HER-2 expression

P1, N=62, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Oct 2025

A high level of agreement between IHC/ISH and mRNA expression determined by the APIS kit was observed for all markers. Subtype call agreement improved when Ki67 status was excluded, likely due to the challenges in distinguishing high and low Ki67 expression with IHC, leading to ambiguity in differentiating luminal B HER2- from luminal A tumours. Molecular subtyping offers additional insights for guiding breast cancer management decisions.

RNA expression data from NGS panels may offer an additional assessment of HER2 status, as it correlates with ERBB2 DNA-level amplification and differentiates between HER2 0, 1+, 2+, and 3+ cases. Further studies to validate the clinical utility of RNA expression and its correlation with clinical outcome would be required. Our study also elucidates the potential use of RNA sequencing data from routine cancer NGS panels to assess biomarkers in addition to fusions.

By leveraging the dynamic range of RNA expression, this study established a ΔCt semi-quantitative scale for evaluating targets with the APIS Breast Cancer Subtyping Kit. This is particularly significant for the classification of HER-low, which has emerged to be critical in identifying patients who may benefit from novel anti-HER2 therapies.

Treatment of Ba/F3 or lung cells expressing MDK::ERBB2 with ERBB2 inhibitors (afatinib, poziotinib, tucatinib) blocked phosphorylation of ERBB2 and downstream effectors, and inhibited growth of both cell lines. ERBB2 fusions are rare oncogenic drivers that are candidates for targeted therapy. The subset of recurrent ERBB2 fusions with C-terminal/3' partners may represent an alternative mechanism of fusion oncogenicity.

The APIS kit accurately measures HER2/ERBB2 expression. The findings indicate that relying solely on IHC stratification may not be sufficient to predict responses to novel anti-HER2 treatments, like T-Dxd. By leveraging the dynamic range of RNA expression, a ΔCt semi-quantitative scale using additional cut-offs has been developed to enhance the stratification of ERBB2 mRNA expression.

P1/2, N=368, Recruiting, Innovent Biologics (Suzhou) Co. Ltd. | Not yet recruiting --> Recruiting | Trial completion date: Jul 2025 --> Oct 2025

P=N/A, N=160, Recruiting, The First Affiliated Hospital of Jinzhou Medical University; The First Affiliated Hospital of Jinzhou Medical University

P=N/A, N=150, Recruiting, Henan University; Henan University

P2, N=80, Not yet recruiting, Sichuan Mianyang 404 Hospital; Sichuan Mianyang 404 Hospital

P2, N=30, Not yet recruiting, Fujian Medical University Affiliated Union Hospital; Fujian Medical University Affiliated Union Hospital

P2, N=180, Recruiting, Fudan University Shanghai Cancer Center; Fudan University Shanghai Cancer Center

P2, N=60, Recruiting, The First Affiliated Hospital of Xi'an Jiaotong University; The First Affiliated Hospital of Xi'an Jiaotong University

P1, N=388, Recruiting, Shanghai Chest Hospital; CSPC Megalith Biopharmaceutical Co., Ltd

Within HR + HER2- breast cancer, HER2-low tumors are associated with high RS, especially for histologically invasive ductal carcinoma. A prognostic influence of HER2-low expression among HR + HER2- breast cancer remains as an area that requires further study.

These findings offer valuable insights into the clinicopathologic characteristics and future management for different HER2 ISH groups.

For the treatment of breast cancer, there are three ADCs approved for breast cancer treatment: Trastuzumab emtansine (T-DM1), Trastuzumab Deruxtecan (T-Dxd) targeting HER-2, and Sacituzumab Govitecan (SG) targeting Trop-2. This review summarizes the efficacy and adverse effects of ADC therapies that have completed or are currently undergoing phase I-III clinical trials. Additionally, it analyzes potential combination strategies to overcome ADC resistance, aiming to provide clinicians with a comprehensive clinical guide to the use of ADCs in breast cancer treatment.

In this large cohort of patients with eTNBC treated with NAT, HER2-low status was not associated with pCR or survival after adjusting for clinical factors. The discordance in HER2 IHC pre- and post-NAT likely reflects challenges in HER2 quantification and heterogeneity.

AR expression may be related to good prognostic factors such as ER expression, PgR expression, and lower histologic grade. We also observed that AR expression did not have any association with the Ki67 proliferative index.

P3, N=608, Active, not recruiting, Daiichi Sankyo | Trial completion date: May 2025 --> Jul 2025

This study highlighted the current status of HER2 expression scoring by IHC for breast cancer among pathologists in Japan. These findings underscore the challenges in HER2 IHC scoring cases and emphasize the need for improved standardization and training, especially in the evolving landscape of HER2-targeted therapies.

Whole-lesion histogram parameters derived from sCT IM analysis, and especially the 99th percentile, can serve as imaging biomarkers of HER2 overexpression in GC.

MiRNA-218-5p up-regulates ErbB2 and EGFR expression by suppressing LRIG1 expression, thus promoting the malignant behaviors of BC. miRNA-218-5p may exert a pro-tumor effect on BC and serve as a therapeutic target for BC treatment.

P2, N=66, Recruiting, Henan Cancer Hospital | Trial primary completion date: May 2024 --> Dec 2024

HER2-low breast cancer, defined by low HER2 protein expression (IHC score of 1+ or 2+ without HER2 gene amplification), has achieved clinical significance, particularly following the DESTINY-Breast trials, which demonstrated the efficacy of trastuzumab deruxtecan (T-DXd) in the population of patients with advanced HER2-low disease...This review aims to consolidate current knowledge on HER2-low and ER-low breast cancers, focusing on the challenges associated with their identification, the implications for treatment, and future directions in clinical management. By examining recent studies and interlaboratory assessments, this review emphasizes the critical need for accurate and reproducible testing and reporting, and for the development of tailored therapeutic strategies for these "low" expression cancers.

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Our data indicate that targeted therapy using e.g., trastuzumab deruxtecan, bicalutamide, pembrolizumab, cetuximab, entrectinib or sacituzumab govitecan might be a promising option especially for a relevant subset of patients with RM-SGC not suitable for salvage surgery. However, evidence from clinical studies regarding response rates to these therapies remains sparse, which underlines the need of multicenter clinical trials.

High ENO1 expression was also associated with relapse-free, distant metastasis-free and overall survival, irrespectively of treatment and was mainly related to basal subtype. ENO1 overexpression recruits a range of signalling pathways during disease progression conferring a worse prognosis and can be potentially used as a biomarker of disease progression and therapeutic target, particularly in triple-negative and in ductal invasive carcinoma.

P=N/A, N=517, Completed, AstraZeneca | Recruiting --> Completed | N=385 --> 517 | Trial completion date: Dec 2024 --> Sep 2024 | Trial primary completion date: Dec 2024 --> Sep 2024

PEITC, BITC, and SFN also increased proapoptotic Bax expression and decreased the antiapoptotic B-cell lymphoma 2 (Bcl-2) expression (all, p < .05). These findings suggest that specific ITCs may mitigate cancer cell proliferation induced by LMWH in cancer therapies, highlighting their potential therapeutic efficacy.

P1, N=18, Recruiting, Sichuan University | Trial primary completion date: Dec 2024 --> Dec 2025

These findings underscore the potential of PET to monitor HER2 protein levels across heterogeneous tumors. Furthermore, our results suggest that further optimization of statin dosing and timing could offer a promising strategy to enhance trastuzumab accumulation in HER2-high, HER2-moderate, and HER2-low tumors.

Our findings indicate a strong agreement between mRNA expression quantified by RT-qPCR and HER2 IHC scores, although there was a substantial proportion of discordant HER2 results between both methods owing to overestimation of HER2 expression by MammaTyper compared to IHC. Future large-scale trials should determine which technique is best associated with clinical outcome.

Serum exosomes expressing CD9, CD63 and HER2 are candidate biomarkers of tumor burden in HER2-positive breast-cancer patients.

Higher cytoplasmic Talin-1 expression is associated with less invasive tumor behavior, while increased membranous HER-2 expression is associated with metastasis in SRC-type GC. These findings suggest potential use in assessing diagnosis and screening high-risk cancer patients, particularly those with SRC-type GC.

P1, N=12, Active, not recruiting, Shanghai PerHum Therapeutics Co., Ltd. | Recruiting --> Active, not recruiting | Trial primary completion date: Mar 2024 --> Oct 2024

We emphasize the broadened clinical potential of T-DXd in treating brain metastases from tumors originally classified as HER2-null or HER2-low, extending beyond its current use for breast cancer. This expanded application of T-DXd could provide new hope to patients dealing with challenging brain metastases, addressing an urgent need for effective treatment options.

Though single-arm, the APT trial, in which patients with node-negative, small tumors received single-agent paclitaxel for 12 cycles plus trastuzumab for 1 year, was a practice-changing study. Several other recently published studies, like the PERSEPHONE trial, have shown more convincing data that 6 months of trastuzumab is not inferior to 12 months, in terms of disease-free survival (DFS), suggesting that de-escalating strategies with shorter treatment may be appropriate for some low-risk patients. Other de-escalating strategies involved an adaptive, response-directed approach, and personalized therapy that depends on tumor genomic profiling.

Among agents targeting one or more members of the HER family, the pan‑HER family blocker afatinib was the most effective, inhibiting the proliferation of three out of seven human liver cancer cell lines (LCCLs), while the CDK inhibitor dinacicilib was the most effective agent, inhibiting the proliferation of all human LCCLs tested. Taken together, the present results suggested that EGFRvIII expression and its co‑expression with wtEGFR or CD44 was of prognostic significance. These results also support further investigations of the therapeutic potential of drugs targeting EGFRvIII and other members of the HER family in patients with HCC.

These include inhibitors of signaling pathways such as TGF-β, Wnt/β-catenin, Notch, TNF-α/NF-κB and EGFR, as well as immune checkpoint inhibitors, such as pembrolizumab, 2laparib, and talazoparib have been widely explored. This article reviews recent developments in EMT in TNBC invasion and metastasis and potential targeted therapy strategies.