HER-2 underexpression

The advent of highly effective HER2-targeted antibody-drug conjugates with clinical activity at low levels of HER2 expression, such as trastuzumab deruxtecan, has necessitated the re-evaluation of HER2 testing, particularly for HER2-low tumours...We discuss the importance of accurately defining HER2-low expression for therapeutic decision-making and how newer diagnostic approaches, such as quantitative immunofluorescence and RNA-based assays, might address the limitations of traditional immunohistochemistry-based methods. As the use of HER2-targeted therapies continues to expand to a wider range of tumour types, ensuring the precision and accuracy of HER2 testing will be crucial for guiding treatment strategies and improving patient outcomes.

P=N/A, N=170, Not yet recruiting, Affiliated Hospital of Guangdong Medical University; Affiliated Hospital of Guangdong Medical University

BRCA1-mutated TNBC patients with HER2-low tumors have a significantly favorable survival, highlighting the possibility of stratifying these patients into two subgroups on the basis of HER2-low status.

Based on our findings, HER2-zero status is associated with a significantly higher pathological complete response (pCR) rate compared to HER2-low in early-stage breast cancer, and other survival outcomes. These results suggest that HER2-zero should be considered a prognostic factor in early-stage breast cancer and taken into account in neoadjuvant treatment planning and future clinical research.

Several studies are currently exploring the efficacy of various ADC drugs in breast cancer with HER2 low-expression, opening up new treatment avenues for patients with HER2 low-expression breast cancer. This review aims to summarize the clinical features of HER2 low-expression breast cancer and the recent advances in its therapeutic agents.

Overall, this study reveals that miR-145-5p suppresses the proliferation, migration, and invasion of breast cancer cells by interacting with ARF6 mRNA. Consequently, this miRNA might serve as a new target for accurate diagnosis and treatment of breast cancer.

Radiomics models based on multi-parametric MRI features demonstrated strong clinical utility in assessing HER2 expression status in invasive breast cancer, particularly in identifying HER2-overexpression and HER2-low expression subtypes.

P3, N=532, Recruiting, DualityBio Inc. | Trial primary completion date: Dec 2025 --> May 2026

P1, N=115, Active, not recruiting, Daiichi Sankyo | Trial primary completion date: Dec 2024 --> Jul 2025 | Recruiting --> Active, not recruiting

The therapeutic effect of T-DXd was temporarily observed, such as a decrease in tumor markers. It is useful to repeatedly collect tissues from primary and metastatic lesions and re-evaluate biomarkers in order to develop an appropriate treatment plan.

p53 abnormal molecular subgroup predicts HER2 amplification better than histotype. HER2 low cases present a wide range of histotypes and molecular subgroups including many patients with high-risk uterine cancer. Future trials of anti-HER2 therapies will clarify the clinical relevance of HER2 low status, treatment indications and guidelines for HER2 testing in endometrial carcinoma.

HER2-low expression is prevalent in metastatic breast carcinoma with a unique hormone receptor profile. Findings highlight the need for reassessment of HER2 status in metastatic settings, with potential therapeutic implications.

P4, N=200, Recruiting, Zhongshan Hospital, Fudan University; Zhongshan Hospital, Fudan University

P4, N=30, Recruiting, Sanhuan Cancer Hospital of beijing Chaoyang District; Sanhuan Cancer Hospital of beijing Chaoyang District

P2, N=56, Recruiting, The First Affiliated Hospital of Wenzhou Medical University; The First Affiliated Hospital of Wenzhou Medical University

P1, N=60, hunan cancer hospital; hunan cancer hospital

Patients with HER2 low expression have distinct clinical characteristics and a better prognosis compared to those with HER2(0) expression. Our study provides further real-world evidence for personalized treatment of breast cancer patients.

Despite distinct clinicopathological features, FISH remains inadequate for distinguishing HER2-low from HER2-ZERO expression. Further studies are needed to improve HER2 assessment in this challenging subset of patients.

In Her2-low breast cancer patients, Her2 expression did not correlate with a better response rate. In our study, a ki67 expression value greater than 37% constitutes a predictive biomarker of pathological complete response in the subgroup of patients with luminal B tumors and could be considered, therefore, an indicator for treatment decisions in this subgroup.

HER2-low and HER2-zero TNBC patients show significant clinicopathological differences. Compared to HER2-zero, HER2-low status is linked to better long-term prognosis and serves as an independent low-risk factor for RFS in TNBC patients.

This work represents one of the first proof-of-concept applications of machine learning models to predict a highly relevant phenomenon for drug access in modern BC oncology. Starting with an explainable model and subsequently integrating it with an ensemble approach enabled us to enhance performance while maintaining transparency, explainability, and intelligibility.

After pooling data from 142 female patients with MBC across historic clinical trials and categorizing them according to HER2 expression (i.e., HER2-0 or HER2-low), we evaluated associations between HER2 expression and the outcomes of both progression-free survival (PFS) and overall survival (OS) with both Kaplan-Meier and Cox proportional hazards methods. Studying data from an era when quantifying amounts of tumor HER2 expression in HER2-negative patients was neither standardized nor clinically actionable, we found no meaningful clinical differences in PFS or OS according to HER2-low vs. HER2-0 status, supporting prior findings of no biologic differences.

The DCA demonstrated that the net benefit of the model was significantly greater than zero at a predicted probability of 0.764. The neural network model based on MRI features is an effective tool in predicting HER2-low breast cancer, which may facilitate clinical treatment decision-making.

Follow-up showed that HER2-low patients had the worst prognosis compared with HER2-negative (P=0.02) and HER2 positive (P=0.02) and also had the highest progression rate in TCGA cohort (P=0.02); receiver operator characteristic (ROC) model suggested HER2-low could effectively predict prognosis. HER2 expression is closely related to the TNM stage of urothelial carcinoma; HER2 three-tier assessment can effectively predict clinical prognosis of urothelial carcinoma.

P1, N=26, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

Site-specific recurrence patterns differ between HER2-low and HER2-0 patients. However, it does not support that HER2-low breast cancer is a distinct prognostic subtype.

Patients with HER2-low status exhibited intermediate and specific clinicopathological features within the HER2-negative category. In terms of prognosis, HER2-low patients showed a worsening trend compared with HER2-positive patients. This evidence implies that HER2-low status represents a distinct clinical subset, bridging the gap between the HER2-zero and HER2-positive profiles.

There is an important percentage of Hispanic/Latino individuals who would benefit from HER2-targeted therapies, even in HER2 negative cases. Additional research on the prevalence of HER2-low tumors across a wider range of Latin American countries is required to better understand the molecular epidemiology of this biomarker within the Hispanic/Latino population.

Discrepancy in the HER2 status of the metastases and of CTCs was observed in approximately one third of patients. Measuring HER2 on CTCs could potentially offer a means to longitudinally monitor HER2 status during therapy and simultaneously address challenges such as tumor heterogeneity. Therefore, the predictive value of HER2 on CTCs should be further investigated in clinical trials.

Quantitative parameters from intravoxel incoherent movement imaging and dynamic contrast enhancement MRI can predict different HER2 expressions in breast cancer from different perspectives, with implications for therapy.

Studies evaluating ADCs (trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), MRG002, and RC48-ADC) in patients with HER2-low a/mBC were included. Future studies should focus on bringing ADCs into earlier lines of therapy in this population. This study was registered in PROSPERO (CRD42024452962).

RC48-ADC showcases promising efficacy and manageable safety in patients with both HER2-positive and HER2-low-expression mBC.

At the same time, it is recommended to reevaluate the HER2 status in the event of disease recurrence or metastasis, even if the previous test result is HER2-0. On the other hand, it is recommended to further improve and optimize detection techniques and methods, reduce false negatives and false positives, and enhance the sensitivity and specificity of detection.

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.

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

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.

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.

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

BRCA mutation and PD-L1 positivity are higher in HER2-negative TNBC. Our study revealed that HER2-negative breast cancer has more basal-like clinicopathologic features, while HER2 Low TNBC has non-basal features.

Our findings add valuable information to the current understanding of the HER2 spectrum in the male breast cancer, including frequency distribution and molecular characterization. With some exceptions, HER2-low, ultra-low and null breast cancer in men shared genomic features, suggesting that the disease biology may not be different across the spectrum of what historically has been considered HER2-negative disease. Interestingly, HER2 ultra-low, HER2-low and HER2-null had differential tumor immune microenvironment that warrant further exploration.

Linearity testing, where the cell lines were spiked in 7.5mL blood, showed high levels of reproducibility across the clinical range (1000 cells to 0) with an R2 = 0.99. The CELLSEARCH® CTC-HER2 Low test meets a critical clinical need that breast cancer patients, positive or classified as negative from a tissue biopsy, in need of a current evaluation of their metastatic breast cancer HER2 status, through any line of treatment, can do so from one blood draw using a test that can detect HER2 expression to very low levels.

However, this may be due to lack of sensitivity of IHC, which is currently used to select patients for T-DXd treatment, despite major diagnostic challenges... ERBB2del are frequent events in ER+/HER2- BC that are characterized by low ERBB2 mRNA levels, and are associated with TP53del, higher proliferation and immunogenicity, lower ER signaling and HER2 protein expression, and decreased OS in the metastatic setting.