral crisis. We report the case of a 26-year-old woman who was diagnosed with advanced HER2-positive breast cancer and initially treated with curative intent therapy in a neoadjuvant setting, using Trastuzumab and Pertuzumab in combination with Docetaxel; her cancer recurred two years later, with liver metastases and pulmonary lymphangitic carcinomatosis, causing visceral crisis. Furthermore, the patient’s clinical status worsened when she developed respiratory failure, hepatomegaly and a severe hepatocytolysis. Since the patient was free of disease more than six months, we started with Paclitaxel half dose because of the hepatic dysfunction, and we gradually reintroduced Trastuzumab and then Pertuzumab. In the meantime, the patient changed her lifestyle by increasing her consumption of fresh fruits and vegetables and fiber and reducing her intake of processed meat, dairy and sugar. As a result, the patient showed a significant improvement in her respiratory symptoms and liver tests in less than two months. Imaging reevaluation showed partial remission of liver metastases and pulmonary lymphangitic carcinomatosis. She underwent seven months of dual anti-HER2 blockade before relapsing cerebrally. Our results suggest that the sequential combination therapy with Trastuzumab, Pertuzumab and Paclitaxel presented in this study, associated with a healthy lifestyle, may be a good management for recurrent HER2-positive breast cancer with pulmonary visceral crisis and severe liver dysfunction. Full article

(This article belongs to the Topic Immunotherapy and Targeted Therapy in Breast Cancer)

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16 pages, 2220 KiB

Open AccessArticle

Prolyl Carboxypeptidase Maintains Receptor Tyrosine Kinase Signaling and Is a Potential Therapeutic Target in Triple Negative Breast Cancer

by Lei Duan, Sarah Calhoun, Ricardo E. Perez, Virgilia Macias, Fatima Mir, Melissa R. Pergande, Paolo Gattuso, Jeffrey A. Borgia and Carl G. Maki

Cancers 2022, 14(3), 739; https://doi.org/10.3390/cancers14030739 - 31 Jan 2022

Cited by 2 | Viewed by 3058

Abstract

TNBC is an aggressive cancer sub-type with limited treatment options and poor prognosis. New therapeutic targets are needed to improve outcomes in TNBC patients. PRCP is a lysosomal serine protease that cleaves peptide substrates when the penultimate amino acid is proline. A role [...] Read more.

TNBC is an aggressive cancer sub-type with limited treatment options and poor prognosis. New therapeutic targets are needed to improve outcomes in TNBC patients. PRCP is a lysosomal serine protease that cleaves peptide substrates when the penultimate amino acid is proline. A role for PRCP in TNBC or other cancers, and its potential as a therapy target has not yet been tested. In the current study, we found high tumor expression of PRCP associates with worse outcome and earlier recurrence in TNBC patients. Knockdown of PRCP or treatment with a small molecule PRCP inhibitor blocked proliferation and survival in TNBC cell lines and inhibited growth of TNBC tumors in mice. Mechanistically, we found PRCP maintains signaling from multiple receptor tyrosine kinases (RTKs), potentially by promoting crosstalk between RTKs and G-protein coupled receptors (GPCRs). Lastly, we found that the PRCP inhibitor caused synergistic killing of TNBC cells when combined with the EGFR and ErbB2 inhibitor lapatinib. Our results suggest that PRCP is potential prognostic marker for TNBC patient outcome and a novel therapeutic target for TNBC treatment. Full article

(This article belongs to the Topic Immunotherapy and Targeted Therapy in Breast Cancer)

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