OBJECTIVE: This study aimed to identify ultrasound and clinicopathological characteristics related to recurrence in HER2-positive (HER2+) breast cancer, and to develop nomograms for predicting recurrence.
METHODS: In this dual-center study, we retrospectively enrolled 570 patients with HER2+ breast cancer. The ultrasound and clinicopathological characteristics of hormone receptor (HR)-/HER2+ patients and HR+/HER2+ patients were analyzed separately according to HR status. Eighty percent of the original samples from HR-/HER2+ and HR+/HER2+ patients were extracted by bootstrap sampling as the training cohorts, while the remaining 20% were used as the external validation cohorts. Informative characteristics were screened through univariate and multivariable Cox regression in the training cohorts and used to develop nomograms for predicting recurrence. The predictive accuracy was calculated using Harrell\'s C-index and calibration curves.
RESULTS: Three informative characteristics (axillary nodal status, calcification, and Adler degree) were identified in HR-/HER2+ patients, and another three (histological grade, axillary nodal status, and echogenic halo) in HR+/HER2+ patients. Based on these, two separate nomograms were constructed to assess recurrence risk. In the training cohorts, the C-index was 0.740 (95% CI: 0.667-0.811) for HR-/HER2+ nomogram, and 0.749 (95% CI: 0.679-0.820) for HR+/HER2+ nomogram. In the validation cohorts, the C-index was 0.708 (95% CI: 0.540-0.877) for HR-/HER2+ group, and 0.705 (95% CI: 0.557-0.853) for HR+/HER2+ group. The calibration curves also indicated the excellent accuracy of the nomograms.
CONCLUSIONS: Ultrasound performance of HER2+ breast cancers with different HR status was significantly different. Nomograms integrating ultrasound and clinicopathological characteristics exhibited favorable performance and have the potential to serve as a reliable method for predicting recurrence in heterogeneous breast cancer.

Data on rechallenges of HER2 targetted agents in breast cancer patients is limited. The goal of the study was to evaluate the effectiveness of trastuzumab-based therapy in patients who progressed under trastuzumab emtansine (TDM-1). The study was designed as a retrospective observational study. Survival plots were performed with the Kaplan-Meier method. Fifteen patients were involved in the study. The average age was 45 (range, 30-66). De novo metastatic patient number was six (40%), and the average number of metastatic sites was 2 (range, 1-4) at diagnosis. Fourteen patients (92.3%) had undergone breast surgery (lumpectomy or mastectomy). All patients previously had been treated with trastuzumab-based chemotherapy and TDM-1. Also, nine (60%) patients had received endocrine therapy, and nine (60%) patients had palliative radiotherapy. After progression under TDM-1, patients received trastuzumab with chemotherapy (73.3%) or alone (26.7%). The overall response ratio was 66.7%. Median progression-free survival was 9.4 months (95% CI, 3.4-15.3). The median OS duration was 24.2 (95% CI, 13.5-34.9) months. Toxicity in all grades was observed in ten (66.7%) patients, and grade 3-4 toxicity (anemia and neutropenia) in two patients (13.3%). This study showed that rechallenge trastuzumab-based therapy was effective and good-tolerated in heavily pretreated patients who had progressed under TDM-1.

Understanding which patients with human epidermal growth factor receptor 2 (HER2)-negative or -low metastatic breast cancer (MBC) benefit from HER2-targeted strategies is urgently needed. We assessed the whole-body heterogeneity of HER2 expression on 89Zr-trastuzumab PET (HER2 PET) and the diagnostic performance of HER2 PET in a large series of patients, including HER2-negative and -low MBC. Methods: In the IMPACT-MBC study, patients with newly diagnosed and nonrapidly progressive MBC of all subtypes were included. Metastasis HER2 status was determined by immunohistochemistry and in situ hybridization.89Zr-trastuzumab uptake was quantified as SUVmax and SUVmean HER2 immunohistochemistry was related to the quantitative 89Zr-trastuzumab uptake of all metastases and corresponding biopsied metastasis, uptake heterogeneity, and qualitative scan evaluation. A prediction algorithm for HER2 immunohistochemistry positivity based on uptake was developed. Results: In 200 patients, 89Zr-trastuzumab uptake was quantified in 5,163 metastases, including 186 biopsied metastases. With increasing HER2 immunohistochemistry status, uptake was higher (geometric mean SUVmax of 7.0, 7.6, 7.3, and 17.4 for a HER2 immunohistochemistry score of 0, 1, 2, or 3+, respectively; P < 0.001). High uptake exceeding 14.6 (90th percentile) was observed in one third of patients with a HER2-negative or -low metastasis biopsy. The algorithm performed best when lesion site and size were incorporated (area under the curve, 0.86; 95% CI, 0.79-0.93). Conclusion: HER2 PET had good diagnostic performance in MBC, showing considerable whole-body HER2 heterogeneity and uptake above background in HER2-negative and -low MBC. This provides novel insights into HER2-negative and -low MBC compared with standard HER2 immunohistochemistry on a single biopsy.

HER2 amplification is one of the mechanisms that induce drug resistance to anti-EGFR therapy in colorectal cancer. In recent years, data from several randomized clinical trials show that anti-HER2 therapies improved the prognosis of patients with HER2-positive colorectal cancer. These results indicate that HER2 is a promising therapeutic target in advanced colorectal cancer. Despite the anti-HER2 therapies including monoclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates improving the outcomes, less than 30 % of the patients achieve objective response and eventually have drug resistance. It is necessary to explore the primary and secondary mechanisms for the resistance to anti-HER2 therapies, which will pave the way to overcome the drug resistance. Several studies have reported the potential mechanisms for the resistance to anti-HER2 therapies. In this review, we present a comprehensive overview of the recent advances in clinical research, mechanisms of treatment resistance, and strategies for reversing resistance in HER2-positive colorectal cancer patients.

BACKGROUND: In 2022, our team launched the pioneering national proficiency testing (PT) scheme for the pathological diagnosis of breast cancer, rapidly establishing its credibility throughout China. Aiming to continuously monitor and improve the proficiency of Chinese pathologists in breast pathology, the second round of the PT scheme was initiated in 2023, which will expand the number of participating institutions, and will conduct a nationwide investigation into the interpretation of HER2 0, 1+, and 2+/FISH- categories in China.
METHODS: The methodology employed in the current round of PT scheme closely mirrors that of the preceding cycle in 2022, which is designed and implemented according to the \"Conformity assessment-General requirements for proficiency testing\"(GB/T27043-2012/ISO/IEC 17043:2010). More importantly, we utilized a statistics-based method to generate assigned values to enhance their robustness and credibility.
RESULTS: The final PT results, published on the website of the National Quality Control Center for Cancer ( http://117.133.40.88:3927 ), showed that all participants passed the testing. However, a few institutions demonstrated systemic biases in scoring HER2 0, 1+, and 2+/FISH- with accuracy levels below 59%, considered unsatisfactory. Especially, the concordance rate for HER2 0 cases was only 78.1%, indicating challenges in distinguishing HER2 0 from low HER2 expression. Meanwhile, areas for histologic type and grade interpretation improvement were also noted.
CONCLUSIONS: Our PT scheme demonstrated high proficiency in diagnosing breast cancer in China. But it also identified systemic biases in scoring HER2 0, 1+, and 2+/FISH- at some institutions. More importantly, our study highlighted challenges in the evaluation at the extreme lower end of the HER2 staining spectrum, a crucial area for further research. Meanwhile, it also revealed the need for improvements in interpreting histologic types and grades. These findings strengthened the importance of robust quality assurance mechanisms, like the nationwide PT scheme conducted in this study, to maintain high diagnostic standards and identify areas requiring further training and enhancement.

UNASSIGNED: Breast cancer (BC) is one of the leading causes of cancer and is the first cause of death from malignant tumors among women worldwide. New cancer therapies receive regulatory approval yearly and to avoid health disparities in society, the health systems are challenged to adapt their infrastructure, methodologies, and reimbursement policies to allow broad access to these treatments. In addition, listening to patients\' voices about their therapy preferences is essential. We aim to investigate the administration route preferences [subcutaneous (SC) or intravenous (IV)] among patients diagnosed with HER2 positive BC and healthcare professionals (HCPs) and to investigate healthcare resources utilization (quality and quantity) for each route of administration (SC or IV) for treating those patients.
UNASSIGNED: We conducted a systematic literature review focused on clinical trials and observational and economic studies, using PubMed (MEDLINE), Cochrane Library, Virtual Health Library (VHL), Scientific Electronic Library Online (SciELO), and Latin American and Caribbean Health Sciences Literature (LILACS) databases based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.
UNASSIGNED: The literature review included 25 studies in the analysis. Studies have reported that patients and HCPs prefer the SC route of administration to IV because it saves time in terms of chair time, administration, and preparation and is less painful. In addition, SC administration might be a more cost-saving option when analyzing direct and indirect costs.
UNASSIGNED: As BC stands as a significant global health concern and the leading cause of cancer-related deaths in women worldwide, understanding and incorporating patient and HCPs preferences in the choice of administration route become paramount. The observed preference for SC administration not only aligns with the imperative of adapting health systems to facilitate broad access to new cancer therapies but also underscores the importance of considering patient experiences and economic implications in shaping treatment strategies. These insights are crucial for healthcare policymakers, clinicians, and stakeholders in optimizing healthcare resources and enhancing the overall quality of BC care.

UNASSIGNED: Lung cancer is a highly prevalent malignancy with significant morbidity and mortality rates. MiR-489-3p, a microRNA, has been identified as a regulator of tumor cell proliferation and invasion. Its expression is downregulated in non-small cell lung cancer (NSCLC). Elucidating the molecular mechanisms underlying miR-489-3p\'s role in NSCLC pathogenesis is crucial for identifying potential diagnostic and therapeutic targets.
UNASSIGNED: To investigate the molecular mechanism of miR-489-3p in NSCLC, this study utilized A549, a commonly used NSCLC cell line. MiR-489-3p mimics and inhibitors were transfected into A549 cells. Additionally, co-transfection experiments using wortmannin, an inhibitor of the PI3K/AKT pathway, were performed. Expression of miR-489-3p and related proteins was analyzed by Western blotting and quantitative real-time PCR (qRT-PCR). Cell migration and proliferation were assessed by wound healing and colony formation assays, respectively.
UNASSIGNED: Overexpression of miR-489-3p significantly inhibited the proliferation and migration of A549 cells. This inhibitory effect was further enhanced upon co-transfected with wortmannin. Analysis of human lung specimens showed increased expression of HER2, PI3K, and AKT in lung adenocarcinoma tissues compared to adjacent non-cancerous tissues.
UNASSIGNED: These findings suggest that miR-489-3p overexpression may inhibit NSCLC cell proliferation and migration by suppressing the HER2/PI3K/AKT/Snail signaling pathway. This study elucidates miR-489-3p\'s molecular mechanisms in NSCLC and provides experimental basis for identifying early diagnostic markers and novel therapeutic targets.

UNASSIGNED: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have demonstrated potential benefits for metastatic colorectal cancer (mCRC) patients with HER2 amplification, but are not satisfactory in cases of HER2 mutant CRCs.
UNASSIGNED: Consequently, further elucidation of amplifications and somatic mutations in erythroblastic oncogene B-2 (ERBB2) is imperative. Comprehensive genomic profiling was conducted on 2454 Chinese CRC cases to evaluate genomic alterations in 733 cancer-related genes, tumor mutational burden, microsatellite instability, and programmed death ligand 1 (PD-L1) expression.
UNASSIGNED: Among 2454 CRC patients, 85 cases (3.46%) exhibited ERBB2 amplification, and 55 cases (2.24%) carried ERBB2 mutation. p.R678Q (28%), p.V8421 (24%), and p.S310F/Y (12%) were the most prevalent of the 16 detected mutation sites. In comparison to the ERBB2 altered (alt) group, KRAS/BRAF mutations were more prevalent in ERBB2 wild-type (wt) samples (ERBB2wt vs. ERBB2alt, KRAS: 50.9% vs. 25.6%, p < 0.05; BRAF: 8.5% vs. 2.3%, p < 0.05). 32.7% (18/55) of CRCs with ERBB2 mutation exhibited microsatellite instability high (MSI-H), while no cases with HER2 amplification displayed MSI-H. Mutant genes varied between ERBB2 copy number variation (CNV) and ERBB2 single nucleotide variant (SNV); TP53 alterations tended to co-occur with ERBB2 amplification (92.3%) as opposed to ERBB2 mutation (58.3%). KRAS and PIK3CA alterations were more prevalent in ERBB2 SNV cases (KRAS/PIK3CA: 45.8%/31.2%) compared to ERBB2 amplification cases (KRAS/PIK3CA: 14.1%/7.7%).
UNASSIGNED: Our study delineates the landscape of HER2 alterations in a large-scale cohort of CRC patients from China. These findings enhance our understanding of the molecular features of Chinese CRC patients and offer valuable implications for further investigation.

UNASSIGNED: To evaluate the performance of a clinical-radiomics model based on contrast-enhanced computed tomography (CE-CT) in assessing human epidermal growth factor receptor 2 (HER2) status in urothelial bladder carcinoma (UBC).
UNASSIGNED: From January 2022 to December 2023, 124 patients with UBC were classified into the training (n=100) and test (n=24) sets. CE-CT scans were performed on the patients. Univariate and multivariate analyses were conducted to identify independent predictors of HER2 status in patients with UBC. We employed eight machine learning algorithms to establish radiomic models. A clinical-radiomics model was developed by integrating radiomic signatures and clinical features. Receiver operating characteristic curves and decision curve analysis (DCA) were generated to evaluate and validate the predictive capabilities of the models.
UNASSIGNED: Among the eight classifiers, the random forest radiomics model based on CE-CT demonstrated the highest efficacy in predicting HER2 status, with area under the curve (AUC) values of 0.880 (95% CI: 0.813-0.946) and 0.814 (95% CI: 0.642-0.986) in the training and test sets, respectively. In the training set, the clinical-radiomics model achieved an AUC of 0.935, an accuracy of 0.870, a sensitivity of 0.881, and a specificity of 0.854. In the test set, the clinical-radiomics model achieved an AUC of 0.857, an accuracy of 0.760, a sensitivity of 0.643, and a specificity of 0.900. DCA analysis indicated that the clinical-radiomics model provided good clinical benefit.
UNASSIGNED: The radiomics nomogram demonstrates good diagnostic performance in predicting HER2 expression in patients with UBC.

HER2-positive breast cancer is a significant cause of mortality. Overcoming trastuzumab resistance requires a deeper understanding of its molecular mechanisms to develop effective therapies. This study investigates the role of plasminogen activator inhibitor-1 (PAI1) in migration and drug resistance in trastuzumab-resistant HER2-positive breast cancer. Trastuzumab resistance poses a significant challenge in clinical management due to its association with aggressive disease behaviour and limited treatment options. This study focuses on PAI1, a key player in the TGF-β signalling pathway, which is implicated in cancer progression and metastasis. Trastuzumab-resistant cell lines (SKBR3 and HCC1954) demonstrated markedly elevated PAI1 expression levels, up to 40-fold compared to parental lines. This elevation was accompanied by increased expression of migration markers such as Col4a1, Fibronectin, ICAM1, Timp2, and Vimentin. Through overexpression and silencing experiments, we observed that modulating PAI1 levels significantly impacts cell morphology, transitioning cells from an epithelial to mesenchymal phenotype. Importantly, combining trastuzumab with aleplasinin, a PAI1 inhibitor, synergistically reduced PAI1 expression in both parental and resistant cell lines. This suggests a potential therapeutic strategy to overcome trastuzumab resistance. These findings emphasise PAI1 as a critical mediator of migration and therapeutic response in HER2-positive breast cancer, offering insights into novel treatment approaches targeting PAI1 to improve clinical outcomes in drug resistance.