Conversely, T-DXd administered due to the presence of HER2-low showed excellent effectiveness. Performing a re-biopsy is crucial due to the possible loss of estrogen receptors, which would require a change in therapeutic strategy no longer based on endocrine therapy. In cases that remain luminal, knowledge of the mutational profile may help to offer patients novel targeted treatments.

P1, N=107, Not yet recruiting, Suzhou Suncadia Biopharmaceuticals Co., Ltd.

In patients with high-risk, residual invasive HER2-positive breast cancer, postneoadjuvant T-DXd resulted in a significantly higher likelihood of invasive disease-free survival than T-DM1; toxic effects were mainly gastrointestinal and hematologic. An important identified risk of T-DXd is interstitial lung disease, which requires appropriate monitoring and management. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast05 ClinicalTrials.gov number, NCT04622319.).

AI-assisted interpretation improved observer agreement (Kappa: 0.703 vs. 0.610 in non-amplified cases) and reduced ambiguous immunohistochemistry (IHC) 2+/0 assignments. These findings delineate distinct clinicopathological characteristics of HER2-ultralow/null tumors, highlight HER2 IHC reproducibility challenges, and validate AI as an effective tool for standardizing scoring to optimize patient selection for T-DXd therapy.

Antibody-drug conjugates (ADCs), particularly trastuzumab deruxtecan (T-DXd), have markedly improved survival and also exert antitumor effects through immune activation...Tumor vaccines and genomics-driven targeted drugs, such as trastuzumab-α-amanitin conjugates, hold promise in reactivating antitumor immunity. This review summarizes current progress in immunotherapy for HER2 low-expressing TNBC, with emphasis on ADCs, combination regimens, and emerging precision strategies, aiming to inform future research and clinical application.

The incidence of ILD with T-DXd in the real-world setting was similar to that observed in clinical trials, indicating no new ILD-related safety signals. Further investigation of the identified factors may offer insights into ILD incidence in high-risk populations.

However, T-DXd increased the risks of interstitial lung disease (relative risk &lsqb;RR] = 13.832; P < 0.001), decreased left ventricular ejection fraction (RR = 2.247; P < 0.001), anemia, nausea, vomiting, decreased appetite, and alopecia; neutropenia and diarrhea risks were comparable between groups. These findings highlight T-DXd's survival benefits and toxicity profile warranting monitoring.

Trastuzumab-based therapy has shown survival benefit in HER2-positive SEC, leading to its inclusion in current treatment guidelines...The prognostic value remains debated, though recent trials of antibody-drug conjugates (e.g., T-DXd) show promise...Diagnostic challenges include variable scoring systems, intratumoral heterogeneity, and HER2-low classification. Standardization of testing criteria and further clinical validation of HER2-targeted strategies across gynecologic tumors are essential to guide personalized therapy and improve outcomes.

P2, N=80, Not yet recruiting, Sichuan Baili Pharmaceutical Co., Ltd.

Hb 100 ng/mL, height >160 cm, and the presence of lymph node metastases were associated with HER2 expression and positivity. HER2 testing should be considered mandatory when all these factors are present. The mechanisms linking these four factors to HER2 expression require further investigation.

P1/2, N=103, Recruiting, Chia Tai Tianqing Pharmaceutical Group Nanjing Shunxin Pharmaceutical Co., Ltd. | Trial completion date: Dec 2025 --> Dec 2029 | Trial primary completion date: May 2025 --> May 2027

Combining palbociclib, trastuzumab, and ET was safe and improved significantly PFS, compared to TPC in previously treated HER2-positive, PAM50 luminal A/B ABC patients.