Breaking the oncogene-immune suppression cycle through dual HER2 silencing and innate immune activation by biomineralized DNA nanocomplexes.

A pH-sensitive nanococktail enabled cancer stem cell elimination, deep tumour penetration, and tumour shrinkage.

HER2-positive breast cancer (BC) is an aggressive subtype that affects approximately 15-25% of patients. This study aimed to identify sociodemographic factors associated with mortality among patients with HER2-positive BC treated with trastuzumab under the Ricarte Soto Law (RSL) in Chile between 2015 and 2024. A cross-sectional observational design was used, based on a national database including 4,920 patients who accessed treatment through the RSL. Bivariate and multivariate logistic regression models were applied to evaluate factors associated with mortality. Older age, public healthcare system, and residence outside the Metropolitan Region were associated with higher mortality. These findings suggest that disparities in outcomes persist despite financial coverage of high-cost therapies, indicating the influence of structural and geographic factors on cancer care. This study provides real-world evidence to inform policies aimed at reducing inequities in access and outcomes among patients with breast cancer in Chile.

Anti-HER2 nanobody 5F7-based theranostics using [68Ga]Ga-NOTA-5F7 PET/CT and [131I]SGMIB-5F7 SPECT/CT in HER2-positive breast cancer.

ASO Author Reflections: Nodal Positivity Rates Support Neoadjuvant Systemic Therapy for Early-Stage HER2-Positive and Triple-Negative Breast Cancers.

Pathological response to herceptin-containing neoadjuvant therapy in HER2 IHC2+/ISH+ and IHC3+ early-stage invasive ductal carcinoma.

Redefining first-line standards: The role of next-generation HER2-Targeted therapies in HER2-positive metastatic breast cancer.

Early endometrial metastasis from triple-positive breast cancer is a rare phenomenon in young patients, especially when anti-human epidermal growth factor receptor 2 (HER2) target therapy is used as the primary treatment. We present a case of a 24-year-old patient with advanced triple positive breast cancer. The patient developed abnormal uterine bleeding during chemotherapy combined with anti-HER2 therapy (trastuzumab plus pyrotinib). Due to the transvaginal sonography are not characteristic and the low incidence rate of endometrial metastasis from breast cancer, this potential diagnosis was overlooked. The disease progressed rapidly thereafter, and the overall survival was only 13 months. The swift and devastating progression highlight the immense challenges in managing such complex cases. It remains a current challenge to identify such cases at an early stage and explore more effective therapeutic regimens. Based on this case review and previous studies, we speculate that disease progression might be attributed to the absence of endocrine therapy, chemotherapy resistance, or insufficient anti-HER2 therapeutic intensity. This case provides new insights into the metastatic pattern of HER2-positive breast cancer under targeted drug resistance. Clinicians should be alert to the possibility of reproductive system metastasis during anti-tumor treatment. Timely diagnosis and appropriate treatment are expected to improve patient prognosis.

To compare HER2-targeted with ¹⁸F-FDG PET/CT for detecting axillary lymph node metastasis in patients with newly diagnosed HER2-positive or HER2-low breast cancer. In this prospective study, HER2-expressed breast cancer participants underwent both 18F-FDG and Al18F-NOTA-HER2-BCH PET/CT within 1 week. On the basis of IHC and/or FISH, participants were categorized as HER2-positive (n=25) or HER2-low (n=26). Histopathology or imaging follow-up served as reference standards. Statistical analyses utilized the paired McNemar test for diagnostic performance, and the Wilcoxon signed-rank and Mann-Whitney U tests for paired and unpaired comparisons of uptake parameters, respectively. Between August 2024 and October 2025, 51 participants with breast cancer were enrolled. Among 40 participants with lymph node metastasis, Al18F-NOTA-HER2-BCH detected metastatic lymph nodes exclusively in one HER2-positive participant and more lesions than 18F-FDG in 11 cases. On a per-lesion analysis, Al18F-NOTA-HER2-BCH demonstrated significantly higher sensitivity, accuracy, and negative predictive value than 18F-FDG for detecting metastatic axillary lymph nodes in the HER2-positive cohort (94%, 94%, 93% vs. 79%, 85%, 84%, all P<0.001). This superiority was particularly pronounced for small lymph nodes (<5mm), with a detection rate of 90% versus 62% for 18F-FDG (P<0.001). Al18F-NOTA-HER2-BCH PET/CT directly influenced nodal staging and subsequent treatment decisions in 4 of 25 (16.0%) HER2-positive participants. In the HER2-low cohort, however, the diagnostic performance of the 2 tracers did not differ significantly, although 18F-FDG PET/CT led to clinically relevant nodal upstaging in one case. Al18F-NOTA-HER2-BCH retains developmental potential for detecting axillary lymph node metastasis in HER2-positive breast cancer, complementing 18F-FDG.

Febrile neutropenia (FN) remains a major complication of neoadjuvant chemotherapy (NAC) and is a frequent cause of treatment disruption. However, FN is a heterogeneous clinical entity, and the impact of its timing and clinical severity on treatment continuity has not been fully elucidated. This study aimed to characterize the timing and clinical burden of FN and to clarify their associations with treatment discontinuation during NAC. We retrospectively analyzed 137 consecutive patients with HER2-positive breast cancer who received NAC. FN timing was assessed by chemotherapy cycle and days from NAC initiation, with early FN defined a priori as FN occurring at cycle ≤ 2. FN severity was evaluated based on the requirement for hospitalization. Treatment discontinuation was defined as premature discontinuation of NAC due to chemotherapy-related adverse events; dose reductions or treatment delays without permanent discontinuation were not included in this endpoint. Logistic regression analyses were performed to identify factors associated with treatment discontinuation. FN occurred in 18 patients (13.1%). The median time to FN onset was 46 days (interquartile range, 19-112), with half of FN events occurring by cycle 2. Although FN events were evenly distributed across chemotherapy cycles, cumulative incidence analysis revealed early clustering on a time-based scale. Hospitalization was required in 50.0% of patients with FN. Treatment discontinuation occurred in 8.4% of patients without FN, 11.1% of patients with non-hospitalized FN, and 44.4% of patients with hospitalized FN. Exploratory multivariable analyses demonstrated that hospitalized FN was associated with treatment discontinuation after adjustment for age and host-related factors (odds ratio, 11.20-13.33 across models), whereas low body mass index and reduced renal function were not independent predictors. The impact of FN on treatment continuity during NAC appears to be determined by both its timing and clinical severity. FN requiring hospitalization, particularly when occurring early during NAC, was associated with an increased likelihood of treatment discontinuation. These findings underscore the importance of early identification and prevention of severe FN to optimize treatment delivery during neoadjuvant chemotherapy, while recognizing the statistical uncertainty inherent to the limited number of events.

Treatment of breast cancer brain metastases in the era of novel drugs.

Approximately 15% to 20% of patients with breast cancer are human epidermal growth factor 2 (HER2)-positive, and this type has a high recurrence rate. With the application of anti-HER2 drugs such as trastuzumab, the prognosis of patients with HER2-positive breast cancer has improved significantly. However, more than 30% of patients present with recurrence and distant metastasis due to drug resistance. It is important to develop new drugs to overcome trastuzumab resistance. Therefore, in collaboration with a research group at Dalian University of Technology, we synthesized ZQL-4c, a novel oleanolic acid (OA) derivative that was found to target the lipid metabolism reprogramming function of stearoyl-CoA desaturase (SCD), inducing lipotoxicity-mediated apoptosis. These findings provide an attractive future direction for the treatment of HER2-positive trastuzumab-resistant breast cancer.

To characterise the clinical and morphological features of ocular surface toxicity induced by human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugates (ADCs) in patients with HER2-positive breast cancer, guiding clinical intervention. 21 HER2-positive breast cancer patients receiving HER2-ADC therapy were enrolled. Assessments included best corrected visual acuity, the Ocular Surface Disease Index, conjunctival lissamine green staining, tear break-up time, tear meniscus height, Meibomian Gland Score, Strip Meniscometry Tube (SMTube strips), corneal sensitivity (Cochet-Bonnet esthesiometry), anterior segment optical coherence tomography and in vivo confocal microscopy (IVCM) to evaluate morphology, corneal nerve fibre density and length, and endothelial cell density. Transmission electron microscopy (TEM) was performed in selected cases. All parameters were compared from baseline to follow-up. Ocular surface toxicity occurred in 85.7% (18/21) of patients after HER2-ADC therapy, with a mean onset at 28.0±8.4 days. Vortex-like keratopathy progressed from inferior subepithelial microcysts to linear deposits and a vortex pattern. IVCM revealed severe subepithelial nerve fibre fragmentation and loss. TEM revealed epithelial extracellular matrix fibrosis, mitochondrial damage (swelling, disordered cristae, vacuolisation), nuclear alterations (chromatin dispersion, electron-dense deposits) and suspected endocytic vesicles. Lesions appeared dose- and time-dependent and showed partial reversibility. After 12 cycles, corneal structure and transparency showed restoration trends. HER2-ADC-induced ocular surface toxicity presents as vision loss, dry eye and selective damage to corneal epithelium (vortex-like keratopathy) and nerves (nerve fibre loss and reduced sensitivity), which is dose- and time-dependent and partially reversible.

HER2-positive (HER2+) breast cancer (BC) accounts for 15-20% of all BC. Mutations in the PIK3CA gene are found in 25-30% of HER2 + BC cases and have been implicated in tumor progression and endocrine therapy resistance. Recent evidence suggests that a somatic PIK3CA mutation (PIK3CAm) may serve as a marker of early progression in HER2 + metastatic BC. However, its precise prognostic significance across various lines of therapy and disease stages is not fully understood. We therefore aimed to evaluate the impact of PIK3CAm status on clinical outcomes in HER2 + BC patients. We conducted a retrospective cohort study using data from the American Association for Cancer Research (AACR) Project GENIE Biopharma Collaborative (BPC). Overall survival (OS), Distant Recurrence-Free Survival (DRFS), and progression-free survival (PFS) were the primary outcomes. We compared patients with and without PIK3CAm and performed survival analysis using Kaplan-Meier methods and Cox proportional hazards models. We identified 212 HER2 + patients (150 early-stage and 62 Stage IV), of which 58 had a PIK3CAm. The median OS for the overall cohort was 125.1 months from treatment. Among early-stage patients, PIK3CAm was associated with a longer DRFS from diagnosis (37.7 months [95% CI 28.6-62.6] vs. 22 months [95% CI 16.8-32.8], p = 0.04). In contrast, among patients with Stage IV disease receiving first-line therapy, PIK3CAm was associated with a shorter median PFS (5.5 [95% CI 1.6-32.2] vs. 14.9 months [95% CI 7.2-22.0], p = 0.04). PIK3CAm was not identified as an independent predictor of OS, DRFS, or PFS in univariable or multivariable regression analyses. Within the PIK3CAm subgroup, not having received hormone therapy was the only factor associated with worse survival on multivariable analysis (aHR = 4.51, 95% CI 1.77-11.5). PIK3CAm was not found to be associated with worse OS, however it was associated with a shorter PFS among patients receiving first-line therapy, suggesting PIK3CAm could be explored as a predictive biomarker for identifying HER2 + Stage IV patients at higher risk of disease progression. These findings underscore the need for enhanced surveillance and personalized treatment strategies to manage disease progression in this patient subgroup.

Neoadjuvant dual HER2 blockade with trastuzumab and pertuzumab plus chemotherapy represents the current standard-of-care for HER2-positive breast cancer. However, treatment responses remain heterogeneous, underscoring the lack of clinically practical tools for predicting treatment efficacy and informing personalized therapy. Here, we developed HER2-LADDER (Layered AI-based Dual-targeteD anti-HER2 Recommendation), a spatially interpretable and clinically accessible artificial intelligence framework that integrates clinicopathological and spatial topological features from routine hematoxylin and eosin (H&E) and HER2 immunohistochemistry (IHC) slides. Using these spatially derived features, HER2-LADDER accurately predicted response to neoadjuvant TCbHP/PCbHP, achieving AUCs of 0.944 in the model construction cohort (N = 276), 0.917 in the temporal validation cohort (N = 82), and 0.869 in the trial-based validation cohort (N = 85). On the basis of HER2-LADDER scores, patients were stratified into Low (highly responsive), Medium (responsive), and High (resistant) groups, identifying candidates for treatment de-escalation (THP or TCbH/PCbH), standard-of-care (TCbHP/PCbHP), or alternative regimens (e.g., next-generation anti-HER2 antibody-drug conjugates), respectively. Importantly, Xenium in situ profiling further revealed biological correlates underlying model predictions, including HER2-enriched tumor cell aggregation and neutrophil-helper T-cell interactions, thereby highlighting the mechanistic interpretability of the model. Collectively, HER2-LADDER unites digital pathology and high-resolution spatial profiling into a clinically accessible AI framework, offering a robust, transparent, and biologically grounded tool to tailor individualized HER2-targeted therapy optimization.

A new trastuzumab-ageritin-based immunotoxin that specifically kills breast cancer cells.

"Neoadjuvant trastuzumab deruxtecan for high-risk HER2-positive early breast cancer: Does the evidence support its use as a new standard-of-care?"

Phenotypic plasticity and competition shape therapy sequencing in HER2+/HER2- breast cancer: A mathematical framework.

The clinical management of HER2-positive breast cancer is undergoing a paradigm shift, recognizing that hormone receptor (HR) co-expression defines a fundamental biological dichotomy rather than a minor clinical variation. This perspective evaluates the profound heterogeneity within the HER2-positive subclass, where HR status acts as a master regulator of genomic landscapes and patient outcomes. Evidence from large-scale database analyses reveals that HR+/HER2 + malignancies are associated with a significant survival advantage, contrasting with the heightened phenotypic aggression and advanced staging characteristic of HR-negative disease. At the molecular level, this divergence is underpinned by distinct transcriptomic profiles; specifically, the enrichment of drug-metabolizing pathways-including cytochrome P450 and retinol metabolism involving CYP2A6 and UGT2B7-suggests a mechanism for superior endocrine sensitivity and modulated apoptotic signaling in the double-positive cohort. Furthermore, the tumor microenvironment reflects this biological disparity, with HR status potentially governing local immune responses, as evidenced by the differential infiltration of resting mast cells versus plasma cells. Of note, while somatic mutations in TP53 and PIK3CA persist across both cohorts, the unique metabolic and immunological milieus confirm that these subtypes represent biologically discrete entities. Moving forward, the "HER2-positive" designation must be refined through integrated, biomarker-driven frameworks. Incorporating these molecular nuances into prospective clinical trials is essential for optimizing therapeutic de-escalation and overcoming the persistent challenges of resistance in HER2-targeted care.

Chemotherapy duration and patient-reported outcomes in HER2-positive early breast cancer: Results from the TRAIN-3 study.