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Latest Basic, Translational and Clinical Advancements in HER2-Positive Breast Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (1 October 2022) | Viewed by 43003

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Dr. Serenella Pupa

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Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, AmadeoLab, Via Amadeo 42, 20133 Milan, Italy
Interests: HER2-positive breast cancer; triple-negative breast cancer; cancer stem cells

Dr. Elda Tagliabue

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Head of Molecular Targeting Unit, Department of Research, AmadeoLab, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy
Interests: HER2-positive breast cancer; triple-negative breast cancer; tumor microenvironment
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Special Issue Information

Dear colleagues,

Breast cancer is one of the most common malignancies worldwide. More than 400,000 cases of breast cancer were diagnosed in Europe in 2018, and about 98,000 deaths were recorded. Although the introduction of early diagnosis and novel therapeutic approaches to clinical practice has dramatically improved the clinical outcome of breast cancer patients, this malignant disease remains the second-leading cause of cancer-related death worldwide.

Between 15% and 20% of breast cancers harbor HER2 overexpression and/or amplification, which is associated with an aggressive course of disease. While results overwhelmingly demonstrate the clinical benefit of HER2-targeted therapy, a considerable number of patients do not benefit. Thus, advancements in an improved understanding of HER2-positive breast cancer biology, immunology, metabolism, genomics, and epigenetics, as well as the selection of more suited tailored treatments and predictive criteria of response to therapies, are still mandatory goals to be achieved. Indeed, HER2-driven cancer recurrence continues to be a real and significant clinical concern. This Special Issue will bring together expert researchers and physicians focusing on the latest key findings in the field of HER2-driven basic and translational research. It will also cover innovations in detection tools and treatment options of HER2-positive breast cancer.

Dr. Serenella Pupa
Dr. Elda Tagliabue
Guest Editors

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Keywords

the complexity of the HER2 proteome
epithelial–mesenchymal transition and cancer stem cells
metabolism
cross-talk between tumor and surrounding microenvironment
molecular heterogeneity, prognostic and predictive signatures
epigenetics
non-human determinants
radiomics
HER2 scoring systems
liquid biopsy
bio-chemotherapies in neo-adjuvant, adjuvant and metastatic settings
HER2-targeting vaccines: pre-clinical and clinical strategies
immunotherapy: recent advances
molecular nanoclinics
epidemiological risk factors

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Published Papers (10 papers)

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Research

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17 pages, 3751 KiB

Open AccessArticle

HER2 mRNA Levels, Estrogen Receptor Activity and Susceptibility to Trastuzumab in Primary Breast Cancer

by Tiziana Triulzi, Viola Regondi, Elisabetta Venturelli, Patrizia Gasparini, Cristina Ghirelli, Jessica Groppelli, Martina Di Modica, Francesca Bianchi, Loris De Cecco, Lucia Sfondrini and Elda Tagliabue

Cancers 2022, 14(22), 5650; https://doi.org/10.3390/cancers14225650 - 17 Nov 2022

Cited by 2 | Viewed by 1977

Abstract

While the results thus far demonstrate the clinical benefit of trastuzumab in breast cancer (BC), some patients do not respond to this drug. HER2 mRNA, alone or combined with other genes/biomarkers, has been proven to be a powerful predictive marker in several studies. Here, we provide evidence of the association between HER2 mRNA levels and the response to anti-HER2 treatment in HER2-positive BC patients treated with adjuvant trastuzumab and show that this association is independent of estrogen receptor (ER) tumor positivity. While HER2 mRNA expression was significantly correlated with HER2 protein levels in ER-negative tumors, no correlation was found in ER-positive tumors, and HER2 protein expression was not associated with relapse risk. Correlation analyses in the ER-positive subset identified ER activity as the pathway inversely associated with HER2 mRNA. Associations between HER2 levels and oncogene addiction, as well as between HER2 activation and trastuzumab sensitivity, were also observed in vitro in HER2-positive BC cell lines. In ER-positive but not ER-negative BC cells, HER2 transcription was increased by reducing ligand-dependent ER activity or inducing ER degradation. Accordingly, HER2 mRNA levels in patients were found to be inversely correlated with blood levels of estradiol, the natural ligand of ER that induces ER activation. Moreover, low estradiol levels were associated with a lower risk of relapse in HER2-positive BC patients treated with adjuvant trastuzumab. Overall, we found that HER2 mRNA levels, but not protein levels, indicate the HER2 dependency of tumor cells and low estrogen-dependent ER activity in HER2-positive tumors. Full article

(This article belongs to the Special Issue Latest Basic, Translational and Clinical Advancements in HER2-Positive Breast Cancer)

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22 pages, 7143 KiB

Open AccessArticle

Functional Antagonism of Junctional Adhesion Molecule-A (JAM-A), Overexpressed in Breast Ductal Carcinoma In Situ (DCIS), Reduces HER2-Positive Tumor Progression

by Yvonne E. Smith, Guannan Wang, Ciara L. Flynn, Stephen F. Madden, Owen MacEneaney, Rodrigo G. B. Cruz, Cathy E. Richards, Hanne Jahns, Marian Brennan, Mattia Cremona, Bryan T. Hennessy, Katherine Sheehan, Alexander Casucci, Faizah A. Sani, Lance Hudson, Joanna Fay, Sri H. Vellanki, Siobhan O’Flaherty, Marc Devocelle, Arnold D. K. Hill, Kieran Brennan, Saraswati Sukumar and Ann M. Hopkins Show full author list Hide full author list

Cancers 2022, 14(5), 1303; https://doi.org/10.3390/cancers14051303 - 3 Mar 2022

Cited by 2 | Viewed by 3537

Abstract

Breast ductal carcinoma in situ (DCIS) is clinically challenging, featuring high diagnosis rates and few targeted therapies. Expression/signaling from junctional adhesion molecule-A (JAM-A) has been linked to poor prognosis in invasive breast cancers, but its role in DCIS is unknown. Since progression from DCIS to invasive cancer has been linked with overexpression of the human epidermal growth factor receptor-2 (HER2), and JAM-A regulates HER2 expression, we evaluated JAM-A as a therapeutic target in DCIS. JAM-A expression was immunohistochemically assessed in patient DCIS tissues. A novel JAM-A antagonist (JBS2) was designed and tested alone/in combination with the HER2 kinase inhibitor lapatinib, using SUM-225 cells in vitro and in vivo as validated DCIS models. Murine tumors were proteomically analyzed. JAM-A expression was moderate/high in 96% of DCIS patient tissues, versus 23% of normal adjacent tissues. JBS2 bound to recombinant JAM-A, inhibiting cell viability in SUM-225 cells and a primary DCIS culture in vitro and in a chick embryo xenograft model. JBS2 reduced tumor progression in in vivo models of SUM-225 cells engrafted into mammary fat pads or directly injected into the mammary ducts of NOD-SCID mice. Preliminary proteomic analysis revealed alterations in angiogenic and apoptotic pathways. High JAM-A expression in aggressive DCIS lesions and their sensitivity to treatment by a novel JAM-A antagonist support the viability of testing JAM-A as a novel therapeutic target in DCIS. Full article

(This article belongs to the Special Issue Latest Basic, Translational and Clinical Advancements in HER2-Positive Breast Cancer)

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26 pages, 4275 KiB

Open AccessArticle

HER2 Expression in Circulating Tumour Cells Isolated from Metastatic Breast Cancer Patients Using a Size-Based Microfluidic Device

by Cláudia Lopes, Paulina Piairo, Alexandre Chícharo, Sara Abalde-Cela, Liliana R. Pires, Patrícia Corredeira, Patrícia Alves, Laura Muinelo-Romay, Luís Costa and Lorena Diéguez

Cancers 2021, 13(17), 4446; https://doi.org/10.3390/cancers13174446 - 3 Sep 2021

Cited by 26 | Viewed by 4513

Abstract

HER2 is a prognostic and predictive biomarker in breast cancer, normally assessed in tumour biopsy and used to guide treatment choices. Circulating tumour cells (CTCs) escape the primary tumour and enter the bloodstream, exhibiting great metastatic potential and representing a real-time snapshot of the tumour burden. Liquid biopsy offers the unique opportunity for low invasive sampling in cancer patients and holds the potential to provide valuable information for the clinical management of cancer patients. This study assesses the performance of the RUBYchip™, a microfluidic system for CTC capture based on cell size and deformability, and compares it with the only FDA-approved technology for CTC enumeration, CellSearch^®. After optimising device performance, 30 whole blood samples from metastatic breast cancer patients were processed with both technologies. The expression of HER2 was assessed in isolated CTCs and compared to tissue biopsy. Results show that the RUBYchip^TM was able to isolate CTCs with higher efficiency than CellSearch^®, up to 10 times more, averaging all samples. An accurate evaluation of different CTC subpopulations, including HER2+ CTCs, was provided. Liquid biopsy through the use of the RUBYchip^TM in the clinic can overcome the limitations of histological testing and evaluate HER2 status in patients in real-time, helping to tailor treatment during disease evolution. Full article

(This article belongs to the Special Issue Latest Basic, Translational and Clinical Advancements in HER2-Positive Breast Cancer)

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13 pages, 1430 KiB

Open AccessArticle

The Pan-Immune-Inflammation-Value Predicts the Survival of Patients with Human Epidermal Growth Factor Receptor 2 (HER2)—Positive Advanced Breast Cancer Treated with First-Line Taxane-Trastuzumab-Pertuzumab

by Francesca Ligorio, Giovanni Fucà, Emma Zattarin, Riccardo Lobefaro, Luca Zambelli, Rita Leporati, Carmen Rea, Gabriella Mariani, Giulia V. Bianchi, Giuseppe Capri, Filippo de Braud and Claudio Vernieri

Cancers 2021, 13(8), 1964; https://doi.org/10.3390/cancers13081964 - 19 Apr 2021

Cited by 68 | Viewed by 3529

Abstract

Different peripheral blood parameters have emerged as prognostic biomarkers in breast cancer (BC), but their predictive role in Human Epidermal growth factor Receptor 2 positive (HER2+) advanced BC (aBC) patients receiving dual anti-HER2 blockade remains unclear. We evaluated the impact of the Pan-Immune-Inflammatory Value (PIV), defined as the product of peripheral blood neutrophil, platelet, and monocyte counts divided by lymphocyte counts, on the prognosis of HER2+ aBC patients treated with first line trastuzumab-pertuzumab-based biochemotherapy. We also evaluated the association between the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), and the monocyte to lymphocyte ratio (MLR) and clinical outcomes. Cox regression models were used to estimate the impact of these variables, as well as of other clinically relevant covariates, on patient survival. We included 57 HER2+ aBC patients treated with taxane-trastuzumab-pertuzumab in our Institution. High baseline MLR, PLR, and PIV were similarly predictive of worse PFS at univariate analysis, but only high PIV was associated with a trend toward worse PFS at multivariable analysis. Regarding OS, both high PIV and MLR were associated with significantly worse patient survival at univariate analysis, but only the PIV was statistically significantly associated with worse overall survival at multivariable analysis (HR 7.96; 95% CI: 2.18–29.09). Our study reveals the PIV as a new and potent predictor of OS in HER2+ aBC patients treated with first line trastuzumab-pertuzumab-containing biochemotherapy. Prospective studies are needed to validate this new prognostic parameter in HER2+ aBC. Full article

(This article belongs to the Special Issue Latest Basic, Translational and Clinical Advancements in HER2-Positive Breast Cancer)

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20 pages, 3005 KiB

Open AccessArticle

Fatty Acid Synthase Confers Tamoxifen Resistance to ER+/HER2+ Breast Cancer

by Javier A. Menendez, Adriana Papadimitropoulou, Travis Vander Steen, Elisabet Cuyàs, Bharvi P. Oza-Gajera, Sara Verdura, Ingrid Espinoza, Luciano Vellon, Inderjit Mehmi and Ruth Lupu

Cancers 2021, 13(5), 1132; https://doi.org/10.3390/cancers13051132 - 6 Mar 2021

Cited by 23 | Viewed by 4405

Abstract

The identification of clinically important molecular mechanisms driving endocrine resistance is a priority in estrogen receptor-positive (ER+) breast cancer. Although both genomic and non-genomic cross-talk between the ER and growth factor receptors such as human epidermal growth factor receptor 2 (HER2) has frequently been associated with both experimental and clinical endocrine therapy resistance, combined targeting of ER and HER2 has failed to improve overall survival in endocrine non-responsive disease. Herein, we questioned the role of fatty acid synthase (FASN), a lipogenic enzyme linked to HER2-driven breast cancer aggressiveness, in the development and maintenance of hormone-independent growth and resistance to anti-estrogens in ER/HER2-positive (ER+/HER2+) breast cancer. The stimulatory effects of estradiol on FASN gene promoter activity and protein expression were blunted by anti-estrogens in endocrine-responsive breast cancer cells. Conversely, an AKT/MAPK-related constitutive hyperactivation of FASN gene promoter activity was unaltered in response to estradiol in non-endocrine responsive ER+/HER2+ breast cancer cells, and could be further enhanced by tamoxifen. Pharmacological blockade with structurally and mechanistically unrelated FASN inhibitors fully impeded the strong stimulatory activity of tamoxifen on the soft-agar colony forming capacity—an in vitro metric of tumorigenicity—of ER+/HER2+ breast cancer cells. In vivo treatment with a FASN inhibitor completely prevented the agonistic tumor-promoting activity of tamoxifen and fully restored its estrogen antagonist properties against ER/HER2-positive xenograft tumors in mice. Functional cancer proteomic data from The Cancer Proteome Atlas (TCPA) revealed that the ER+/HER2+ subtype was the highest FASN protein expressor compared to basal-like, HER2-enriched, and ER+/HER2-negative breast cancer groups. FASN is a biological determinant of HER2-driven endocrine resistance in ER+ breast cancer. Next-generation, clinical-grade FASN inhibitors may be therapeutically relevant to countering resistance to tamoxifen in FASN-overexpressing ER+/HER2+ breast carcinomas. Full article

(This article belongs to the Special Issue Latest Basic, Translational and Clinical Advancements in HER2-Positive Breast Cancer)

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Review

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15 pages, 855 KiB

Open AccessReview

The Role of MicroRNAs in HER2-Positive Breast Cancer: Where We Are and Future Prospective

by Valentina Fogazzi, Marcel Kapahnke, Alessandra Cataldo, Ilaria Plantamura, Elda Tagliabue, Serena Di Cosimo, Giulia Cosentino and Marilena V. Iorio

Cancers 2022, 14(21), 5326; https://doi.org/10.3390/cancers14215326 - 29 Oct 2022

Cited by 11 | Viewed by 2392

Abstract

Breast cancer that highly expresses human epidermal growth factor receptor 2 (HER2+) represents one of the major breast cancer subtypes, and was associated with a poor prognosis until the introduction of HER2-targeted therapies such as trastuzumab. Unfortunately, up to 30% of patients with HER2+ localized breast cancer continue to relapse, despite treatment. MicroRNAs (miRNAs) are small (approximately 20 nucleotides long) non-coding regulatory oligonucleotides. They function as post-transcriptional regulators of gene expression, binding complementarily to a target mRNA and leading to the arrest of translation or mRNA degradation. In the last two decades, translational research has focused on these small molecules because of their highly differentiated expression patterns in blood and tumor tissue, as well as their potential biological function. In cancer research, they have become pivotal for the thorough understanding of oncogenic biological processes. They might also provide an efficient approach to early monitoring of tumor progression or response to therapy. Indeed, changes in their expression patterns can represent a flag for deeper biological changes. In this review, we sum up the recent literature regarding miRNAs in HER2+ breast cancer, taking into account their potential as powerful prognostic and predictive biomarkers, as well as therapeutic tools. Full article

(This article belongs to the Special Issue Latest Basic, Translational and Clinical Advancements in HER2-Positive Breast Cancer)

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30 pages, 1080 KiB

Open AccessReview

HER-2-Targeted Nanoparticles for Breast Cancer Diagnosis and Treatment

by Leopoldo Sitia, Marta Sevieri, Lorena Signati, Arianna Bonizzi, Arianna Chesi, Francesco Mainini, Fabio Corsi and Serena Mazzucchelli

Cancers 2022, 14(10), 2424; https://doi.org/10.3390/cancers14102424 - 13 May 2022

Cited by 31 | Viewed by 6730

Abstract

Human epidermal growth factor receptor-2 (HER-2) overexpressing breast cancer is a breast cancer subtype characterized by high aggressiveness, high frequency of brain metastases and poor prognosis. HER-2, a glycoprotein belonging to the ErbB receptor family, is overexpressed on the outer membrane of cancer cells and has been an important therapeutic target for the development of targeted drugs, such as the monoclonal antibodies trastuzumab and pertuzumab. These therapies have been available in clinics for more than twenty years. However, despite the initial enthusiasm, a major issue emerged limiting HER-2 targeted therapy efficacy, i.e., the evolution of drug resistance, which could be tackled by nanotechnology. The aim of this review is to provide a first critical update on the different types of HER-2-targeted nanoparticles that have been proposed in the literature in the last decade for therapeutic purposes. We focus on the different targeting strategies that have been explored, their relative outcomes and current limitations that still need to be improved. Then, we review the nanotools developed as diagnostic kits, focusing on the most recent techniques, which allow accurate quantification of HER-2 levels in tissues, with the aim of promoting more personalized medicinal approaches in patients. Full article

(This article belongs to the Special Issue Latest Basic, Translational and Clinical Advancements in HER2-Positive Breast Cancer)

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22 pages, 4105 KiB

Open AccessReview

Immunotherapy for HER2-Positive Breast Cancer: Clinical Evidence and Future Perspectives

by Elisa Agostinetto, Filippo Montemurro, Fabio Puglisi, Carmen Criscitiello, Giampaolo Bianchini, Lucia Del Mastro, Martino Introna, Carlo Tondini, Armando Santoro and Alberto Zambelli

Cancers 2022, 14(9), 2136; https://doi.org/10.3390/cancers14092136 - 25 Apr 2022

Cited by 29 | Viewed by 5753

Abstract

Breast cancer is the most common malignancy among women worldwide, and HER2-positive breast cancer accounts for approximately 15% of all breast cancer diagnoses. The advent of HER2-targeting therapies has dramatically improved the survival of these patients, significantly reducing their risk of recurrence and death. However, as a significant proportion of patients ultimately develop resistance to these therapies, it is extremely important to identify new treatments to further improve their clinical outcomes. Immunotherapy has revolutionized the treatment and history of several cancer types, and it has already been approved as a standard of care for patients with triple-negative breast cancer. Based on a strong preclinical rationale, immunotherapy in HER2-positive breast cancer represents an intriguing field that is currently under clinical investigation. There is a close interplay between HER2-targeting therapies (both approved and under investigation) and the immune system, and several new immunotherapeutic strategies, including immune checkpoint inhibitors, CAR-T cells and therapeutic vaccines, are being studied in this disease. In this narrative review, we discuss the clinical evidence and the future perspectives of immunotherapy for patients with HER2-positive breast cancer. Full article

(This article belongs to the Special Issue Latest Basic, Translational and Clinical Advancements in HER2-Positive Breast Cancer)

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16 pages, 1142 KiB

Open AccessReview

Impact of Immune Cell Heterogeneity on HER2+ Breast Cancer Prognosis and Response to Therapy

by Milena Perrone, Giovanna Talarico, Claudia Chiodoni and Sabina Sangaletti

Cancers 2021, 13(24), 6352; https://doi.org/10.3390/cancers13246352 - 17 Dec 2021

Cited by 5 | Viewed by 3974

Abstract

Breast cancer is a heterogeneous disease with a high degree of diversity among and within tumors, and in relation to its different tumor microenvironment. Compared to other oncotypes, such as melanoma or lung cancer, breast cancer is considered a “cold” tumor, characterized by low T lymphocyte infiltration and low tumor mutational burden. However, more recent evidence argues against this idea and indicates that, at least for specific molecular breast cancer subtypes, the immune infiltrate may be clinically relevant and heterogeneous, with significant variations in its stromal cell/protein composition across patients and tumor stages. High numbers of tumor-infiltrating T cells are most frequent in HER2-positive and basal-like molecular subtypes and are generally associated with a good prognosis and response to therapies. However, effector immune infiltrates show protective immunity in some cancers but not in others. This could depend on one or more immunosuppressive mechanisms acting alone or in concert. Some of them might include, in addition to immune cells, other tumor microenvironment determinants such as the extracellular matrix composition and stiffness as well as stromal cells, like fibroblasts and adipocytes, that may prevent cytotoxic T cells from infiltrating the tumor microenvironment or may inactivate their antitumor functions. This review will summarize the state of the different immune tumor microenvironment determinants affecting HER2+ breast tumor progression, their response to treatment, and how they are modified by different therapeutic approaches. Potential targets within the immune tumor microenvironment will also be discussed. Full article

(This article belongs to the Special Issue Latest Basic, Translational and Clinical Advancements in HER2-Positive Breast Cancer)

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19 pages, 1735 KiB

Open AccessReview

HER2 Signaling and Breast Cancer Stem Cells: The Bridge behind HER2-Positive Breast Cancer Aggressiveness and Therapy Refractoriness

by Serenella M. Pupa, Francesca Ligorio, Valeria Cancila, Alma Franceschini, Claudio Tripodo, Claudio Vernieri and Lorenzo Castagnoli

Cancers 2021, 13(19), 4778; https://doi.org/10.3390/cancers13194778 - 24 Sep 2021

Cited by 28 | Viewed by 4633

Abstract

HER2 overexpression/amplification occurs in 15–20% of breast cancers (BCs) and identifies a highly aggressive BC subtype. Recent clinical progress has increased the cure rates of limited-stage HER2-positive BC and significantly prolonged overall survival in patients with advanced disease; however, drug resistance and tumor recurrence remain major concerns. Therefore, there is an urgent need to increase knowledge regarding HER2 biology and implement available treatments. Cancer stem cells (CSCs) represent a subset of malignant cells capable of unlimited self-renewal and differentiation and are mainly considered to contribute to tumor onset, aggressiveness, metastasis, and treatment resistance. Seminal studies have highlighted the key role of altered HER2 signaling in the maintenance/enrichment of breast CSCs (BCSCs) and elucidated its bidirectional communication with stemness-related pathways, such as the Notch and Wingless/β-catenin cascades. d16HER2, a splice variant of full-length HER2 mRNA, has been identified as one of the most oncogenic HER2 isoform significantly implicated in tumorigenesis, epithelial-mesenchymal transition (EMT)/stemness and the response to targeted therapy. In addition, expression of a heterogeneous collection of HER2 truncated carboxy-terminal fragments (CTFs), collectively known as p95HER2, identifies a peculiar subgroup of HER2-positive BC with poor prognosis, with the p95HER2 variants being able to regulate CSC features. This review provides a comprehensive overview of the current evidence regarding HER2-/d16HER2-/p95HER2-positive BCSCs in the context of the signaling pathways governing their properties and describes the future prospects for targeting these components to achieve long-lasting tumor control. Full article

(This article belongs to the Special Issue Latest Basic, Translational and Clinical Advancements in HER2-Positive Breast Cancer)

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