Gastric cancer and gastroesophageal junction cancer represent the leading cause of tumor-related death worldwide. Although advances in immunotherapy and molecular targeted therapy have expanded treatment options, they have not significantly altered the prognosis for patients with unresectable or metastatic gastric cancer. A minority of patients, particularly those with PD-L1-positive, HER-2-positive, or MSI-high tumors, may benefit more from immune checkpoint inhibitors and/or HER-2-directed therapies in advanced stages. However, for those lacking specific targets and unique molecular features, conventional chemotherapy remains the only recommended effective and durable regimen. In this review, we summarize the roles of various signaling pathways and further investigate the available targets. Then, the current results of phase II/III clinical trials in advanced gastric cancer, along with the superiorities and limitations of the existing biomarkers, are specifically discussed. Finally, we will offer our insights in precision treatment pattern when encountering the substantial challenges.

UNASSIGNED: To explore the application of multiparametric MRI-based radiomic nomogram for assessing HER-2 2+ status of breast cancer (BC).
UNASSIGNED: Patients with pathology-proven HER-2 2+ invasive BC, who underwent preoperative MRI were divided into training (72 patients, 21 HER-2-positive and 51 HER-2-negative) and validation (32 patients, 9 HER-2-positive and 23 HER-2-negative) sets by randomization. All were classified as HER-2 2+ FISH-positive (HER-2-positive) or -negative (HER-2-negative) according to IHC and FISH. The 3D VOI was drawn on MR images by two radiologists. ADC, T2WI, and DCE images were analyzed separately to extract features (n = 1906). L1 regularization, F-test, and other methods were used to reduce dimensionality. Binary radiomics prediction models using features from single or combined imaging sequences were constructed using logistic regression (LR) classifier then and validated on a validation dataset. To build a radiomics nomogram, multivariate LR analysis was conducted to identify independent indicators. An evaluation of the model\'s predictive efficacy was made using AUC.
UNASSIGNED: On the basis of combined ADC, T2WI, and DCE images, ten radiomic features were extracted following feature dimensionality reduction. There was superior diagnostic efficiency of radiomic signature using all three sequences compared to either one or two sequences (AUC for training group: 0.883; AUC for validation group: 0.816). Based on multivariate LR analysis, radiomic signature and peritumoral edema were independent predictors for identifying HER-2 2 +. In both training and validation datasets, nomograms combining peritumoral edema and radiomics signature demonstrated an effective discrimination (AUCs were respectively 0.966 and 0. 884).
UNASSIGNED: The nomogram that incorporated peritumoral edema and multiparametric MRI-based radiomic signature can be used to effectively predict the HER-2 2+ status of BC.

As an important prognostic indicator in breast cancer, human epithelial growth factor receptor-2 (HER-2) is of importance for assessing prognosis of breast cancer patients, whose accurate and facile analysis are imperative in clinical diagnosis and treatment. Herein, photoactive Z-scheme UiO-66/CdIn2S4 heterojunction was constructed by a hydrothermal method, whose optical property and photoactivity were critically investigated by a range of techniques, combined by elucidating the interfacial charge transfer mechanism. Meanwhile, PtPdCu nanoflowers (NFs) were fabricated by a simple aqueous wet-chemical method, whose peroxidase (POD)-mimicking catalytic activity was scrutinized by representative tetramethylbenzidine (TMB) oxidation in H2O2 system. Taken together, the UiO-66/CdIn2S4 based photoelectrochemical (PEC) aptasensor was established for quantitative analysis of HER-2, where the detection signals were further magnified through catalytic precipitation reaction towards 4-chloro-1-naphthol (4-CN) oxidation (assisted by the PtPdCu NFs nanozyme). The PEC aptasensor presented a broader linear range within 0.1 pg mL-1-0.1 μg mL-1 and a lower limit of detection of 0.07 pg mL-1. This work developed a new PEC aptasensor for ultrasensitive determination of HER-2, holding substantial promise for clinical diagnostics.

This study explores the potential of radiomics to predict the proliferation marker protein Ki-67 levels and human epidermal growth factor receptor 2 (HER-2) status based on MRI images of patients with spinal metastasis from primary breast cancer. A total of 110 patients with pathologically confirmed spinal metastases from primary breast cancer were enrolled between Dec. 2017 and Dec. 2021. All patients underwent T1-weighted contrast-enhanced MRI scans. The PyRadiomics package was used to extract features from the MRI images based on the intraclass correlation coefficient and least absolute shrinkage and selection operator. The most predictive features were used to develop the radiomics signature. The Chi-Square test, Fisher\'s exact test, Student\'s t-test, and Mann-Whitney U test were used to evaluate the clinical and pathological characteristics between the high- and low-level Ki-67 groups and the HER-2 positive/negative groups. The radiomics models were compared using receiver operating characteristic curve analysis. The area under the receiver operating characteristic curve (AUC), sensitivity (SEN), and specificity (SPE) were generated as comparison metrics. From the spinal MRI scans, five and two features were identified as the most predictive for the Ki-67 level and HER-2 status, respectively. The developed radiomics signatures generated good prediction performance for the Ki-67 level in the training (AUC = 0.812, 95% CI: 0.710-0.914, SEN = 0.667, SPE = 0.846) and validation (AUC = 0.799, 95% CI: 0.652-0.947, SEN = 0.722, SPE = 0.833) cohorts. Good prediction performance for the HER-2 status was also achieved in the training (AUC = 0.796, 95% CI: 0.686-0.906, SEN = 0.720, SPE = 0.776) and validation (AUC = 0.705, 95% CI: 0.506-0.904, SEN = 0.733, SPE = 0.762) cohorts. The results of this study provide a better understanding of the potential clinical implications of spinal MRI-based radiomics on the prediction of Ki-67 levels and HER-2 status in breast cancer.

Whether radiotherapy can improve the long-term survival of HER-2+ metastatic breast cancer remains unclear. We launched this study to explore the effect of HER-2+ metastatic breast cancer patients through anti-HER-2 targeted therapy + radiotherapy.
488 HER-2 + metastatic breast cancer patients who received anti-HER2 targeted ± local radiotherapy from March 2006 to September 2021 were retrospectively collected. Patients were divided into a radiotherapy group (n=207) and a non-radiotherapy group (n=281) based on whether they received radiotherapy or not. 1: 1 propensity matching analysis was used to determine two groups of patients with similar baselines.
Before matching, the radiotherapy group (n=207) had a median overall survival (mOS) of 51.7 months (48.8-63.8), which was superior to the non-radiotherapy group\'s (n=281) mOS of 33.9 months (27.9-39.9) (P < 0.0001). Moreover, the radiotherapy group exhibited better 1-year (94.6% vs 83.9%), 3-year (70.8% vs 45.5%), and 5-year (43.3% vs 25.0%) survival rates compared to the control group. Propensity score matching analysis identified 135 pairs of baseline-matched patients. In the matched groups, the mOS was 57.2 (44.5-69.8) months in the radiotherapy group (n=135) and 34.1 (27.5-40.6) months in the non-radiotherapy group (n=135), showing a statistically significant difference (P < 0.0001). Additionally, the radiotherapy group demonstrated 1-, 3-, and 5-year survival rates of 93.2%, 71.5%, and 46.9%, respectively, while those in the non-radiotherapy group were 89.4%, 45.8%, and 22.2%, respectively. Multivariate Cox analysis revealed that the presence of brain metastasis, liver metastasis, and radiotherapy were identified as independent predictive factors significantly associated with OS.
In patients with HER-2 positive metastatic breast cancer, radiotherapy was associated with better survival benefits compared to those who did not receive radiotherapy.

(1) Introduction: Claudin-9 (CLDN9) is a member of the claudin protein family, a critical transmembrane protein family for tight junctions that are implemented in the progression of numerous cancer types. The present study investigated the role that CLDN9, along with the subcoat proteins, Zonula Occludens (ZOs), plays in clinical breast cancer and subsequent impact on drug response of patients. (2) Methods: CLDN9 protein and CLDN9 transcript were determined and correlated with clinical and pathological indicators, together with the status of hormonal receptors. The levels of CLDN9 transcript were also assessed against the therapeutic responses of the patients to chemotherapies by using a dataset from the TCGA database. Breast cancer cell models, representing different molecular subtypes of breast cancer, with differential expression of CLDN9 were created and used to assess the biological impact and response to chemotherapeutic drugs. (3) Results: Breast cancer tissues expressed significantly higher levels of the CLDN9, with the high levels being associated with shorter survival. CLDN9 was significantly correlated with its anchorage proteins ZO-1 and ZO-3. Integrated expression of CLDN9, ZO-1 and ZO-3 formed a signature that was significantly linked to overall survival (OS) (p = 0.013) and relapse-free survival (RFS) (p = 0.024) in an independent matter. CLDN9 transcript was significantly higher in patients who were resistant to chemotherapies (p < 0.000001). CLDN9 connection to chemoresistance was particularly prominent in patients of ER-positive (ER(+)), Her-2-negative((Her-2(-)), ER(+)/Her-2(-) and triple-negative breast cancers (TNBCs), but not in patients with HER-2-positive tumors. In Her-2-negative MCF7 and MDA-MB-231 cancer cells, loss of CLDN9 significantly increased sensitivity to several chemotherapeutic drugs including paclitaxel, gemcitabine and methotrexate, which was not seen in Her-2(+) SKBR3 cells. However, suppressing Her-2 using neratinib, a permanent Her-2 inhibitor, sensitized cellular response to these chemodrugs in cells with CLDN9 knockdown. (4) Conclusions: CLDN9 is an important prognostic indicator for patients with breast cancer and also a pivotal factor in assessing patient responses to chemotherapies. Her-2 is a negating factor for the treatment response prediction value by CLDN9 and negating Her-2 and CLDN9 may enhance breast cancer cellular response to chemotherapeutic drugs.

UNASSIGNED: Identifying biological markers of colorectal cancer (CRC) development and prognosis and exploring the intrinsic connection between these molecular markers and CRC progression is underway. However, a single molecular tumor marker is often difficult to assess and predict the progression and prognosis of CRC. Consequently, a combination of tumor-related markers is much needed. Ki67, Her-2, and mutant P53 (MutP53) proteins play pivotal roles in CRC occurrence, progression and prognosis.
UNASSIGNED: Based on the expressions by immunochemistry, we developed a risk model, nomogram and lymph node metastasis model by R software and Pythons to explore the value of these proteins in predicting CRC progression, prognosis, and examined the relationship of these proteins with the CRC clinicopathological features from 755 (training set) and 211 CRC (validation set) patients collected from the hospital.
UNASSIGNED: We found that Ki67 expression was significantly correlated with T-stage, N-stage, TNM-stage, vascular invasion, organization differentiation, and adenoma carcinogenesis. Moreover, Her-2 expression was significantly correlated with T-stage, N-stage, TNM-stage, vascular and nerve invasion, pMMR/dMMR, signet ring cell carcinoma, and organization differentiation. MutP53 expression was significantly correlated with T-stage, N-stage, TNM-stage, vascular and nerve invasion, adenoma carcinogenesis, signet ring cell carcinoma, organization differentiation, and pMMR/dMMR. Increased expression of each of the protein indicated a poor prognosis. The established risk model based on the three key proteins showed high predictive value for determining the pathological characteristics and prognosis of CRC and was an independent influencer for prognosis. The nomogram prediction model, which was based on the risk model, after sufficient evaluation, showed more premium clinical value for predicting prognosis. Independent cohort of 211 CRC patients screened from the hospital verified the strong predictive efficacy of these models. The utilization of the XGBoost algorithm in a lymph node metastasis model, which incorporates three crucial proteins, demonstrated a robust predictive capacity for lymph node metastasis.
UNASSIGNED: The risk model, nomogram and lymph node metastasis model have all provided valuable insights into the involvement of these three key proteins in the progression and prognosis of CRC. Our study provides a theoretical basis for further screening of effective models that utilize biological markers of CRC.

UNASSIGNED: The aim of this study was to verify TCGA subtypes in endometrial clear cell carcinoma (ECCC) and determine their clinical and molecular characteristics.
UNASSIGNED: We summarized and compared the clinical features of 28 clear cell carcinoma and 112 endometrioid carcinoma patients. Of the 28 ECCCs, 19 underwent TCGA classification, and other markers (ER, PR, ARID1A, ARIB1B, TAF1, and HER-2) were also detected by IHC, and outcomes were assessed.
UNASSIGNED: Compared to endometrioid carcinoma, ECCC had an older age of onset (median age, 64.5 years, range 31-81 years), higher rate of myometrial invasion (42.8% vs. 21.5% in endometrioid carcinoma), LVSI (33% vs. 16%), and more advanced FIGO stage. Among the ECCCs, LVSI was a poor prognostic factor. TCGA classification was performed for 19 ECCCs: two POLEmut cases (10.5%), three MMRd (15.8%), 11 p53wt (57.9%), and three p53abn (15.8%). Of the 19 ECCCs, six (31.6%) showed HER-2 positive expression, and eight (42.1%) had TAF1 expression loss. ECCCs possessed HER-2 and TAF1 expression had worse outcomes.
UNASSIGNED: Our study summarized the clinical features of ECCC. The outcomes of patients with ECCC with TCGA subtypes differed from those of patients with endometrioid carcinoma. HER-2 and TAF1 may be new prognostic factors.

Colorectal cancer (CRC) represents 10% of all cancer types, making it the third leading cause of cancer-related deaths globally. Metastasis is the primary factor causing mortality in CRC patients. Approximately 22% of CRC-related deaths have metastasis present at diagnosis, with approximately 70% of these cases recurring. Recently, with the application of novel targeted drugs, targeted therapy has become the first-line option for individualized and comprehensive treatment of CRC. The management of these patients remains a significant medical challenge. The most prevalent targeted therapies for CRC in clinical practice focus on anti-vascular endothelial growth factor and its receptor, epidermal growth factor receptor (EGFR), and multi-target kinase inhibitors. In the wake of advancements in precision diagnosis and widespread adoption of second-generation sequencing (NGS) technology, rare targets such as BRAF V600E mutation, KRAS mutation, HER2 overexpression/amplification, and MSI-H/dMMR in metastatic colorectal cancer (mCRC) are increasingly being discovered. Simultaneously, new therapeutic drugs targeting these mutations are being actively investigated. This article reviews the progress in clinical research for developing targeted therapeutics for CRC, in light of advances in precision medicine and discovery of new molecular target drugs.

Cisplatin-based chemotherapy has been the first choice for advanced penile squamous cell carcinoma (PSCC) in the last decade, but its utility is limited by the low response rate, systemic toxicity, and chemoresistance, which contribute to a poor prognosis. There is no standard second-line therapy for advanced PSCC. Human epidermal growth factor receptor 2 (Her-2)-targeted antibody-drug conjugates (ADCs) are novel low-toxicity agents which have greatly improved clinical outcomes for several advanced cancers. We aimed to explore the expression pattern, clinical significance, and oncogenic roles of Her-2 and the therapeutic potential of Her-2-targeted ADCs in PSCC.
Her-2 immunohistochemistry was performed for the largest single-centre PSCC cohort to date (367 patients). PSCC cell lines, cisplatin-resistant cell lines, subcutaneous xenograft, and footpad metastatic models were used to investigate the biological roles of Her-2 in PSCC progression. Cytotoxicity, apoptosis assays, and western blotting investigated the mechanism of Her-2 induced cisplatin-chemoresistance. The efficacy of Disitamab Vedotin (RC48), a Her-2-targeted ADC, was evaluated in PSCC.
Her-2 was identified as an adverse prognostic indicator associated with advanced Tumor-Node-Metastasis (TNM) stages and poor survival with an immunohistochemical expression rate of approximately 47.7% (1+, 23.2%; 2+, 18.0%; 3+, 6.5%) in PSCC. Her-2 promotes cell proliferation, migration, invasion, tumour progression, and cisplatin resistance in PSCC. Mechanistically, Her-2 inhibits cisplatin-induced cell apoptosis by the activation of Akt phosphorylation at Ser473 and disrupts the balance between proapoptotic and antiapoptotic proteins. Meanwhile, cisplatin-resistant PSCC cells present aggressive oncogenic abilities and Her-2 upregulation. More importantly, RC48 displayed remarkable antitumor activities in both Her2-positive and cisplatin-resistant PSCC tumours.
Our study suggests that Her-2 is an available therapeutic biomarker for PSCC. Her-2-targeted ADC might have the potential to improve clinical outcomes in high-risk Her-2-positive advanced PSCC patients and provide precious second-line clinical choice for appropriate cisplatin-based chemoresistance patients.