HER-2 amplification

Our AI model is able to directly predict HER2 expression through HE images with strong interpretability, and has a better ACC particularly in HER2-low breast cancers, which provides a method for AI evaluation of HER2 status and helps to perform HER2 evaluation economically and efficiently. It has the potential to assist pathologists to improve diagnosis and assess biomarkers for companion diagnostics.

On-target mechanisms of resistance include new mutations (e.g., C797S) in the kinase domain of EGFR, while among the off-target mechanisms, amplification of MET or HER2, mutations in downstream signaling molecules, oncogenic fusions, and phenotypic changes (e.g., EMT) have been described. This review focuses on the strategies that are currently being investigated, in preclinical and clinical settings, to overcome resistance to osimertinib, including the use of fourth-generation TKIs, PROTACs, bispecific antibodies, and ADCs, as monotherapy and as part of combination therapies.

Our findings underscore the strong prognostic and predictive correlation between HER2 histo-morphometric features and response to targeted anti-HER2 therapy.

P1, N=91, Terminated, Black Diamond Therapeutics, Inc. | Phase classification: P1/2 --> P1

We observed that more than 50% of 2,024 advanced UC tumors demonstrated some degree of HER2 protein expression detected using a standardized IHC method, whereas about 12% of specimens had ERBB2 gene amplification, including about 3% of those scored as either IHC 0 or 1+. Continued development of optimized and standardized HER2 testing methods is warranted to identify patients with HER2-expressing UC who may benefit from novel HER2-targeting therapies.

ICIs combined with standard treatment regimens for patients with advanced HER-2-positive gastric cancer demonstrate favorable clinical efficacy, significantly prolonging PFS with manageable safety. ECOG performance status, peritoneal metastasis, positive PD-L1 expression, and treatment regimen are independent factors influencing PFS, warranting increased clinical attention to patients exhibiting these factors.

ICIs and pyrotinib may be effective in treating HER2-amplified advanced rectal cancer. Chemotherapy following disease progression could enhance efficacy synergistically.

Given the rarity of the disease and the consequent lack of high quality data in literature, it is of importance a cross-fertilization process from other, more common disease such as breast and prostate cancers. In the current narrative review we analyze current evidence on the targeted treatment on salivary gland carcinomas and shared features with breast and prostate cancer.

Male invasive breast cancer is rare, and it is more common in the elderly over 60 years old. The positive rate of ER and PR is high, and the incidence of HER2 low is high. The high HER2 low expression rate of male breast cancer can provide a new anti-HER2 treatment decision.

© 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

P1, N=24, Active, not recruiting, City of Hope Medical Center | Recruiting --> Active, not recruiting | N=39 --> 24 | Trial completion date: Mar 2025 --> Feb 2026 | Trial primary completion date: Mar 2025 --> Feb 2026

Factors influencing HER2-low detection include tumour heterogeneity, antibody clones, observer variability, and lack of validated scoring criteria. Given the significant proportion of HER2-low cases, many patients could benefit from T-DXd, but limitations in detection accuracy necessitate further research and standardisation in diagnostic methods and criteria to advance the clinical utility of T-DXd for HER2-low tumours.

HER2 amplification was found in 10% of advanced BTC and was not identified as an independent prognostic factor for OS. Patients with HER2-amplified BTC derive significant benefit from HER2-targeted therapy.

The visualization of HER2-low breast cancer with Al18F-NOTA-HER2-BCH PET/CT was feasible and safe. The observed intra- and inter-individual heterogeneity in the uptake of Al18F-NOTA-HER2-BCH indicates its potential use as a noninvasive tool for assessing disease heterogeneity and identifying patients who may derive clinical benefit from HER2-targeted therapies.

P2, N=38, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2025 --> Mar 2026

P1, N=66, Completed, University of Washington | Active, not recruiting --> Completed

P1/2, N=28, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | N=106 --> 28

Within NSCLC, 26% of activating mutations were not included in clinical trials that led to approval of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd)...We identified substantial populations of patients with diverse ERBB2/ERBB3 activating alterations, which represent unmet therapeutic needs. We demonstrate that CGP provides additional genomic information, inclusive of ERBB2 amplification and mutation status together with potential resistance/response-modifying co-alterations, allowing for more nuanced HER2 status interpretation than is possible with IHC/FISH alone.

Although the addition of modified FOLFOX (fluorouracil, leucovorin, and oxaliplatin) to active symptom control improved the overall survival of patients with progressing advanced BTC despite gemcitabine plus cisplatin treatment, its efficacy was modest. This review delineates the evolution of systemic therapies in patients with pretreated advanced BTC. By examining past developments and recent advances through prospective trials, it highlights novel approaches that may improve outcomes in this challenging disease.

P2, N=24, Not yet recruiting, Peking Union Medical College Hospital; Peking Union Medical College Hospital

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

P4, N=161, Not yet recruiting, Xiangya Hospital, Central South University; Xiangya Hospital, Central South University

P=N/A, N=30, Recruiting, The First Affiliated Hospital of Chongqing Medical University; The First Affiliated Hospital of Chongqing Medical University

P4, N=500, Recruiting, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Pierre Fabre (Shanghai) Medical Co.,Ltd.

A major landmark was recently reached when trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate, became the first Food and Drug Administration (FDA)-approved therapy for pretreated HER2-mutant NSCLC, following the promising efficacy demonstrated in the DESTINY-Lung trials...In this review, the authors describe the different HER2 alterations and their clinical consequences, including their impact on prognosis and response to standard therapies. They provide an up-to-date overview of the current treatment landscape and add a comprehensive review of pivotal and ongoing clinical trials of HER2-targeted therapies, including tumor-agnostic drug development strategies.

P=N/A, N=150, Not yet recruiting, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital; The Affiliated Cancer Hospital of Zhengzhou University & Henan

P4, N=24, Not yet recruiting, Beijing Chao-Yang Hospital, Capital Medical University; Beijing Chao-Yang Hospital, Capital Medical University

P4, N=200, Not yet recruiting, Henan Provincial People's Hospital; Henan Provincial People's Hospital

As the landscape of HER2-directed therapies continues to evolve, these findings suggest that ERBB2 alterations and HER2 expression may represent a potential therapeutic target in LGSC.

P3, N=737, Active, not recruiting, Suzhou Suncadia Biopharmaceuticals Co., Ltd. | Trial completion date: Jun 2025 --> Oct 2025 | Trial primary completion date: Mar 2025 --> May 2024

Notable differences are present in the genomic landscape of CDX2-induced gastric cancer depending on the level of expression of SOX2 mRNA. Despite this, SOX2 mRNA expression levels were not prognostic.

The KATHERINE trial assessed HER2 status of residual disease from 845 patients with HER2-positive status on pretherapy biopsies, of which 70 were negative on retesting. With 8 years of median follow-up, 7-year IDFS was 60.3 % with trastuzumab compared to 95.2 % with T-DM1, consistent with clinically meaningful benefit from T-DM1 in these 70 patients.

Approved therapies for refractory mCRC, including regorafenib, trifluridine/tipiracil (FTD/TPI), and fruquintinib, demonstrate modest survival benefits but are often associated with significant toxicities...The potential of rechallenge strategies using previously administered therapies, such as oxaliplatin and anti-EGFR agents, is examined, supported by retrospective and prospective studies. Furthermore, the role of older drugs like mitomycin C in combination with capecitabine is revisited, offering insights into their viability in advanced treatment settings. Ongoing clinical trials with novel agents and combinations are expected to provide further clarity on optimizing sequential treatment regimens and personalizing therapy for mCRC patients. This review emphasizes the need for comprehensive molecular profiling and shared decision-making to improve outcomes and quality of life in this challenging patient population.

P3, N=360, Recruiting, National Cancer Institute (NCI) | Phase classification: P2/3 --> P3 | N=525 --> 360

In conclusion, our in-silico analysis proposes that MAT could mediate a multi-target and multi-pathway anti-TNBC effect with the MAPK pathway as its novel target pathway. These insights into the potential therapeutic mechanisms of MAT offer valuable directions for further research and the development of interventions against TNBC.

In the range of 1 to 105 ng·mL-1, there was a good linear relationship between the HER2 concentration and the signal intensity, with a limit of detection of 0.19 pg·mL-1. Moreover, this method has good selectivity and stability, and then still maintains good detection performance and strong anti-interference ability in the complex environment of normal human serum, which is expected to be applied in clinical application.

Our findings elucidate different germline tumorigenic patterns not driven by deficient MMR. Somatic ERBB2 amplification in CRC can serve as an indicator for germline genetic testing when traditional risk features are absent.

This underscores the rationale for HER2-targeted therapies in these malignancies, including the use of HER2-directed tyrosine kinase inhibitors, antibody-drug conjugates, and immune-stimulating antibody conjugates. Understanding mechanisms of resistance to HER2-targeted therapies will inform possible combinatorial strategies.

One case showed both HER2 point mutation and HER2 amplification, while the AM-ICN associated with an invasive adenocarcinoma harbored TP53 mutation and p53 overexpression. In conclusion, our findings suggest the separation of AM-ICNs from other gallbladder dysplastic lesions.

P2, N=25, Recruiting, Brown University | Trial completion date: Jan 2027 --> Sep 2027 | Trial primary completion date: Jan 2025 --> Sep 2025

HER2-targeting antibody-drug conjugates (ADCs), trastuzumab deruxtecan (T-DXd), and patritumab deruxtecan (P-DXd) effectively suppressed the viability of the tumoroids. Therefore, the establishment of esophageal tumoroids with long-term cultivability makes it possible to obtain reproducible basic data, including drug sensitivity studies, which are important for the development of personalized therapies and treatment strategies.

These carcinomas belong to the molecular apocrine carcinoma family, which includes HER2-enriched tumors driven by HER2 addiction and androgen receptor-positive luminal tumors, a subtype of triple-negative breast cancers. The latter are defined by androgen receptor pathway activation and are frequently associated with PI3K pathway alterations and cell cycle dysregulation, suggesting potential therapeutic targets.