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Cancers
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Anti-HER2 Therapy Resistance in Breast Cancer
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Anti-HER2 Therapy Resistance in Breast Cancer

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

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 37263

Special Issue Editors

Dr. Joan Albanell

E-Mail Website
Guest Editor
Hospital del Mar, Barcelona 08003, Spain
Interests: breast cancer; clinical subtype; HER2; ctDNA; heterogeneity; liquid biopsy; anti-HER2 therapies; mechanism of resistance; preclinical and translational studies; Phase I clinical trials
Dr. Ana Rovira Guerín

E-Mail Website
Guest Editor
Hospital del Mar Medical Research Institute (IMIM), Barcelona 08003, Spain
Interests: HER2-positive breast cancer; anti-HER2 therapies; combination therapy; mechanism of resistance; biomarker of response; tumor stroma; immunotherapy; preclinical and translational studies

Special Issue Information

Dear Colleagues,

In this Special Issue on the topic “Anti-HER2 Therapy Resistance in Breast Cancer”, we will   discuss current and future HER2+ breast cancer therapeutic challenges. Breast cancers with epidermal growth factor receptor 2 (ERBB2) gene amplification and/or HER2 protein overexpression account for 15–20% of all breast cancers. Though patients with early-stage breast cancer are frequently cured with the advent of anti-HER2 therapies, there are still many patients that progress to metastatic breast cancer (MBC) or have de novo MBC. Despite very important advances, patients with HER2 positive MBC cannot be cured with current therapies, with few exceptions. Better knowledge regarding how to prevent resistance in the upfront neoadjuvant and adjuvant settings, and how to increase survival, and eventually cure, in the metastatic setting, needs further advances in understanding resistance and the design of novel ways to overcome it. Given the great extent of literature on the mechanisms of resistance to anti-HER2 therapy, in this Special Issue, experts in the field will offer their perspective on some of the most promising research areas that should be critically considered toward the finding of clinically relevant biomarkers that could help to identify patients in whom the risk of recurrence is greater and in the development of new strategies. This issue also approaches some of the ongoing and future directions of clinical investigation in HER2-positive breast cancer: novel HER2-directed therapies and combinations, the potential of immunotherapy, and the role of the tumor stroma. The topics are generally organized according to clinically defined questions that are under redefinition and active research, ranging from pathological evaluation to the newest therapies in the horizon. The current view and future ahead on each of these topics will be addressed by pathologists, medical oncologists, and basic researchers, mainly from investigators of the HER2 field from the CIBERONC (Spanish Network of Biomedical Cancer Research Center) Breast Cancer Program.

Dr. Joan Albanell
Dr. Ana Rovira Guerín
Guest Editors

Manuscript Submission Information

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

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

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

Keywords

  • HER2-positive breast cancer
  • anti-HER2 therapies
  • resistance
  • biomarker of response
  • intrinsic subtypes
  • HER2-based immunotherapeutic approaches
  • liquid biopsy

Published Papers (10 papers)

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Research

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13 pages, 11055 KiB  
Article
Evaluation of ERBB2 mRNA Expression in HER2-Equivocal (2+) Immunohistochemistry Cases
by Irene Carretero-Barrio, Tamara Caniego-Casas, Marta Rosas, María Concepción Sánchez, Noelia Martínez-Jáñez, Miguel Chiva, David Sarrió, Gema Moreno-Bueno, José Palacios and Belén Pérez-Mies
Cancers 2023, 15(6), 1688; https://doi.org/10.3390/cancers15061688 - 09 Mar 2023
Cited by 3 | Viewed by 1684
Abstract
Xpert Breast Cancer STRAT4 is a RT-qPCR platform that studies the mRNA expression of ESR1, PGR, MKI67 and ERBB2, providing a positive or negative result for each of these breast cancer biomarkers. Its concordance with immunohistochemistry (IHC) and in situ [...] Read more.
Xpert Breast Cancer STRAT4 is a RT-qPCR platform that studies the mRNA expression of ESR1, PGR, MKI67 and ERBB2, providing a positive or negative result for each of these breast cancer biomarkers. Its concordance with immunohistochemistry (IHC) and in situ hybridization (ISH) has been previously demonstrated, but none of the previous works was focused on HER2-equivocal (2+) cases identified by IHC. Thus, we studied the concordance between IHC/ISH and STRAT4 results for 112 HER2 2+ IBC samples, using 148 HER2 0+, 1+ and 3+ (no-HER2 2+) samples for comparison. We found 91.3% accuracy for the determination of HER2 status globally, 99.3% for no-HER2 2+ samples and 80.7% for HER2 2+ samples. Regarding the other biomarkers, we obtained 96.4% accuracy for estrogen receptor, 84.1% for progesterone receptor and 58.2% for Ki67. Our results suggest that the use of ERBB2 mRNA for the evaluation of HER2 2+ cases is not a reliable reflex method to assess the ERBB2 amplification status. Full article
(This article belongs to the Special Issue Anti-HER2 Therapy Resistance in Breast Cancer)
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Review

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17 pages, 1107 KiB  
Review
Clinical Impact of New Treatment Strategies for HER2-Positive Metastatic Breast Cancer Patients with Resistance to Classical Anti-HER Therapies
by Marta Tapia, Cristina Hernando, María Teresa Martínez, Octavio Burgués, Cristina Tebar-Sánchez, Ana Lameirinhas, Anna Ágreda-Roca, Sandra Torres-Ruiz, Iris Garrido-Cano, Ana Lluch, Begoña Bermejo and Pilar Eroles
Cancers 2023, 15(18), 4522; https://doi.org/10.3390/cancers15184522 - 12 Sep 2023
Cited by 1 | Viewed by 2007
Abstract
HER2-positive breast cancer accounts for 15–20% of all breast cancer cases. This subtype is characterized by an aggressive behavior and poor prognosis. Anti-HER2 therapies have considerably improved the natural course of the disease. Despite this, relapse still occurs in around 20% of patients [...] Read more.
HER2-positive breast cancer accounts for 15–20% of all breast cancer cases. This subtype is characterized by an aggressive behavior and poor prognosis. Anti-HER2 therapies have considerably improved the natural course of the disease. Despite this, relapse still occurs in around 20% of patients due to primary or acquired treatment resistance, and metastasis remains an incurable disease. This article reviews the main mechanisms underlying resistance to anti-HER2 treatments, focusing on newer HER2-targeted therapies. The progress in anti-HER2 drugs includes the development of novel antibody–drug conjugates with improvements in the conjugation process and novel linkers and payloads. Moreover, trastuzumab deruxtecan has enhanced the efficacy of trastuzumab emtansine, and the new drug trastuzumab duocarmazine is currently undergoing clinical trials to assess its effect. The combination of anti-HER2 agents with other drugs is also being evaluated. The addition of immunotherapy checkpoint inhibitors shows some benefit in a subset of patients, indicating the need for useful biomarkers to properly stratify patients. Besides, CDK4/6 and tyrosine kinase inhibitors are also included in the design of new treatment strategies. Lapitinib, neratinib and tucatinib have been approved for HER2-positive metastasis patients, however clinical trials are currently ongoing to optimize combined strategies, to reduce toxicity, and to better define the useful setting. Clinical research should be strengthened along with the discovery and validation of new biomarkers, as well as a deeper understanding of drug resistance and action mechanisms. Full article
(This article belongs to the Special Issue Anti-HER2 Therapy Resistance in Breast Cancer)
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16 pages, 1929 KiB  
Review
Unlocking the Resistance to Anti-HER2 Treatments in Breast Cancer: The Issue of HER2 Spatial Distribution
by Federica Giugliano, Ambra Carnevale Schianca, Chiara Corti, Mariia Ivanova, Nadia Bianco, Silvia Dellapasqua, Carmen Criscitiello, Nicola Fusco, Giuseppe Curigliano and Elisabetta Munzone
Cancers 2023, 15(5), 1385; https://doi.org/10.3390/cancers15051385 - 22 Feb 2023
Cited by 5 | Viewed by 3672
Abstract
Approximately 15% of breast cancers are classified as HER2-positive, with an amplification of the ERBB2 gene and/or an overexpression of the HER2 protein. Up to 30% of HER2-positive breast cancers shows heterogeneity in HER2 expression and different patterns of spatial distribution, i.e., the [...] Read more.
Approximately 15% of breast cancers are classified as HER2-positive, with an amplification of the ERBB2 gene and/or an overexpression of the HER2 protein. Up to 30% of HER2-positive breast cancers shows heterogeneity in HER2 expression and different patterns of spatial distribution, i.e., the variability in the distribution and expression of the HER2 protein within a single tumour. Spatial heterogeneity may potentially affect treatment, response, assessment of HER2 status and consequently, may impact on the best treatment strategy. Understanding this feature can help clinicians to predict response to HER2-targeted therapies and patient outcomes, and to fine tune treatment decisions. This review summarizes the available evidence on HER2 heterogeneity and spatial distribution and how this may affect current available treatment choices, exploring possible opportunities for overcoming this issue, such as novel pharmacological agents, belonging to the group of antibody–drug conjugates. Full article
(This article belongs to the Special Issue Anti-HER2 Therapy Resistance in Breast Cancer)
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14 pages, 1509 KiB  
Review
Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges
by Lorenzo Guidi, Gloria Pellizzari, Paolo Tarantino, Carmine Valenza and Giuseppe Curigliano
Cancers 2023, 15(4), 1130; https://doi.org/10.3390/cancers15041130 - 10 Feb 2023
Cited by 8 | Viewed by 6454
Abstract
The treatment of HER2-positive metastatic breast cancer (mBC) with Trastuzumab emtansine (T-DM1) and Trastuzumab deruxtecan (T-DXd), two antibody-drug conjugates (ADCs) targeting HER2, is burdened by progression of disease related to the acquisition of mechanisms of resistance. Resistance to T-DM1 is caused by the [...] Read more.
The treatment of HER2-positive metastatic breast cancer (mBC) with Trastuzumab emtansine (T-DM1) and Trastuzumab deruxtecan (T-DXd), two antibody-drug conjugates (ADCs) targeting HER2, is burdened by progression of disease related to the acquisition of mechanisms of resistance. Resistance to T-DM1 is caused by the decrease of HER2 expression, the alteration of intracellular trafficking, the impairment of lysosome functions, the drug expulsion through efflux pumps and the activation of alternative signal pathways. Instead, the decrease of HER2 expression and SLX4 loss of function mutations represent the first evidences of mechanisms of resistance to T-DXd, according to the results of DAISY trial. Several strategies are under evaluation to overcome resistances to anti-HER2 ADCs and improve clinical outcomes in patients progressing on these agents: combinations with tyrosine kinase inhibitors, statins, immune checkpoint inhibitors and synthetic DNA-damaging agents are emerging as promising approaches. Furthermore, novel anti-HER2 ADCs with innovative structures and mechanisms of action are in development, in the attempt to further improve the activity and tolerability of currently available agents. Full article
(This article belongs to the Special Issue Anti-HER2 Therapy Resistance in Breast Cancer)
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24 pages, 760 KiB  
Review
Immunotherapies against HER2-Positive Breast Cancer
by Santiago Duro-Sánchez, Macarena Román Alonso and Joaquín Arribas
Cancers 2023, 15(4), 1069; https://doi.org/10.3390/cancers15041069 - 08 Feb 2023
Cited by 6 | Viewed by 3039
Abstract
Breast cancer is the leading cause of cancer-related deaths among women worldwide. HER2-positive breast cancer, which represents 15–20% of all cases, is characterized by the overexpression of the HER2 receptor. Despite the variety of treatments available for HER2-positive breast cancer, both targeted and [...] Read more.
Breast cancer is the leading cause of cancer-related deaths among women worldwide. HER2-positive breast cancer, which represents 15–20% of all cases, is characterized by the overexpression of the HER2 receptor. Despite the variety of treatments available for HER2-positive breast cancer, both targeted and untargeted, many patients do not respond to therapy and relapse and eventually metastasize, with a poor prognosis. Immunotherapeutic approaches aim to enhance the antitumor immune response to prevent tumor relapse and metastasis. Several immunotherapies have been approved for solid tumors, but their utility for HER2-positive breast cancer has yet to be confirmed. In this review, we examine the different immunotherapeutic strategies being tested in HER2-positive breast cancer, from long-studied cancer vaccines to immune checkpoint blockade, which targets immune checkpoints in both T cells and tumor cells, as well as the promising adoptive cell therapy in various forms. We discuss how some of these new approaches may contribute to the prevention of tumor progression and be used after standard-of-care therapies for resistant HER2-positive breast tumors, highlighting the benefits and drawbacks of each. We conclude that immunotherapy holds great promise for the treatment of HER2-positive tumors, with the potential to completely eradicate tumor cells and prevent the progression of the disease. Full article
(This article belongs to the Special Issue Anti-HER2 Therapy Resistance in Breast Cancer)
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16 pages, 666 KiB  
Review
Tumor-Infiltrating Lymphocytes and Immune Response in HER2-Positive Breast Cancer
by Melani Luque, Marta Sanz-Álvarez, Miriam Morales-Gallego, Juan Madoz-Gúrpide, Sandra Zazo, Carolina Domínguez, Alicia Cazorla, Yann Izarzugaza, Juan Luis Arranz, Ion Cristóbal and Federico Rojo
Cancers 2022, 14(24), 6034; https://doi.org/10.3390/cancers14246034 - 08 Dec 2022
Cited by 6 | Viewed by 1947
Abstract
Human epidermal growth factor receptor 2–positive (HER2-positive) breast cancer accounts for 15 to 25% of breast cancer cases. Although therapies based on the use of monoclonal anti-HER2 antibodies present clinical benefit for a subtype of patients with HER2-positive breast cancer, more than 50% [...] Read more.
Human epidermal growth factor receptor 2–positive (HER2-positive) breast cancer accounts for 15 to 25% of breast cancer cases. Although therapies based on the use of monoclonal anti-HER2 antibodies present clinical benefit for a subtype of patients with HER2-positive breast cancer, more than 50% of them are unresponsive to targeted therapies or they eventually relapse. In recent years, reactivation of the adaptive immune system in patients with solid tumors has emerged as a therapeutic option with great potential for clinical benefit. Since the approval of the first treatment directed against HER2 as a therapeutic target, the range of clinical options has expanded greatly, and, in this sense, cellular immunotherapy with T cells relies on the cytotoxicity generated by these cells, which ultimately leads to antitumor activity. Lymphocytic infiltration of tumors encompasses a heterogeneous population of immune cells within the tumor microenvironment that exhibits distinct patterns of immune activation and exhaustion. The prevalence and prognostic value of tumor-infiltrating lymphocyte (TIL) counts are associated with a favorable prognosis in HER2-positive breast cancers. This review discusses emerging findings that contribute to a better understanding of the role of immune infiltrates in HER2-positive breast cancer. In addition, it summarizes the most recent results in HER2-positive breast cancer immunotherapy and anticipates which therapeutic strategies could be applied in the immediate future. Full article
(This article belongs to the Special Issue Anti-HER2 Therapy Resistance in Breast Cancer)
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25 pages, 1539 KiB  
Review
Novel Therapies and Strategies to Overcome Resistance to Anti-HER2-Targeted Drugs
by Manuel Gámez-Chiachio, David Sarrió and Gema Moreno-Bueno
Cancers 2022, 14(18), 4543; https://doi.org/10.3390/cancers14184543 - 19 Sep 2022
Cited by 10 | Viewed by 3569
Abstract
The prognosis and quality of life of HER2 breast cancer patients have significantly improved due to the crucial clinical benefit of various anti-HER2 targeted therapies. However, HER2 tumors can possess or develop several resistance mechanisms to these treatments, thus leaving patients with a [...] Read more.
The prognosis and quality of life of HER2 breast cancer patients have significantly improved due to the crucial clinical benefit of various anti-HER2 targeted therapies. However, HER2 tumors can possess or develop several resistance mechanisms to these treatments, thus leaving patients with a limited set of additional therapeutic options. Fortunately, to overcome this problem, in recent years, multiple different and complementary approaches have been developed (such as antibody–drug conjugates (ADCs)) that are in clinical or preclinical stages. In this review, we focus on emerging strategies other than on ADCs that are either aimed at directly target the HER2 receptor (i.e., novel tyrosine kinase inhibitors) or subsequent intracellular signaling (e.g., PI3K/AKT/mTOR, CDK4/6 inhibitors, etc.), as well as on innovative approaches designed to attack other potential tumor weaknesses (such as immunotherapy, autophagy blockade, or targeting of other genes within the HER2 amplicon). Moreover, relevant technical advances such as anti-HER2 nanotherapies and immunotoxins are also discussed. In brief, this review summarizes the impact of novel therapeutic approaches on current and future clinical management of aggressive HER2 breast tumors. Full article
(This article belongs to the Special Issue Anti-HER2 Therapy Resistance in Breast Cancer)
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18 pages, 986 KiB  
Review
Unveiling the Potential of Liquid Biopsy in HER2-Positive Breast Cancer Management
by Ana Godoy-Ortiz, Alfonso Alba-Bernal, Javier Pascual, Iñaki Comino-Méndez and Emilio Alba
Cancers 2022, 14(3), 587; https://doi.org/10.3390/cancers14030587 - 24 Jan 2022
Cited by 8 | Viewed by 2910
Abstract
Invasive breast cancer (BC) is the most common cancer in women with a slightly increasing yearly incidence. BC immunohistochemical characterisation is a crucial tool to define the intrinsic nature of each tumour and personalise BC patients’ clinical management. In this regard, the characterisation [...] Read more.
Invasive breast cancer (BC) is the most common cancer in women with a slightly increasing yearly incidence. BC immunohistochemical characterisation is a crucial tool to define the intrinsic nature of each tumour and personalise BC patients’ clinical management. In this regard, the characterisation of human epidermal growth factor receptor 2 (HER2) status guides physicians to treat with therapies tailored to this membrane receptor. Standardly, a tumour solid biopsy is therefore required, which is an invasive procedure and has difficulties to provide the complete molecular picture of the tumour. To complement these standard-of-care approaches, liquid biopsy is a validated methodology to obtain circulating tumour components such as circulating tumour DNA (ctDNA) and circulating tumour cells (CTCs) from body fluids in an easy-to-perform minimal-invasive manner. However, its clinical validity in cancer is still to be demonstrated. This review focusses on the utilisation of both ctDNA and CTCs in early and metastatic HER2-positive BC tumours. We discuss recently published studies deciphering the capacity of liquid biopsy to determine the response to neoadjuvant and adjuvant therapies as well as to predict patients’ outcomes. Full article
(This article belongs to the Special Issue Anti-HER2 Therapy Resistance in Breast Cancer)
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15 pages, 316 KiB  
Review
HER2+ Breast Cancer Escalation and De-Escalation Trial Design: Potential Role of Intrinsic Subtyping
by Coralia Bueno Muiño, Miguel Martín, María del Monte-Millán, José Ángel García-Saénz and Sara López-Tarruella
Cancers 2022, 14(3), 512; https://doi.org/10.3390/cancers14030512 - 20 Jan 2022
Cited by 2 | Viewed by 1774
Abstract
Long-term outcomes in breast cancer patients differ based on the molecular subtype, with HER2-E being the most aggressive one. Advances in clinical practice have dramatically shifted HER2+ breast cancer prognosis. Risk adapted strategies to individualize therapies are necessary. De-escalation approaches have been encouraged [...] Read more.
Long-term outcomes in breast cancer patients differ based on the molecular subtype, with HER2-E being the most aggressive one. Advances in clinical practice have dramatically shifted HER2+ breast cancer prognosis. Risk adapted strategies to individualize therapies are necessary. De-escalation approaches have been encouraged based on the risks of clinical-pathological factors. Molecular gene subtyping could further accurately define HER2 addicted tumours that are sensitive to anti-HER2 therapies, thus sparing unnecessary treatments. The transition from immunochemistry to molecular profiling in HER2+ breast cancer is discussed. Full article
(This article belongs to the Special Issue Anti-HER2 Therapy Resistance in Breast Cancer)
24 pages, 2153 KiB  
Review
Novel ADCs and Strategies to Overcome Resistance to Anti-HER2 ADCs
by Elena Díaz-Rodríguez, Lucía Gandullo-Sánchez, Alberto Ocaña and Atanasio Pandiella
Cancers 2022, 14(1), 154; https://doi.org/10.3390/cancers14010154 - 29 Dec 2021
Cited by 31 | Viewed by 9059
Abstract
During recent years, a number of new compounds against HER2 have reached clinics, improving the prognosis and quality of life of HER2-positive breast cancer patients. Nonetheless, resistance to standard-of-care drugs has motivated the development of novel agents, such as new antibody-drug conjugates (ADCs). [...] Read more.
During recent years, a number of new compounds against HER2 have reached clinics, improving the prognosis and quality of life of HER2-positive breast cancer patients. Nonetheless, resistance to standard-of-care drugs has motivated the development of novel agents, such as new antibody-drug conjugates (ADCs). The latter are a group of drugs that benefit from the potency of cytotoxic agents whose action is specifically guided to the tumor by the target-specific antibody. Two anti-HER2 ADCs have reached the clinic: trastuzumab-emtansine and, more recently, trastuzumab-deruxtecan. In addition, several other HER2-targeted ADCs are in preclinical or clinical development, some of them with promising signs of activity. In the present review, the structure, mechanism of action, and potential resistance to all these ADCs will be described. Specific attention will be given to discussing novel strategies to circumvent resistance to ADCs. Full article
(This article belongs to the Special Issue Anti-HER2 Therapy Resistance in Breast Cancer)
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