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Therapy for HER2 Breast Cancer
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Therapy for HER2 Breast Cancer

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

Deadline for manuscript submissions: 31 August 2026 | Viewed by 3271

Special Issue Editors

Prof. Dr. Junji Tsurutani

E-Mail Website
Guest Editor
Advanced Cancer Translational Research Institute, Showa University, Tokyo 142-8555, Japan
Interests: clinical oncology; medical oncology; breast cancer; clinical trial; drug development; molecular target medicine; antibody drug conjugate; cell signaling
Dr. Sandra M. Swain

E-Mail Website
Guest Editor
Department of Medicine, Georgetown Lombardi Comprehensive Cancer Center and MedStar Health, Washington, DC, USA
Interests: HER2-positive breast cancer; clinical cancer research

Special Issue Information

Dear Colleagues,

HER2, a HER family member, is a receptor tyrosine kinase expressed on the cell membrane, and constitutive activation of the protein via overexpression or gene aberrations such as amplification or single nucleotide variation transforms epithelial cells to cancer as demonstrated in preclinical models (ref.). HER2-driven breast cancer is an aggressive and distinct form of disease that occurs in young adults in advanced stages. Cancer with HER2 pathway activation spreads to the central nervous system easily and becomes resilient to systemic therapies.

The discovery of HER2 as a driving molecule of cancer, followed by the development of a targeting agent, led to a breakthrough, and trastuzumab, the monoclonal antibody against HER2, has caused a paradigm shift and changed the landscape of therapy for HER2-positive breast cancer. Treatment evolved and was combined with pertuzumab, another antibody against a different epitope of HER2, and OS has been prolonged significantly with the dual blockade.  

The advent of drug delivery systems such as antibody–drug conjugates (ADCs) further transformed the treatment of HER2-positive breast cancer, as shown in the pivotal trials of trastuzumab deruxtecan, and the disease has exhibited an increasingly more favorable prognosis with the ADC. This Special Issue will highlight the role of a new generation of HER2-targeting agents in their therapy, covering both basic and more (pre)clinical aspects that advance our understanding of targeting this pathway in breast cancer.

Prof. Dr. Junji Tsurutani
Dr. Sandra M. Swain
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 communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

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

  • antibody–drug conjugate
  • trastuzumab
  • pertuzumab
  • tyrosine kinase inhibitor
  • trastuzumab deruxtecan

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Published Papers (3 papers)

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Research

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15 pages, 1402 KB  
Article
Characterization of HER2-Positive Murine Breast Cancer Models for Investigating HER2-Targeted Therapy and Immunotherapy
by Yun Lu, Benjamin P. Lee, Abbigael V. Eli, Shannon E. Lynch, Ar Rafi Md Faisal, Jonathan Moye and Anna G. Sorace
Cancers 2026, 18(6), 997; https://doi.org/10.3390/cancers18060997 - 19 Mar 2026
Cited by 1 | Viewed by 852
Abstract
Background/Objectives: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is linked to poorer overall survival and a higher risk of brain metastases compared to HER2-negative breast cancer. Current preclinical studies lack robust HER2+ metastatic syngeneic mouse models for investigating targeted and [...] Read more.
Background/Objectives: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is linked to poorer overall survival and a higher risk of brain metastases compared to HER2-negative breast cancer. Current preclinical studies lack robust HER2+ metastatic syngeneic mouse models for investigating targeted and immunomodulatory therapies. This study aims to develop effective HER2+ mouse models to investigate response dynamics to HER2-targeted therapy and immunotherapy. Methods: The human HER2 gene (WT or mutant p.A775_G776insYVMA, GFP-tagged at the C-terminus) was introduced into triple-negative breast cancer (TNBC) mouse mammary carcinoma cells with known metastatic potential (4T1 and EO771) via lentiviral transduction. HER2 expression and phosphorylation were analyzed using Western blotting and immunohistochemistry. Tumors were treated with HER2-targeted therapy (trastuzumab and tucatinib), immune checkpoint blockade (anti-PD-1 and anti-CTLA-4), and anti-HER2 antibody–drug conjugate (ADC) to evaluate treatment efficacy. Metastatic potential was assessed with brain fluorescence imaging. Statistical analysis included ANOVA and Kaplan–Meier tests. Results: Newly established lines demonstrated expression of HER2+, with HER2YVMA lines showing higher phosphorylation than HER2WT lines. Cells were tumorigenic, demonstrating in vivo tumor take rates at 100% for 4T1-HER2 and 15–30% for EO771-HER2. HER2 overexpression led to a 30% increase in spontaneous brain metastasis in the 4T1-HER2 models. Trastuzumab alone did not reduce primary tumor size but significantly reduced brain GFP signal by 17% ± 8% and 26% ± 7% in the 4T1-HER2WT and 4T1-HER2YVMA models, respectively. Combinational therapies with anti-HER2 therapy and immune checkpoint blockade effectively suppressed primary tumor growth and prolonged survival in EO771-HER2YVMA model. T-Dxd, but not T-DM1, demonstrated partial treatment response in the EO771-HER2WT model. Conclusions: HER2+ syngeneic tumor models were developed that spontaneously metastasize to the brain and demonstrate variable responses to immunotherapies and ADCs. These models are valuable for advancing molecular imaging modalities for HER2+ brain metastasis, studying blood–brain barrier penetration of HER2-targeted drugs, and exploring the combination of therapies, including immunotherapy. Full article
(This article belongs to the Special Issue Therapy for HER2 Breast Cancer)
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13 pages, 263 KB  
Article
Association Between Single-Nucleotide Polymorphism and Trastuzumab Deruxtecan-Induced Interstitial Lung Disease in Breast Cancer Using the Japonica Array NEO
by Saori Fujiwara, Nao Saito, Mio Yasukawa, Akira Narita, Mika Sakurai-Yageta, Shinya Sato, Toshinari Yamashita and Daisuke Hoshino
Cancers 2026, 18(6), 927; https://doi.org/10.3390/cancers18060927 - 12 Mar 2026
Cited by 1 | Viewed by 612
Abstract
Background/Objectives: Trastuzumab deruxtecan (T-DXd) is an effective antibody–drug conjugate for human epidermal growth factor receptor 2-expressing solid tumors; however, interstitial lung disease (ILD) remains a clinically significant adverse event. Although both clinical characteristics and genetic susceptibility have been implicated in drug-induced ILD, [...] Read more.
Background/Objectives: Trastuzumab deruxtecan (T-DXd) is an effective antibody–drug conjugate for human epidermal growth factor receptor 2-expressing solid tumors; however, interstitial lung disease (ILD) remains a clinically significant adverse event. Although both clinical characteristics and genetic susceptibility have been implicated in drug-induced ILD, the factors specifically associated with T-DXd-induced ILD remain unclear. This study aimed to evaluate clinical and genetic factors associated with the development of ILD in patients treated with T-DXd. Methods: We retrospectively analyzed the clinical data of 54 patients treated with T-DXd. The baseline clinical and treatment-related characteristics of patients with ILD and those without were compared. Genome-wide single-nucleotide polymorphism (SNP) analyses with genotype imputation and targeted candidate SNP analyses were performed to evaluate genetic susceptibility. Results: ILD occurred in 15 patients (27.8%), with a median time to onset of 215 days (range, 48–1187). None of the baseline clinical or treatment-related factors were significantly associated with ILD development. Genome-wide analyses did not reveal any significant SNPs after correcting for multiple testing. Contrarily, a targeted analysis focusing on SNPs previously associated with drug-induced ILD identified one variant rs12625311 that was significantly associated with ILD in this cohort. Conclusions: In this exploratory study, baseline clinical characteristics alone were insufficient to discriminate the risk of ILD among patients treated with T-DXd. Although no high-penetrance genetic variants were identified, candidate-based genetic analyses suggested that host genetic factors may contribute to ILD susceptibility. Integrating genetic information with clinical assessment may help refine the risk stratification for T-DXd-induced ILD in future studies. Full article
(This article belongs to the Special Issue Therapy for HER2 Breast Cancer)

Review

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24 pages, 964 KB  
Review
Overcoming Trastuzumab–Pertuzumab Resistance and Optimizing Sequential Anti-HER2 Therapy in HER2-Positive Metastatic Breast Cancer
by Yutaka Yamamoto
Cancers 2026, 18(6), 932; https://doi.org/10.3390/cancers18060932 - 13 Mar 2026
Cited by 1 | Viewed by 1395
Abstract
HER2-positive breast cancer accounts for 15–20% of all breast cancers. The introduction of anti-HER2 therapies has markedly improved the clinical outcomes; however, overcoming drug resistance in metastatic disease remains a major challenge. This review summarizes the multilayered mechanisms of resistance to trastuzumab and [...] Read more.
HER2-positive breast cancer accounts for 15–20% of all breast cancers. The introduction of anti-HER2 therapies has markedly improved the clinical outcomes; however, overcoming drug resistance in metastatic disease remains a major challenge. This review summarizes the multilayered mechanisms of resistance to trastuzumab and pertuzumab and outlines the rationale for sequential treatment strategies based on the emerging evidence. Resistance arises through diverse and often coexisting mechanisms, including structural alterations in the HER2 receptor (e.g., p95HER2 and HER2 mutations), constitutive activation of the PI3K–AKT–mTOR pathway, and engagement of bypass signaling through receptors such as HER3 and IGF-1R, as well as immune evasion and metabolic reprogramming. Given this complexity, the strategic sequencing of agents with distinct mechanisms of action is critical beyond first-line therapy. Trastuzumab deruxtecan demonstrates substantial antitumor activity through potent cytotoxic effects and a bystander effect, supporting its efficacy in tumors with intratumoral heterogeneity or downstream pathway activation. In contrast, tucatinib-based regimens represent an important option for patients with brain metastases and tumors expressing p95HER2. The ongoing development of novel antibody–drug conjugates and bispecific antibodies is expected to further advance personalized sequential therapy targeting composite resistance mechanisms. Full article
(This article belongs to the Special Issue Therapy for HER2 Breast Cancer)
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