HER2 Expression Research Articles

Impact of HER2 Expression on the Prognosis of Muscle-Invasive Bladder Cancer Patients Treated with Bladder-Preservation Comprehensive Therapy

BackgroundHER2 expression has been confirmed to be associated with bladder cancer aggressiveness. Anti-HER2 RC48-ADC is approved in China for the treatment of patients with advanced urothelial carcinoma with failed chemotherapy who are HER2 positive (IHC 2 + or 3 +). The discovery of HER2 positivity in urothelial carcinoma and the development of anti-HER2 drugs have brought new hope for bladder preservation treatment in MIBC.ObjectiveTo investigate HER2 expression in MIBC patients and its correlations with clinical characteristics, to analyze the impact of HER2 expression on the prognosis of MIBC patients administered bladder-preservation comprehensive therapy, and to explore the efficacy and safety of RC48-ADC in MIBC patients administered bladder-preservation comprehensive therapy.MethodsWe retrospectively collected information on MIBC patients. All 217 patients underwent cTURBT, of whom 175 received GC chemotherapy, while the remaining 42, due to intolerance to GC chemotherapy and HER2 positivity (IHC 2 + or 3 +), received RC48-ADC treatment. Of the 175 patients administered cTURBT combined with GC chemotherapy, 92 and 83 were HER2-negative and HER2-positive, respectively. Recurrence-free survival (RFS) and overall survival (OS) in HER2-negative and HER2-positive patients were compared to analyze the correlation between HER2 expression and prognosis. RFS and OS in the 83 HER2-positive patients administered cTURBT combined with GC chemotherapy and the 42 HER2-positive patients administered cTURBT combined with RC48-ADC were compared to analyze the differences in prognosis between the two treatment methods. The adverse reactions of GC and RC48-ADC were also compared.ResultsAmong the 217 included patients, 125 (57.6%) were HER2 positive (IHC 2 + or 3 +). HER2 positivity was significantly associated with tumor size, multifocality, pathological grade, tumor stage, and pelvic lymph node metastasis (P < 0.05). Totally 175 patients underwent cTURBT combined with GC chemotherapy, including 92 HER2-negative and 83 HER2-positive cases. There were no significant differences in gender, age, smoking status, tumor location, and ECOG score between the two groups (P > 0.05), but the proportions of patients with tumors > 3 cm, multifocal tumors, T3 stage, high-grade tumors, and pelvic lymph node metastasis were higher in the HER2-positive group versus the HER2-negative group (P < 0.05). Tumor recurrence rate in the 83 HER2-positive patients was 67.5%, with a median RFS of 19.0 months (95% CI: 10.3–27.7). Totally 22 deaths occurred during the follow-up period, with a median OS of 56.0 months (95% CI: 45.7–66.3). In the 92 HER2-negative patients, the tumor recurrence rate was 56.5%, with a median RFS of 36.0 months (95% CI: 26.1–45.9); 4 deaths occurred during the follow-up period, with the median OS not reached. After cTURBT, of the 125 HER2-positive patients examined, 83 were included in the GC treatment group versus 42 in the RC48-ADC group. There were no differences in gender, age, smoking status, tumor location, tumor size, multifocality, clinical T stage, pathological grade, pelvic lymph node metastasis, and ECOG score between the two groups (P > 0.05). In the GC group, 56 recurrences (67.5%) were detected during the follow-up period, with a median RFS of 19.0 months (95% CI: 10.3–27.7); meanwhile, 22 deaths (52.4%) occurred, with a median OS of 56.0 months (95% CI: 45.7–66.3). In the RC48-ADC group, 15 recurrences (35.7%) were recorded during the follow-up period, with the median RFS not reached; there were 2 deaths (4.8%), with the median OS not reached. The incidence rates of any-grade and grade ≥ 3 adverse reactions were both lower in the RC48-ADC group than in the GC treatment group.ConclusionsThis study confirms that cTURBT combined with RC48-ADC treatment for HER2-positive MIBC is superior to combined GC treatment in terms of RFS and OS, representing an effective treatment regimen for bladder preservation in MIBC patients.

Non-invasive Assessment of Human Epidermal Growth Factor Receptor 2 Expression in Gastric Cancer Based on Deep Learning: AComputed Tomography-based Multicenter Study.

The expression of human epidermal growth factor receptor 2 (HER2) in gastric cancer is closely associated with its treatment outcomes and prognosis. This study aims to develop and validate a HER2 prediction model based on computed tomography (CT). Additionally, the study evaluates the robustness of the proposed model. This retrospective study included 1059 patients from three hospitals (A, B, and C), where patients from hospitals A and B formed the training set (720 cases), and patients from hospital C served as the external test set (339 cases). Venous-phase CT radiomic features were extracted, normalized using the Z-score method, and simplified via principal component analysis. Feature selection was performed using recursive feature elimination (RFE), analysis of variance, Relief, and the Kruskal-Wallis (KW) test, followed by modeling using Lasso-regularized logistic regression and Support Vector Machine (SVM) methods. The models were evaluated and validated using the area under the curve (AUC) and decision curve analysis to determine the best-performing model. The positive proportions of HER2 expression were 8.60% (52/658) in the training set and 5.60% (19/320) in the test set. Eight distinct models were developed to predict HER2 expression. Among these, the model utilizing RFEand Lasso-regularized logistic regression (LR-Lasso) exhibited the highest predictive performance, with AUC values of 0.7874 (95% CI: 0.7346-0.8402) in the training set and 0.8033 (95% CI: 0.7288-0.8788) in the test set. Compared to other models, this model provided a greater net benefit on the decision curve analysis. These results suggest that the proposed model can be effectively applied to predict HER2 expression in patients. The HER2 prediction model demonstrated promising performance in predicting HER2 expression in gastric cancer patients.

Targeting HER2 in Gastroesophageal Cancer: A New Appetite for an Old Plight.

The incidence of gastroesophageal cancers is rising, driven, in part, by an increasing burden of risk factors of obesity and gastroesophageal reflux. Despite efforts to address these risk factors, and a growing interest in methods of population screening, the bulk of these tumours are unresectable at diagnosis. In this setting, effective systemic treatments are paramount to improve survival and quality of life. Early and accurate identification of oncogenic drivers, such as human epidermal growth factor receptor 2 (HER2), present in 5-30% of gastroesophageal adenocarcinomas (GEAs), is integral to guide choice of therapies due to the clear predictive implications that arise from overexpression of this receptor. After trastuzumab, the first anti-HER2 agent with approved use in HER2-positive GEA, the addition of pembrolizumab to first-line trastuzumab-chemotherapy and trastuzumab deruxtecan in the refractory space have more recently changed practice. Yet, the response to these agents has been vastly different across patients with HER2-positive disease, underpinning the need for reliable biomarkers of response. Emergent data have suggested that levels of HER2 expression on tissue or liquid biopsies may predict response to first-generation HER2 therapies while HER2 heterogeneity, receptor changes, co-occurring molecular alterations and oncogenic genomic and metabolic reprogramming may be implicated in resistance. A robust knowledge of the mechanisms of resistance and response to HER2-directed therapies is necessary to inform novel strategies of HER2-targeting and guide choice combinations with other biomarker-directed therapies, to improve outcomes from a new generation of clinical trials in HER2-positive GEA. Understanding and close examination of previous failures in this space form an important part of this assessment, as does correlative biomarker and translational work pertaining to the role of HER2 and dynamic changes that result through treatment exposure. In this review, we aim to provide an overview of strategies for HER2 targeting, summarising both the successes and disappointments in this therapeutic landscape and discuss existing challenges and future perspectives on development in this highly morbid tumour type.

Human Epidermal Growth Factor Receptor 2 Loss Following Treatment with Trastuzumab Deruxtecan in Patients with Metastatic Breast Cancer.

Trastuzumab deruxtecan (T-DXd) is currently approved for treating metastatic breast cancer (MBC) which is HER2-positive (immunohistochemistry [IHC] score of 3+ or ISH positivity) or HER2-low (IHC score of 1+ or IHC 2+/ISH negative), as well as for HER2-positive gastric cancer, HER2-mutant lung cancer, and HER2 overexpressing solid tumors. Given the increasing utilization of T-DXd, we sought to determine how HER2 receptor status might change following T-DXd therapy. We retrospectively reviewed patients with MBC who received T-DXd at The University of Texas MD Anderson Cancer Center. We included patients with paired pre- and post-treatment biopsies assessed for HER2 status using IHC. We included 41 patients with MBC who received treatment with T-DXd, and had paired pre- and post-treatment biopsies assessed for HER2 status using IHC. HER2 loss was observed in 11 patients (32.4% of 34 patients with pre-treatment HER2 expression (1+, 2+, or 3+)) following treatment with T-DXd. In addition to the 11 patients with HER2 loss, another 10 patients (29.4%) had a decrease in HER2 score after treatment with T-DXd. HER2 loss and decrease in HER2 expression are common in patients with MBC receiving treatment with T-DXd. Re-evaluation of HER2 status post-T-DXd should be considered prior to certain alternate HER2-targeted therapies which require HER2 overexpression for efficacy.

Bone-Induced Her2 Promotes Secondary Metastasis in HR+/Her2- Breast Cancer.

Bone metastases can disseminate to secondary sites and promote breast cancer progression creating additional clinical challenges. The mechanisms contributing to secondary metastasis are barely understood. Here, we evaluate the prediction power of Her2-expressing (Her2E) circulating tumor cells (CTCs) after analyzing over 13,000 CTCs from a cohort of 137 metastatic breast cancer (MBC) patients with initial HR+/Her2- status and employ preclinical models of bone metastasis (BM) to validate the role of Her2E CTCs in multi-organ metastases. While Her2 expression was higher in patients with bone metastasis, experimental analyses revealed that Her2E CTCs derived from bone lesions were more dependent on Her2 activity and more susceptible to anti-Her2 therapy. Targeting the bone-mediated Her2 induction reduces CTC detection and abrogates secondary metastasis from bone. Overall, we elucidate that Her2E CTCs can serve as a non-invasive biomarker for BM formation with high therapeutic benefit for HR+ MBC patients.

Utilizing Patient-Derived Xenografts to Model Precision Oncology for Biliary Tract Cancer.

Biliary tract cancers, which are rare and aggressive malignancies, are rich in clinically actionable molecular alterations. A major challenge in the field is the paucity of clinically relevant biliary tract cancer models that recapitulate the diverse molecular profiles of these tumors. The purpose of this study was to curate a collection of patient-derived xenograft (PDX) models that reflect the spectrum of genomic alterations present in biliary tract cancers to create a resource for modeling precision oncology. PDXs were derived from biliary tract cancer samples collected from surgical resections or metastatic biopsies. Alterations present in the PDXs were identified by whole-exome sequencing and RNA sequencing. PDXs were treated with approved and investigational agents. Efficacy was assessed by change in tumor volume from baseline. Event-free survival was defined as the time to tumor doubling from baseline. Responses were categorized at day 21: >30% decrease in tumor volume = partial response, >20% increase in tumor volume = progressive disease, and any non-partial response/progressive disease was considered stable disease. Genomic sequencing demonstrated key actionable alterations across this cohort, including alterations in FGFR2, isocitrate dehydrogenase I, ERRB2, PIK3CA, PTEN, and KRAS. RNA sequencing demonstrated fusions and expression of antibody-drug conjugate targets, including TROP2, HER2, and Nectin4. Therapeutic matching revealed objective responses to approved and investigational agents that have been shown to have antitumor activity clinically. In this study, we developed a catalog of biliary tract cancer PDXs that underwent comprehensive molecular profiling and therapeutic modeling. To date, this is one of the largest collections of biliary tract cancer PDX models and will facilitate the development of personalized treatments for patients with these aggressive malignancies.

A retrospective multicenter study on the efficacy and safety of disitamab vedotin monotherapy versus combination with anti-PD-1 immunotherapy in advanced gastric cancer

Novel therapeutic agents including disitamab vedotin (RC48, an antibody-drug conjugate) and immune-checkpoint inhibitors (e.g., PD-1 inhibitors) have provided new hope as an advanced gastric-cancer (GC) treatment. This multicenter retrospective study studied RC48 monotherapy (MT)’s efficacy and safety against its combination with anti-PD-1 immunotherapy (IT) in advanced GC. Patients treated with RC48 MT or RC48 combined with anti-PD-1 IT from July 2021 to April 2023 were recruited for the study. The progression-free survival (PFS), overall survival (OS), objective-response rate (ORR), disease-control rate (DCR), and safety were studied. After propensity score matching (PSM) (1:1), this study included 34 in the RC48 plus anti-PD-1 IT group and 34 in the RC48 MT group. The median PFS was significantly longer in the combination-therapy (CT) group than in the MT group (5.3 versus 3.8 months, HR: 0.51, 95% CI: 0.31–0.85, p = 0.010), and the median OS was also notably increased (10.0 versus 6.8 months, HR: 0.45, 95% CI: 0.27–0.77, p = 0.003). The ORR and DCR were higher in the combination group (41.18% versus 14.71%, p = 0.031; 61.76% versus 35.30%, p = 0.052). Moreover, subgroup analyses further revealed that those in the CT group experienced a longer PFS and OS, particularly those with high HER2 expression or a PD-L1 CPS score of 1 or higher. The combination therapy (CT) achieved acceptable tolerability and manageable adverse events. Furthermore, the most common grade 3–5 treatment-related adverse events (TRAEs) included decreased white-blood-cell (WBC) count, decreased neutrophil count, and anemia. No new safety risks were observed. In sum, the RC48 and anti-PD-1 IT combination showed good efficacy and a manageable safety profile, indicating its strong potential as an advanced GC therapeutic option.

HER2 Status in Gastric and Gastroesophageal Carcinomas: Evaluation of Histopathological Fingings, Paired ResectionBiopsy Specimens, and the Effect of Neoadjuvant Therapy: A Single Center Study.

Accurately determining the human epidermal growth factor receptor 2 (HER2) status is crucial in identifying suitable candidates for targeted therapy in gastric cancer, considering the cost and potential side effects of anti-HER2 treatments. This study aimed to assess HER2 overexpression/amplification prevalence in gastric and gastroesophageal cancer patients, its correlation with clinicopathological characteristics, and the consistency of HER2 status between biopsy and radical specimens. We analyzed data from 667 specimens of 600 gastric/gastroesophageal cancer patients at Dokuz Eylül University Faculty of Medicine from 2012 to 2021. The correlation of HER2 expression and amplification status and clinicopathological parameters were assessed. Furthermore, we compared HER2 status concordance between paired biopsy-radical specimens when both endoscopic and radical materials were present. Additionally, we compared HER2 status before and after treatment in patients receiving neoadjuvant chemotherapy. In our study, +3 HER2 immunohistochemistry results were more common in gastroesophageal junction tumors (23%). Human epidermal growth factor receptor 2 immunohistochemistry positivity and HER2 gene amplification were found to be significantly more common in males, people over 65 years of age, and intestinal morphology. Overall concordance of HER2 status between radical and biopsy materials was 95.5%. The high HER2 concordance between the paired biopsy and radical samples holds significant importance in clinical management. This finding is particularly noteworthy since the HER2 assessment can generally be conducted on small/limited biopsy materials in routine practice. Our study is the most extensive series from Türkiye and the Balkans, which will shed light on our country's data by investigating the relationship of HER2 with clinicopathological parameters in gastric/gastroesophageal carcinomas.

Predicting breast cancer prognosis using PR and PIK3CA biomarkers: a comparative analysis of diagnostic groups

PurposeTo evaluate the prognostic significance of progesterone receptor (PR) expression and the PIK3CA mutation status in HR+/HER2 − breast cancer patients, with the goal of screening patients who may derive the greatest benefit from PI3K-targeted therapy.MethodsA retrospective analysis was conducted on 152 HR+/HER2 − breast cancer patients stratified by PR expression levels and PIK3CA mutation status. The study population was divided into groups on the basis of a median PR threshold of 50% and further subdivided by PIK3CA mutation status. To evaluate the variability of clinicopathologic features among these groups, t tests and ANOVA were employed. The influence of these variables on survival was analyzed via Cox regression. Additionally, a risk prediction model was developed using the PR expression level and PIK3CA mutation status. The prognostic utility of this model was examined via both Kaplan‒Meier (KM) survival curves and receiver operating characteristic (ROC) analyses. These methods have also been utilized to explore the associations between clinicopathologic parameters and clinical outcomes with respect to survival prediction and prognosis.ResultsSignificant differences in age, ER expression, and Ki67, HER2, and PIK3CA mutation status were detected between the groups (P < 0.05). Specifically, elevated PR expression was correlated with lower levels of Ki67 and low HER2 expression. The presence of a PIK3CA mutation was significantly linked to survival outcomes according to both univariate and multivariate Cox regression analyses. Moreover, ROC analysis revealed that models incorporating both PR expression and PIK3CA mutation status achieved the highest level of diagnostic precision (AUC = 0.82).ConclusionPR expression and PIK3CA mutation status are significant prognostic markers in HR+/HER2 − breast cancer patients. Assessing these biomarkers in combination can enhance prognostic stratification, potentially guiding more informed clinical decision-making.

Exploring the heterogeneity of HER2 gene status and expression in non-positive breast cancer patients: insights from immunohistochemistry and fluorescence in situ hybridization

Breast cancer became the most prevalent malignancy among women, and HER2 expression status is critical for treatment decisions. With the emergence of ADC drugs, HER2 low-expressing patients who previously did not respond well to traditional anti-HER2 therapies may now benefit. In this study, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were applied to assess HER2 expression in 349 patients with HER2-non-positive breast cancer. Our analysis revealed that HER2-low tumors exhibited fewer grade III tumors (39.74% and 55.65%, respectively, P = 0.005) and higher positivity for estrogen receptor (ER, 88.89% vs. 61.74%, P < 0.001) and progesterone receptor (PR, 84.62% vs. 57.39%, P < 0.001) compared to HER2-ZERO tumors. Of the 349 cases, IHC was ultimately evaluated in 327, the antibodies demonstrated only 64.22% (95% CI: 58.76–69.42%) agreement between clone 4B5 and clone EP3. Pathologist 1, who had more extensive working experience, demonstrated higher consistency (94.19%) with the gold standard when using clone EP3, compared to Pathologist 2 (74.31%). FISH analysis revealed significant differences in HER2/CEP17 ratio and average HER2 copy numbers between HER2-ZERO and HER2-low tumors, but no clear cut-off value could be identified. Notably, HER2/CEP17 ratio mostly between 1 and 2, with HER2-ZERO tumors primarily ≤ 1.4, and average HER2 copy numbers were mostly ≥ 2 and < 4, with HER2-ZERO tumors primarily ≤ 2.5. Despite distinct clinicopathological features, FISH remains inadequate for distinguishing HER2-low from HER2-ZERO expression. Further studies are needed to improve HER2 assessment in this challenging subset of patients.

Development and validation of a metabolic syndrome and its components to predict the efficacy of neoadjuvant chemotherapy in breast cancer: An observational, single-center, cohort study.

To assess whether metabolic syndrome can be used as a reference index to evaluate the efficacy of neoadjuvant chemotherapy treatment for breast cancer (BC). Seventy cases of female BC patients who received neoadjuvant chemotherapy treatment and surgical treatment at the Glandular Surgery Department of Hebei Provincial People's Hospital from January 2021 to December 2023 were retrospectively collected, and clinical data such as puncture pathology were recorded. The clinical data were analyzed by 1-way analysis using the χ2 test, and further multifactorial logistic regression analysis was performed for statistically significant differences. The independent risk factor metabolic syndrome (MetS) and its components were plotted in the receiver operating characteristic curve (ROC) curve and baseline graph by R Studio 4.41 software, and the meaningful components were plotted in the column graph by lasso regression analysis for internal validation, and the quality of the model was evaluated by the ROC curve and calibration graph, and then the clinical decision curve analysis was used to evaluate the clinical effectiveness of the model. The neoadjuvant efficacy was statistically associated with whether the patient was first diagnosed between 45 and 55 years of age, estrogen receptors (ER), progesterone receptors (PR) expression status, Her-2 expression status, and whether the patient had MetS, as determined by univariate analysis through χ2 (P < .05). On multifactorial binary logistic regression analysis, ER, PR status, Her-2 status, and the presence of MetS were statistically significant (P < .05) for the efficacy of neoadjuvant chemotherapy. Patients with MetS were less likely to achieve complete pathological remission than those without MetS. MetS and its components were analyzed by lasso regression analysis with RStudio 4.41 software to conclude that hypertension, hyperglycemia, and high-density lipoprotein were all correlates affecting the pathologic complete response (pCR), and a column-line graph was plotted, with a C-index of 0.76, indicating a good predictive efficacy. ER, PR status, Her-2 status and the presence of MetS are independent predictors for assessing the efficacy of neoadjuvant chemotherapy in BC, and MetS can be used as a predictor of the efficacy of neoadjuvant chemotherapy. Clinical references are provided.

Noninvasive identification of HER2 status by integrating multiparametric MRI-based radiomics model with the vesical imaging-reporting and data system (VI-RADS) score in bladder urothelial carcinoma.

HER2 expression is crucial for the application of HER2-targeted antibody-drug conjugates. This study aims to construct a predictive model by integrating multiparametric magnetic resonance imaging (mpMRI) based multimodal radiomics and the Vesical Imaging-Reporting and Data System (VI-RADS) score for noninvasive identification of HER2 status in bladder urothelial carcinoma (BUC). A total of 197 patients were retrospectively enrolled and randomly divided into a training cohort (n = 145) and a testing cohort (n = 52). The multimodal radiomics features were derived from mpMRI, which were also utilized for VI-RADS score evaluation. LASSO algorithm and six machine learning methods were applied for radiomics feature screening and model construction. The optimal radiomics model was selected to integrate with VI-RADS score to predict HER2 status, which was determined by immunohistochemistry. The performance of predictive model was evaluated by receiver operating characteristic curve with area under the curve (AUC). Among the enrolled patients, 110 (55.8%) patients were demonstrated with HER2-positive and 87 (44.2%) patients were HER2-negative. Eight features were selected to establish radiomics signature. The optimal radiomics signature achieved the AUC values of 0.841 (95% CI 0.779-0.904) in the training cohort and 0.794 (95%CI 0.650-0.938) in the testing cohort, respectively. The KNN model was selected to evaluate the significance of radiomics signature and VI-RADS score, which were integrated as a predictive nomogram. The AUC values for the nomogram in the training and testing cohorts were 0.889 (95%CI 0.840-0.938) and 0.826 (95%CI 0.702-0.950), respectively. Our study indicated the predictive model based on the integration of mpMRI-based radiomics and VI-RADS score could accurately predict HER2 status in BUC. The model might aid clinicians in tailoring individualized therapeutic strategies.

Metabolic Syndrome and Risks of Breast Cancer Outcomes for Luminal, Triple-Negative, and HER2-Overexpressing Subtypes.

We evaluated the association between metabolic syndrome (MetS; obesity plus two metabolic risk factors) and breast cancer outcomes according to molecular subtype. This population-based prospective cohort consisted of 3,267 women ages 20 to 69 years diagnosed with a first primary invasive breast cancer from 2004 to 2015 in the Seattle-Puget Sound region. Breast cancer was categorized into three subtypes based on estrogen receptor (ER), progesterone receptor, and HER2 expression: luminal (ER+), triple-negative (ER-/progesterone receptor negative/HER2-), and HER2-overexpressing (H2E; ER-/HER2+) subtypes. We used time-varying Cox models to assess the association of prevalent and incident MetS with risks of recurrence, breast cancer-specific mortality (BCSM), and all-cause mortality (ACM). MetS was associated with a greater risk of recurrence [HR, 3.24; 95% confidence interval (CI), 1.13-9.33] and BCSM (HR, 5.34; 95% CI, 2.32-12.31) only for the H2E subtype and greater risks of ACM for luminal (HR, 1.92; 95% CI, 1.37-2.68), H2E (HR, 5.09; 95% CI, 2.51-10.32), and all cases combined (HR, 1.90; 95% CI, 1.42-2.53). We also observed heterogeneity in recurrence and mortality outcomes across specific components of MetS and molecular subtypes. MetS is associated with ACM among women with breast cancer and with BCSM among women with the H2E subtype. These results highlight the importance of managing comorbidities to decrease the risk for adverse outcomes among breast cancer survivors.

Histamine N-methyltransferase (HNMT) as a potential auxiliary biomarker for predicting adaptability to anti-HER2 drug treatment in breast cancer patients

BackgroundUp to 23% of breast cancer patients recurred within a decade after trastuzumab treatment. Conversely, one trial found that patients with low HER2 expression and metastatic breast cancer had a positive response to trastuzumab-deruxtecan (T-Dxd). This indicates that relying solely on HER2 as a single diagnostic marker to predict the efficacy of anti-HER2 drugs is insufficient. This study highlights the interaction between histamine N-methyltransferase (HNMT) and HER2 as an adjunct predictor for trastuzumab response. Furthermore, modulation of HER2 expression by HNMT may explain why those with low HER2 expression still respond to T-Dxd.MethodsWe investigated the impact of HNMT protein expression on the efficacy of anti-HER2 therapy in both in vivo and ex vivo models of patient-derived xenografts and cell line-derived xenografts. Our analysis included Förster resonance energy transfer (FRET) to assess the interaction strength between HNMT and HER2 proteins in trastuzumab-resistant and sensitive tumor tissues. Additionally, we used fluorescence lifetime imaging microscopy (FLIM), cleaved luciferase, and immunoprecipitation to study the interaction dynamics of HNMT and HER2. Furthermore, we evaluated the influence of HNMT activity on the binding of anti-HER2 antibodies to their targets through flow cytometry. We also observed the nuclear translocation of HNMT/HER2-ICD cells using fluorescent double staining and DeltaVision microscopy. Finally, ChIP sequencing was employed to identify target genes affected by the HNMT/HER2-ICD complex.ResultsThis study highlights HNMT as a potential auxiliary biomarker for diagnosing HER2 + breast cancer. FRET analysis demonstrated a significant interaction between HNMT and HER2 protein in trastuzumab-sensitive tumor tissue (n = 50), suggesting the potential of HNMT as a predictor of treatment response. Mechanistic studies revealed that the interaction between HNMT and HER2 contributes to increased HER2 protein expression at the transcriptional level, thereby impacting the efficacy of anti-HER2 therapy. Furthermore, a subset of triple-negative breast cancers characterized by HNMT overexpression was found to be sensitive to HER2 antibody–drug conjugates such as T-Dxd.ConclusionsThese findings offer crucial insights for clinicians evaluating candidates for anti-HER2 therapy, especially for HER2-low breast cancer patients who could gain from T-Dxd treatment. Identifying HNMT expression could help clinicians pinpoint patients who would benefit from anti-HER2 therapy.

Clinical utility of quantitative ultrasonography parameters combined with serum cancer antigen 15‑3, human epidermal growth factor receptor 2 and soluble E‑cadherin in diagnosing mass‑type breast cancer.

Contrast-enhanced ultrasonography (CEUS), a newly developed imaging technique, holds certain value in differentiating benign from malignant tumors. Additionally, serum tumor markers also exhibit significant clinical importance in the diagnosis and monitoring of malignant tumors. Reports have indicated abnormal expression of HER-2, CA153 and sE-cad in breast cancer. Early diagnosis of breast cancer facilitates early clinical intervention and enhances the overall quality of life for patients. Therefore, this study aims to explore the clinical value of quantitative CEUS parameters combined with serum levels of CA153, HER-2 and sE-cad in diagnosing mass-type breast cancer. In total, 49 patients with breast cancer (breast cancer group) and 56 patients with benign breast tumors (benign group) were selected as the study participants, while 50 healthy women served as the control group. Ultrasonography was performed on the patients in the breast cancer and benign groups using diagnostic color Doppler ultrasonography. The serum CA15-3, HER-2 and sE-cad levels in all three study groups were measured using a fully automated electrochemiluminescence immunoassay. Pearson's correlation test was used to analyze the correlation between the quantitative ultrasonography parameters and serum CA15-3, HER-2 and sE-cad levels. Logistic multivariate regression analysis was performed to analyze the independent risk factors, and a receiver operating characteristic curve was plotted to assess the diagnostic value of these factors. The peak intensity (PI), wash-in slope (WIS), gradient (Grad) and local mean transit time (mTTI), along with the CA15-3, HER-2 and sE-cad levels in the breast cancer group were significantly higher, and the time to peak (TTP) was significantly lower, compared with those values in the benign and control groups. CA15-3, HER-2 and sE-cad were negatively correlated with TTP in the breast cancer group (all P<0.05) and positively correlated with PI, WIS, Grad and mTTI (all P<0.05). The area under the curve (AUC) values for CA15-3, HER-2, sE-cad, PI, WIS, Grad, mTTI and TTP for the diagnosis of malignant breast cancer were 0.640, 0.730, 0.687, 0.683, 0.692, 0.737, 0.697 and 0.671, respectively. The AUC for the combined diagnosis was 0.919, with a sensitivity of 0.857 and a specificity of 0.911, outperforming each index alone for a single diagnosis. Logistic multivariate regression analysis revealed that HER-2, TTP, PI, WI and Grad were independent risk factors for malignant breast cancer. In conclusion, combining the quantitative ultrasonography parameters with the CA15-3, HER-2 and sE-cad levels facilitated the differential diagnosis of benign and malignant breast lesions, and may provide a reference for clinical treatment in the future.

Automatic image generation and stage prediction of breast cancer immunobiological through a proposed IHC-GAN model.

Invasive breast cancer diagnosis and treatment planning require an accurate assessment of human epidermal growth factor receptor 2 (HER2) expression levels. While immunohistochemical techniques (IHC) are the gold standard for HER2 evaluation, their implementation can be resource-intensive and costly. To reduce these obstacles and expedite the procedure, we present an efficient deep-learning model that generates high-quality IHC-stained images directly from Hematoxylin and Eosin (H&E) stained images. We propose a new IHC-GAN that enhances the Pix2PixHD model into a dual generator module, improving its performance and simplifying its structure. Furthermore, to strengthen feature extraction for HE-stained image classification, we integrate MobileNetV3 as the backbone network. The extracted features are then merged with those generated by the generator to improve overall performance. Moreover, the decoder's performance is enhanced by providing the related features from the classified labels by incorporating the adaptive instance normalization technique. The proposed IHC-GAN was trained and validated on a comprehensive dataset comprising 4,870 registered image pairs, encompassing a spectrum of HER2 expression levels. Our findings demonstrate promising results in translating H&E images to IHC-equivalent representations, offering a potential solution to reduce the costs associated with traditional HER2 assessment methods. We extensively validate our model and the current dataset. We compare it with state-of-the-art techniques, achieving high performance using different evaluation metrics, showing 0.0927 FID, 22.87 PSNR, and 0.3735 SSIM. The proposed approach exhibits significant enhancements over current GAN models, including an 88% reduction in Frechet Inception Distance (FID), a 4% enhancement in Learned Perceptual Image Patch Similarity (LPIPS), a 10% increase in Peak Signal-to-Noise Ratio (PSNR), and a 45% reduction in Mean Squared Error (MSE). This advancement holds significant potential for enhancing efficiency, reducing manpower requirements, and facilitating timely treatment decisions in breast cancer care.

HER2-Targeted Affibody Molecule 99mTc-ABH2 for Imaging HER2 Expression in Breast Cancer.

Accuracy in in vivo assessment of human epidermal growth factor receptor type 2 (HER2) status is crucial for predicting the response to HER2-targeted therapies in breast cancer. This study assessed the safety, feasibility, and diagnostic accuracy of 99mTc-ABH2, a reengineered affibody molecule with radionuclide labeling, for HER2 expression in breast cancer using SPECT/CT imaging, compared with 18F-FDG PET/CT. Thirty-six patients suspected of primary breast cancer were enrolled in this prospective, single-center study from March to July in 2023. Each participant underwent SPECT/CT imaging with 99mTc-ABH2 SPECT/CT and 18F-FDG PET/CT. The imaging results were validated against immunohistochemistry and fluorescence in situ hybridization, employing visual scores and quantitative values for analysis. Optimal imaging contrast was observed around 2 hours postinjection of 99mTc-ABH2. Among the evaluated 27 patients with immunohistochemistry and fluorescence in situ hybridization findings, the 99mTc-ABH2 SPECT/CT visual evaluation displayed a sensitivity of 71.4%, specificity of 72.2%, and accuracy of 71.9%. Using an SUVmax cutoff of 2.32, the sensitivity, specificity, and accuracy for detecting HER2 status were 92.86%, 72.22%, and 81.25%, respectively. Notably, 99mTc-ABH2 precisely identified all immunohistochemistry (3+) tumors and showed increased uptake in bone and lymph node metastases. Meanwhile, 18F-FDG PET/CT showed no significant difference in uptake between HER2 (2+/3+) and HER2 (0/1+) tumors (P = 0.81). This study validated 99mTc-ABH2 SPECT/CT as a promising diagnostic tool for precise HER2 assessment. The robust sensitivity for immunohistochemistry (3+) tumors and the visualization of metastases highlight its diagnostic significance, potentially impacting patient outcomes positively.

Exploring the clinicopathological parameters of HER2 low breast cancers: insights from a retrospective cohort study.

Breast cancer subtypes are delineated by human epidermal growth factor receptor 2 (HER2) expression, pivotal in treatment selection. HER2-positive tumors typically respond to targeted therapies, whereas HER2-negative tumors lack HER2 overexpression. However, a subset exhibits low HER2 expression without amplification, termed HER2 low breast cancer. Despite being distinct, its clinicopathological characteristics and therapeutic implications remain less understood. A retrospective cohort study was conducted on histologically confirmed breast cancer cases from January 2022 to December 2023. Clinicopathological data including age, tumor size, nodal involvement, and hormone receptor status were collected. Immunohistochemistry categorized tumors into luminal, triple-negative, and HER2-enriched subtypes. HER2 expression was re-evaluated, classifying tumors into HER2 low and HER2-negative based on staining intensity and amplification status. Statistical analysis was performed using SPSS software. Seventy female patients with breast cancer were included, exhibiting diverse clinicopathological features. HER2 low tumors (40%) were significantly associated with higher tumor stage (P=0.03), nodal involvement (P=0.01), and positive androgen receptor expression (P=0.01). Subgroup analysis revealed HER2 low hormone receptor-positive cases (78.6%) were associated with higher tumor stage (P=0.01) and nodal involvement (P=0.01), while HER2 low triple-negative cases (21.4%) demonstrated distinct characteristics such as higher histological grade (P=0.02). This study underscores the complexity of HER2 low breast cancer and its implications for clinical management, emphasizing the need for personalized treatment strategies. It provides insights into the clinicopathological parameters of HER2 low breast cancers, highlighting their diverse characteristics and clinical implications.

Distribution and clinicopathological characteristics of G-CSF expression in tumor cells and stromal cells in upper tract urothelial carcinoma

Abstract Background Urothelial carcinoma (UC) is a common type of malignant disease; however, the diagnostic and prognostic markers of upper urinary tract urothelial cancer (UTUC) remain poorly understood because of its rarity. Methods To clarify the clinicopathological significance of granulocyte-colony stimulating factor (G-CSF) in UTUC, we analyzed the expression and distribution of G-CSF in 112 upper tract urothelial carcinoma (UTUC) samples with immunohistochemistry. Results In normal urothelium, G-CSF expression was weak or absent, whereas high expression of G-CSF was observed in UTUC tissues, both in tumor cells (TCs) and stromal cells (SCs). G-CSF expression in the TCs and SCs was associated with nodular/flat morphology, high grade, advanced T stage, and lymphovascular invasion in UTUC. G-CSF expression in SCs was associated with poor prognosis and was an independent prognostic factor. Public data showed that G-CSF expression was also associated with decreased progression-free survival and disease-specific survival. A prognostic model was constructed by incorporating the presence or absence of G-CSF expression along with clinicopathologic factors, which allowed for a more accurate prediction of poor prognosis. We further showed that G-CSF expression was associated with a high Ki-67 labeling index and with PD-L1, HER2, and p53 expression in UTUC. Conclusion G-CSF expression in TCs and SCs may play a crucial role in UTUC tumor progression. Notably, stromal G-CSF expression showed significant prognostic value, even when compared to major clinicopathological factors, suggesting that the evaluation of G-CSF expression may contribute to clinical decision-making in patients with UTUC.

Induction of SUSD2 by STAT3 Activation Is Associated with Tumor Recurrence in HER2-Positive Breast Cancer.

Sushi domain-containing protein 2 (SUSD2), a transmembrane protein containing a sushi motif, has been reported to have tumor-promoting functions in various types of cancer, including breast cancer. However, the regulatory mechanism of SUSD2 and its function in HER2-positive (HER2+) breast cancer have not been fully identified as yet. In this study, we explored the potential of targeting SUSD2 to overcome trastuzumab (TRZ) resistance in HER2+ breast cancer. SUSD2 expression was found to be significantly increased in HER2-overexpressing cells. Endogenous SUSD2 expression was observed in HER2+ breast cancer cells but not in estrogen receptor-positive or triple-negative breast cancer cells. We also found that SUSD2 expression was positively correlated with HER2 expression in a publicly available human primary breast cancer dataset. Although SUSD2 expression was associated with HER2, its expression levels were not affected by TRZ. Through kinase array experiments, we found that SUSD2 expression was modulated downstream of STAT3-dependent signaling in breast cancer cells overexpressing HER2. STAT3 activity was increased in EGFR+ HER2+ breast cancer cells compared to EGFR+ cells. Furthermore, we observed that SUSD2 expression was decreased by C188-9, a STAT3-specific inhibitor. Finally, we analyzed the association between patient survival and SUSD2 expression in breast cancer. Our results showed that SUSD2 expression had a negative correlation with the relapse-free survival of patients with EGFR+ HER2+ breast cancer when compared to EGFR+ breast cancer patients. Collectively, our results demonstrate that SUSD2 expression is mediated by STAT3 and imply the potential of using SUSD2 as a biomarker to stratify HER2+ breast cancer.