HER2 Expression Research Articles

Incidence and Prognostic Values in Human Epidermal Growth Factor Receptor 2-Low Expression Metastatic Breast Cancer in Southeast Asian Population: A 10-Year Retrospective Study.

Breast cancer progression varies across molecular subtypes, and treatment options for human epidermal growth factor receptor 2 (HER2)-low expression tumors are limited compared with those of HER2 overexpression tumors. Comprehensive information regarding the epidemiology and clinical outcomes of metastatic HER2-low expression breast cancer in a Southeast Asian population is lacking. This retrospective cohort study was performed to analyze data from patients with de novo advanced breast cancer, including HER2 expression, tumor stage, and metastatic pattern. Statistical analyses, including chi-square tests and survival analyses, were used to compare HER2-low expression and HER2-negative groups. Of the 491 patients, 21.2% had HER2-low expression, 30% had HER2 overexpression, and 50% had HER2-negative expression. Among the hormone receptor (HR)-positive patients, 34% had HER2-low expression; in the triple-negative patients, the HER2-low incidence was 20.6%. No significant differences in clinical characteristics between HER2-low and HER2-negative groups were observed, except for more HR-positive patients in the HER2-low group. HER2-low patients had a longer overall survival (OS) than HER2-negative patients (43 v 23 months; hazard ratio, 0.7; P < .001), especially in HR-positive patients. After adjusting for HR status, HER2-low patients maintained improved outcomes. HR-positive HER2-low patients showed nonsignificant OS gains compared with HR-positive HER2-negative patients, regardless of first-line chemotherapy or endocrine therapy. This study revealed the incidence and clinical outcomes of HER2-low expression in de novo advanced breast cancer, suggesting favorable outcomes, particularly in HR-positive breast cancer. These findings may inform personalized treatment strategies. Further research into the mechanisms and implications of HER2-low expression in breast cancer is required.

Bag-1-mediated HSF1 phosphorylation regulates expression of heat shock proteins in breast cancer cells.

According to the World Health Organization in 2022, 2.3 million women were diagnosed with breast cancer. Investigating the interaction networks between Bcl-2-associated athanogene (Bag)-1 and other chaperone proteins may further the current understanding of the regulation of protein homeostasis in breast cancer cells and contribute to the development of treatment options. The present study aimed to determine the interactions between Bag-1 and heat shock proteins (HSPs); namely, HSP90, HSP70 and HSP27, to elucidate their role in promoting heat shock factor-1 (HSF1)-dependent survival of breast cancer cells. HER2-negative (MCF-7) and HER2-positive (BT-474) cell lines were used to examine the impact of Bag-1 expression on HSF1 and HSPs. We demonstrated that Bag-1 overexpression promoted HER2 expression in breast cancer cells, thereby resulting in the concurrent constitutive activation of the HSF1-HSP axis. The activation of HSP results in the stabilization of several tumor-promoting HSP clients such as AKT, mTOR and HSF1 itself, which substantially accelerates tumor development. Our results suggest that Bag-1 can modulate the chaperone activity of HSPs, such as HSP27, by directly or indirectly regulating the phosphorylation of HSF1. This modulation of chaperone activity can influence the activation of genes involved in cellular homeostasis, thereby protecting cells against stress.

Analysis of HER2 expression changes from breast primary to brain metastases and the impact of HER2-low expression on overall survival.

There are limited data regarding HER2-low expression dynamics between matched primary tumors and brain metastases (BrMs) in breast cancer. HER2-low expression has emerged as a new therapeutic biomarker for highly active antibody-drug conjugates with emerging intracranial activity. Patients with metastatic breast cancer (MBC) and BrMs seen at an NCI-designated center between 2003-2023 were identified. HER2 expression was defined as HER2-positive (3+,2+/ISH amplified), HER2-low (1+,2+/ISH negative), or HER2-0 by ASCO-CAP guidelines. Estrogen receptor (ER) status was defined as ER≥1%. Multivariate survival analyses by Cox proportional hazard models were determined from time of BrM resection to death or last follow-up between the 3 subtypes, controlling for ER and age. Among 197 matched primary and resected BrMs, 81% exhibited HER2 expression in the brain:61% HER2-positive, 20% HER2-low, and 19% HER2-0. Concordance was high in HER2-positive primary tumors with 100% retaining HER2 expression (97% retained HER2+ expression and 2.7% switched to HER2-low). HER2-0 primaries frequently showed HER2 gain in BrMs to HER2-low (35%) or HER2-positive (5.4%) status. Among 48 HER2-low primary tumors, 52% were discordant for HER2 status in the brain with 21% testing HER2-positive and 31% testing HER2-0. In adjusted analyses, patients with HER2-positive BrMs had significantly lower death risk than patients with HER2-low BrMs (HR=0.41, P=0.0006); no difference was observed between HER2-0 and HER2-low. In this retrospective analysis, HER2 expression is common in breast cancer BrMs, emphasizing the need for improved, non-invasive diagnostics. Patients with HER2-low and HER2-0 BrMs face inferior survival, presenting an unmet clinical need.

The prognostic significance of circulating tumor cell enumeration and HER2 expression by a novel automated microfluidic system in metastatic breast cancer

BackgroundThe prognostic value of circulating tumor cells (CTCs) in metastatic breast cancer (MBC) has been extensively studied and verified by the CellSearch® system. Varieties of microfluidic systems have been developed to improve capture efficiency with the lack of standardization and automation. This study systematically verified the positive threshold for prognosis and its guidance value in anti-HER2 therapy based on a novel automated microfluidic system OmiCell®.MethodsCTCs isolation, enumeration and labeling were performed using the OmiCell® system. CTCs identification and reporting were performed using the DeepSight® scanning system.ResultsThe capture efficiency and specificity of OmiCell® system was 91.9% and 90%, respectively. Then, 65 MBC patients with known HER2 status of their metastatic tumors were enrolled. In the cohort, we detected ≥ 1 CTCs in 59 patients (90.8%, range: 1–55 CTCs, median = 6), < 8 CTCs in 45 (69.2%) and ≥ 8 CTCs in 20 (30.8%) patients at baseline. The patients with < 8 CTCs had longer PFS than ≥ 8 CTCs (median, 7 vs. 4.4 months, p = 0.028). CTC enumeration was found to be an independent prognostic factor in our cohort. Moreover, we found a weak concordance between tissue HER2 (tHER2) status and the corresponding CTCs (k = 0.16, p = 0.266). The patients with tHER2 positive and cHER2 negative had better PFS compared with patients with both tHER2 and cHER2 positive (median, 8.2 vs. 3.3 months, p = 0.022).ConclusionsThis clinical study shows the prognosis value of a new threshold of CTC number and meanwhile the guidance value of cHER2 status in anti-HER2 therapy.

Human Epidermal Growth Factor 2 (Her-2) Expression in Gastric and Gastroesophageal Carcinomas: A Clinicopathological Evaluation in a Tertiary Care Institute.

Introduction Gastric carcinoma is a significant global health concern, known for its high mortality rate. HER-2 overexpression is observed in a notable proportion of gastric carcinoma and is associated with a worse prognosis. However, HER-2 expression enables targeting the protein by monoclonal antibodies that improve overall survival in HER-2-positive gastric cancers. This study aims to evaluate the HER-2 expression in gastric and gastroesophageal carcinomas. Materials and methods This observational study was conducted in the Department of Pathology, involving 60 endoscopic biopsy and resection specimens of gastric and gastroesophageal carcinomas. HER-2 expression was assessed by immunohistochemistry (IHC) based on the Trastuzumab for GAstric Cancer (ToGA) trial's scoring system. The primary outcome was HER-2 status, with statistical analysis performed to evaluate associations with various clinicopathological parameters. Results Among 60 cases, 26 (43.3%) showed HER-2 positivity. HER-2 positivity was significantly (p=0.004) associated with age, being higher in 20-39 years and ≥80 years age groups. Gender and tumor location were not significantly associated with HER-2 positivity. Moderate and poorly differentiated carcinomas exhibited higher HER-2 positivity. Histological types, tubular adenocarcinoma, and papillary adenocarcinoma showed significant (p=0.01) association with HER-2 positivity compared to other types. Conclusion HER-2 status assessment is crucial in managing gastric and gastroesophageal carcinomas. HER-2 positivity is notably higher in certain age groups and histological types particularly tubular and papillary adenocarcinoma, and in moderately to poorly differentiated carcinomas. These insights can aid in selecting appropriate gastric and gastroesophageal carcinomas that warrant HER-2 testing on IHC. Identifying gastric and gastroesophageal carcinomas that show HER2 expression may highlight potential candidates for targeted therapy.

The Impact of Pembrolizumab as a Salvage Therapy Based on HER2 Expression in Advanced Gastric Cancer.

Immune checkpoint inhibitors (ICIs) are used as salvage treatments for advanced gastric cancer (AGC) regardless of HER2 status. This study assessed the efficacy of ICIs based on HER2 expression in AGC patients who received pembrolizumab as salvage monotherapy at Samsung Medical Center from November 2017 to March 2023. HER2 status was determined via immunohistochemistry, and tumor response and survival outcomes were compared accordingly. Among the 113 patients analyzed, with a median age of 61 years and 64.6% being male, 12 patients (10.6%) were HER2-positive, and 101 patients (89.4%) were HER2-negative. Of 92 evaluable patients, none had a complete response. However, 50% of HER2-positive patients had a partial response, compared to 4.9% of HER2-negative patients (p < 0.001). The disease control rate was 70% in HER2-positive and 37.8% in HER2-negative patients (p = 0.086). Median progression-free survival was 5.53 months for HER2-positive patients versus 1.81 months for HER2-negative patients (p = 0.037). Pembrolizumab as a salvage chemotherapy for the treatment of AGC demonstrated superior effectiveness in HER2-positive patients compared with HER2-negative patients.

When destiny doesn't pan out: Implications for the treatment of sarcomas after the agnostic approval of trastuzumab deruxtecan.

In April 2024, the Food and Drug Administration provided accelerated approval for trastuzumab deruxtecan for adult patients with advanced solid tumors which have positive immunochemical staining for HER2 expression, including sarcomas. There should be ample consideration prior to utilization of trastuzumab deruxtecan for patients with sarcomas, as HER2 targeted therapy has been ineffective in certain subtypes.

The Comparison of Immunohistochemistry Characteristics Between Breast Cancer Patients Under 35 Years Old and Above

The increasing incidence rate of breast cancer in young women necessitates investigations of clinical and pathological features in this age group. Less hormone receptor expressions and more aggressive behavior have been discussed in very young breast cancer patients. In this study, pathological data of patients diagnosed with Invasive ductal carcinoma referred to Shariati hospital and Tehran cancer institute between 2015 and 2018 was evaluated in two groups: under 35 years old (Group 1) and above (Group 2). Each group contained 156 cases. Estrogen and Progesterone Receptor expression was reported in 62.8% and 63.5% of Group 1, in comparison to 77.6% and 74.4% in Group 2 (P value= 0.004 and 0.0038). Her2 expression was found in 41% of Group 1 and 21.2% of Group 2 (P value= 0.0001). Ki67 was reported as 41.2 ± 25.2 in Group 1 and 29.6 ± 21.7 in Group 2 (P value= 0.001). In conclusion, negative hormone receptor, positive Her2 expression, and higher proliferation rates are found in breast cancer patients under 35 years old.

UBR1 is a prognostic biomarker and therapeutic target associated with immune cell infiltration in gastric cancer.

Ubiquitination is a targeted protein modification process mediated by intracellular molecules. UBR1 encodes a protein that binds to unstable N-terminal residues of substrate proteins and contributes to the formation of substrate-linked polyubiquitin chains. However, the function and cellular pathways of UBR1 in tumors have received inadequate attention. This study aimed to investigate the potential of UBR1 as a prognostic biomarker and immunotherapy target for stomach adenocarcinoma (STAD) as well as its biological function and molecular mechanism in relation to the disease. Differential expression and pan-cancer gene set enrichment analysis (GSEA) were conducted using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Genotype-Tissue Expression (GTEx) datasets. The Human Protein Atlas (HPA) database was utilized to identify UBR1-enriched pathways in AGS cells and to compare immunohistochemical differences between cancerous and adjacent non-cancerous tissues in gastric cancer. Quantitative Polymerase Chain Reaction (QPCR) and Western blot (WB) analyses were employed to validate these findings in both cancerous and adjacent non-cancerous tissues of gastric cancer. UBR1 expression in GES-1 and four gastric cancer cell lines was assessed using QPCR and WB. Kaplan-Meier curves, univariate and multivariate Cox regression analyses, and receiver operating characteristic (ROC) curve analyses were performed to evaluate the prognostic and diagnostic roles of UBR1. Additionally, the correlation between UBR1 expression and clinical parameters was analyzed using TCGA and GEO databases. UBR1 mutation data were obtained from the cBioPortal database. The mutation landscape, mutation-associated genes, protein structure, tumor mutation burden (TMB), and microsatellite instability (MSI) correlations were analyzed and illustrated. The biological functions of UBR1 were investigated using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The correlation between UBR1 and immune infiltration was assessed using TIMER and EPIC computational methods. Protein expression levels of UBR1 in gastric cancer cell lines were determined by immunohistochemistry (IHC) and WB analysis. Quantitative real-time PCR (qRT-PCR) was employed to analyze mRNA expression. Immunoprecipitation (IP) assays were conducted to detect protein-protein interactions between UBR1 and PDL1, while cellular immunofluorescence was used to observe the co-localization of these proteins. Cell proliferation was evaluated using CCK8 and colony formation assays. Cell migration was assessed using Transwell and wound healing assays. Finally, apoptosis was analyzed using flow cytometry, and WB was used to detect changes in apoptotic proteins and NF-κB P65 pathway proteins. UBR1 was upregulated in 28 cancer types, including STAD, and its overexpression was validated in gastric cancer cell lines and tissues. UBR1 expression was associated with advanced pathological characteristics. High UBR1 expression was linked to poor prognostic outcomes, including overall survival (OS), progression-free interval (PFI), disease-specific survival (DSS), as well as responses to surgery, chemotherapy, and HER2 expression. UBR1 expression showed significant correlations with clinical parameters such as age, gender, TNM stage, pathological stage, tumor resection, and anti-reflux therapy. Amplifications and deletions were the most frequent genetic alterations associated with UBR1. According to KEGG and GSEA analyses, UBR1 was significantly associated with several cancer pathways, oxidative phosphorylation, and the TNF-NFκB pathway. UBR1 also exhibited a significant correlation with immune cell infiltration and immunotherapy, including a direct interaction with PDL1. Knockdown of UBR1 inhibited the proliferation, migration, and invasion of STAD cells and promoted apoptosis. UBR1 is overexpressed in STAD, promoting its progression and positively correlating with immune cell infiltration and immunotherapeutic responses. Therefore, UBR1 could be a promising biomarker for the prognosis and immunotherapy of STAD.

Analysis of Factors Associated With Pathological Complete Response in Patients With HER2-Positive Breast Cancer Receiving Neoadjuvant Chemotherapy

PurposeThis study aimed to examine the impact of the level of HER2 overexpression on pathologic and clinical outcomes in HER2-positive breast cancer (BC) patients treated with neoadjuvant therapy (NAT). MethodsWomen with Stage II or III HER2-positive BC who received anthracycline-taxane-trastuzumab NAT regimens followed by curative-intent surgery were included. Patients were classified according to tumor HER2 expression into HER2-high (immunohistochemistry (IHC) 3+ or fluorescence in situ hybridization (FISH) HER2/CEP17 ratio ≥5 or HER2 copy number ≥10) and HER2-intermediate (IHC 2+ with HER2/CEP17 ratio ≥2 to <5 or copy number ≥4 to <10). Univariate and multivariate logistic regression analyses were performed using HER2 expression as a categorical variable. The primary outcome was pathological complete response (pCR). Estimated 3-year disease-free survival (DFS) and Overall Survival (OS) were secondary outcomes. ResultsAmong 161 patients with HER2-positive BC, 139 (86%) and 22 (14%) were classified as HER2-high and HER2-intermediate, respectively; 105 (65.2%) had hormone receptor (HR)-positive tumors; 72 (45%) achieved a pCR. In the overall population, pCR rates of 18% and 49% were achieved in HER2-intermediate and HER2-high cases, respectively (odds ratio [OR] = 0.23 95% CI 0.07-0.72; P = .007). No pCRs were observed among HR-positive, HER2-intermediate cases. Estimated 3-year DFS was 97.1% versus 89.3% for patients achieving a pCR versus those with residual disease, respectively (P = .0011). ConclusionWe found that patients with HER2-high disease were more likely to achieve pCR after NAT compared to patients with HER2-intermediate BC, a subgroup of patients that may benefit from more personalized NAT strategies.

Patient characteristics and treatment patterns of patients with locally advanced or metastatic HER2-low breast cancer, a single site descriptive study

PurposeTo evaluate the prevalence and characteristics of different HER2 categories among patients with advanced breast cancer (aBC) and describe treatment patterns and outcomes of those with HER2-low disease.MethodsA retrospective cohort study was conducted via chart review at the Huntsman Cancer Institute, including patients diagnosed with aBC (stages IIIB, IIIC and IV) between 2010 and 2019. All patients with IHC1+ were considered HER2-low unless FISH was positive. Patients with IHC2+ were only classified as HER2-low if a negative FISH was documented. The prevalence and characteristics of each HER2 category were reported. Treatment patterns and survival outcomes of HER2-low patients who received first line treatment in 2017 or later were presented.ResultsA total of 240 of 414 patients (58%) with aBC were HER2-low, with the majority of patients (83%) classified as hormone receptor (HR)-positive. In first line, most HR-positive patients received endocrine therapy with chemotherapy for stage IIIB/IIIC (47%) and with CDK4/6 inhibitors for stage IV breast cancer (50%) Most HR-negative patients received chemotherapy alone (92% for stage IIIB/IIIC, 60% for stage IV). In second line, chemotherapy alone was the most common modality (21.4% for HR-positive; 45.5% for HR-negative). Median overall survival was 37.7 months while median progression-free survival from first line was 18.0 months, decreasing to 8.0 months in second line.ConclusionA substantial proportion of patients previously classified as HER2-negative have low but detectable HER2 expression and may benefit from novel HER2-directed agents, which have demonstrated clinical benefit in this population post-chemotherapy.

Therapeutic indications for antibody-drug conjugates estimated from HER2 and p53 expressions in endometrial carcinoma

ObjectiveWhile human epidermal growth factor receptor 2 (HER2) is upregulated in endometrial carcinoma—especially in the p53 aberrant type— conventional anti-HER2 therapy is not typically used for this cancer type. Recently, HER2-targeted antibody-drug conjugates have shown antitumor effects against HER2 low-expressing cancers. Therefore, we analyzed the clinicopathological characteristics of HER2-positive endometrial carcinomas including those with low expression, as well as the prognostic significance of p53 and HER2 co-expression. MethodsImmunohistochemistry for HER2 and p53 was performed in 530 patients with endometrial carcinoma; 124 cases (23%) were HER2-positive. ResultsOf the HER2-positive cases, >50% were 1+. A high prevalence of HER2 expression was observed in serous (64%), clear-cell (73%), and mixed (64%) carcinomas. Notably, 19% of endometrioid carcinomas were HER2-positive. HER2 positivity was significantly associated with age ≥60 years, high-grade histological subtype, deep myometrium invasion, stage III/IV, recurrence, and death. Univariate analysis showed that HER2-positive cases had reduced progression-free survival (PFS) (p = 0.007) and overall survival (OS) (p = 0.012). However, after adjusting for stage, HER2 positivity was not associated with survival. In the early stage, co-expression of HER2-positive and p53 aberrant types was associated with shorter PFS (p < 0.001) and OS (p < 0.001) compared with at least one negative result. Multivariate analysis of PFS showed HER2 and p53 co-expression (hazard ratio, 1.891; 95% confidence interval, 1.183–5.971, p = 0.008) as an independent prognostic factor. ConclusionsThis study presents detailed clinicopathological characteristics and the prognostic impact of HER2-positivity in endometrial carcinomas. HER2-targeted antibody-drug conjugate therapy may be broadly applicable to endometrial carcinoma.

The DNA repair pathway as a therapeutic target to synergize with trastuzumab deruxtecan in HER2-targeted antibody–drug conjugate–resistant HER2-overexpressing breast cancer

BackgroundAnti-HER2 therapies, including the HER2 antibody–drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), have led to improved survival outcomes in patients with HER2-overexpressing (HER2+) metastatic breast cancer. However, intrinsic or acquired resistance to anti-HER2–based therapies remains a clinical challenge in these patients, as there is no standard of care following disease progression. The purpose of this study was to elucidate the mechanisms of resistance to T-DM1 and T-DXd in HER2+ BC patients and preclinical models and identify targets whose inhibition enhances the antitumor activity of T-DXd in HER2-directed ADC-resistant HER2+ breast cancer in vitro and in vivo.MethodsTargeted DNA and whole transcriptome sequencing were performed in breast cancer patient tissue samples to investigate genetic aberrations that arose after anti-HER2 therapy. We generated T-DM1 and T-DXd–resistant HER2+ breast cancer cell lines. To elucidate their resistance mechanisms and to identify potential synergistic kinase targets for enhancing the efficacy of T-DXd, we used fluorescence in situ hybridization, droplet digital PCR, Western blotting, whole-genome sequencing, cDNA microarray, and synthetic lethal kinome RNA interference screening. In addition, cell viability, colony formation, and xenograft assays were used to determine the synergistic antitumor effect of T-DXd combinations.ResultsWe found reduced HER2 expression in patients and amplified DNA repair–related genes in patients after anti-HER2 therapy. Reduced ERBB2 gene amplification in HER2-directed ADC–resistant HER2+ breast cancer cell lines was through DNA damage and epigenetic mechanisms. In HER2-directed ADC–resistant HER2+ breast cancer cell lines, our non-biased RNA interference screening identified the DNA repair pathway as a potential target within the canonical pathways to enhance the efficacy of T-DXd. We validated that the combination of T-DXd with ataxia telangiectasia and Rad3-related inhibitor, elimusertib, led to significant breast cancer cell death in vitro (P < 0.01) and in vivo (P < 0.01) compared to single agents.ConclusionsThe DNA repair pathways contribute to HER2-directed ADC resistance. Our data justify exploring the combination treatment of T-DXd with DNA repair–targeting drugs to treat HER2-directed ADC–resistant HER2+ breast cancer in clinical trials.

Prognostic and Predictive Significance of Primary Tumor Localization and HER2 Expression in the Treatment of Patients with KRAS Wild-Type Metastatic Colorectal Cancer: Single-Centre Experience from Serbia.

The treatment of patients with metastatic colorectal cancer (mCRC) is complex and is impacted by the location of the primary tumor (LPT). Our study aims to emphasize the importance of LPT as a prognostic and predictive marker as well as to examine the significance of HER2 overexpression in patients with mCRC, particularly in relation to the response to Epidermal Growth Factor Receptor Antibody treatment (anti-EGFR therapy). In this study, 181 patients with Kirsten RAS (KRAS) wild-type mCRC who received anti-EGFR therapy were included. Among them, 101 had left colon cancer (LCC) and 80 had right colon cancer (RCC). Results demonstrated that patients with KRAS wild-type LCC had better median overall survival (OS) (43 vs. 33 months, p = 0.005) and progression-free survival (PFS) (6 vs. 3 months, p < 0.001) compared to those with RCC. Multivariate analysis identified mucinous adenocarcinoma (p < 0.001), RCC location (p = 0.022), perineural invasion (p = 0.034), and tumors at the resection margin (p = 0.001) as independent predictors of OS, while mucinous adenocarcinoma (p = 0.001) and RCC location (p = 0.004) independently correlated with significantly shorter PFS. In addition, human epidermal growth factor receptor 2 (HER2) positive expression was significantly associated with worse PFS compared to HER2 negative results (p < 0.001). In conclusion, LPT is an important marker for predicting outcomes in the treatment of wild-type mCRC using anti-EGFR therapy, since patients with RCC have a statistically significantly shorter PFS and OS. Further investigation is needed to understand the role of HER2 overexpression in wild-type mCRC, as these patients also exhibit shorter survival.

Clinicopathological and prognostic features of HER2-null and HER2-low advanced breast cancer treated with eribulin or capecitabine

BackgroundHER2-low populations constitute a heterogeneous group, and the cytotoxic anticancer agent efficacy based on HER2 status remains unclear. This study evaluated the clinicopathological features and outcomes of patients with advanced breast cancer showing HER2-low expression treated with eribulin or capecitabine, two treatment options after anthracycline and taxane treatment.MethodsWe retrospectively evaluated patients who were treated with eribulin or capecitabine between 2011 and 2015. HER2 status was evaluated according to the ASCO/CAP guidelines.ResultsNo significant difference was observed in overall survival (OS; eribulin: hazard ratio [HR], 0.66; 95% CI 0.40–1.10; capecitabine: HR, 0.76; 95% CI 0.45–1.30) or progression-free survival (PFS; eribulin: HR, 1.13; 95% CI 0.72–1.78; capecitabine: HR, 0.90; 95% CI 0.56–1.44) between patients receiving eribulin (HER2-null: 35, HER2-low: 44) and those receiving capecitabine (HER2-null: 41, HER2-low: 33). Subgroup analysis revealed no significant differences in OS between the two groups in the hormone-positive and -negative populations for eribulin and capecitabine. HER2-null and HER2-low patients showed objective response rates (ORRs) of 22.5% and 9.1% (p = 0.09) overall, and 32.0% and 10.5% (p = 0.03), respectively, in hormone-positive cases among eribulin-treated patients. No response was observed in hormone-negative patients. Capecitabine treatment in HER2-null and HER2-low patients had overall ORRs of 26.8% and 15.2% (p = 0.23), respectively, with 27.3% and 16.1% (p = 0.28) for hormone-positive cases; and 25.0% and 0% (p = 1.0), respectively, for hormone-negative cases.ConclusionsEribulin and capecitabine sensitivity may vary based on HER2 expression in patients with HER2-low and HER2-null breast cancer. Prognosis was similar between the HER2-low and the HER2-null groups.

Contrast-enhanced computed tomography-based radiomics nomogram for predicting HER2 status in urothelial bladder carcinoma.

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). 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. 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. The radiomics nomogram demonstrates good diagnostic performance in predicting HER2 expression in patients with UBC.

Molecular aspects of BRAF and HER2 in prognosis of periampullary carcinoma

BackgroundBiological behaviour of Periampullary cancers (PACS) differs from pancreatic head cancer, and analysis of molecular alteration is needed. BRAF and HER2 are keys members of the RAS/RAF and EGFR pathway, playing roles in prognostic markers and therapeutic targets. MethodsA study on 89 PACS patients, undergoing Whipple Pancreaticoduodenectomy, PCR-RFLP, and qPCR methods used for SNP and mRNA expression studies. Clinicopathological and survival data collected. Molecular changes were correlated with Clinicopathological parameters. Survival outcomes were assessed by Kaplan Meir Log rank test. ResultsThe study revealed that homozygous mutant BRAF V600E was significantly higher in PAC compared to a healthy control (p = 0.0012). Whereas the genotype frequency of HER2 I1655V was similar among PAC and healthy control. The A > G change in HER2 was associated with tumor arising from duodenum (p = 0.004) and showed poor survival outcome (p = 0.001). Upregulation of BRAF and HER2 was found in 43 % of patients with synergistic effect, the median overall survival (OS) being 50.5 ± 13 months. The increased expression of HER2 was higher in early stage (p = 0.04) PAC. The gene expression did not impact the OS, whereas female gender, G3 tumors, T3-T4 depth of tumour, advanced stage, LN metastasis, LVI and PNI were poor predictors of OS. ConclusionsBRAF V600E SNP was associated with disease susceptibility, and had increased mRNA expression while HER2 I1655V SNP was associated with poor survival outcome in PAC. The increased expression of BRAF and HER2 in early tumors and their co-expression in PAC exhibit cross talk between RAS/RAF and EGFR pathway in PAC.

A single-arm, exploratory study of disitamab vedotin (DV) combined with camrelizumab and platinum-based chemotherapy as first-line treatment in patients with HER2 expressing locally advanced or metastatic esophageal squamous cell carcinoma (ESCC).

TPS217 Background: Esophageal cancer (EC) is one of the most common cancers worldwide with esophageal squamous cell carcinoma (ESCC) being the predominant histological subtype. PD-1 blockades combined with chemotherapy are now standard-of-care in first-line setting for patients with ESCC. HER2 expression, prevalent in an estimated 7.6% to 28.5% of ESCC cases, correlates with diminished overall survival, suggesting HER2-targeted therapy as a potential novel approach. To our knowledge, there is currently no clinical trial regarding anti-HER2 therapy in ESCC. Clinical evidence has suggested the potential synergistic anti-tumor effect of Disitamab Vedotin (DV) with PD-1 inhibitors in HER2-expressing gastric or gastroesophageal junction (G/GEJ) cancers. This single-arm, exploratory study aimed to evaluate the safety and preliminary anti-tumor activity of DV combined with camrelizumab and platinum-based chemotherapy in ESCC. Methods: This is a single-arm, exploratory study (NCT06055153). Approximately 20 patients will be enrolled in this study, phase 1 will initiate with a 3+3 dose-escalation scheme (2.5mg/kg to 2.0mg/kg) to identify dose-limiting toxicities (DLTs) and establish a safe dosage of DV. The expansion cohort will subsequently evaluate this dose for both efficacy and safety. The study population will included both male and female patients over the age of 18 with histologically confirmed ESCC, and locally advanced unresectable, recurrent unresectable or metastatic EC verified by imaging examination. This group also includes those patients who have experienced relapse or progression more than six months post the conclusion of last therapeutic regimen. Required HER2 expression levels in tumor specimens range from IHC 1+ to 3+. According to RECIST v1.1, participants must have at least one measurable lesion, an ECOG performance status of 0 or 1, and a minimum expected survival of 12 weeks with suitable organ function. Treatment protocol includes intravenous administration of DV (either 2.5 mg/kg or 2.0 mg/kg on day 1), Camrelizumab (200 mg on day 1), and Cisplatin (75mg/m2) or Nedaplatin (75mg/m2) on a 21-day cycle, continued until disease progression or the advent of unacceptable toxicity. The primary outcomes for evaluation are DLT for safety and the objective response rate (ORR) for efficacy. Adverse events will be monitored in accordance with the CTCAE 5.0 criteria. Secondary endpoints encompass progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DoR), and time to response (TTR). Clinical trial information: NCT06055153 .

Differences in the expression heterogeneity of ADC-related markers between primary tumors and metastatic lymph nodes in advanced urothelial cancers.

111 Background: The booming development of antibody‒drug conjugates (ADCs), which represent a novel, effective and low-toxicity therapeutic approach, has dramatically improved clinical outcomes in urothelial cancers, especially those with advanced disease. However, previous studies focused less on the targeted genes expression pattern and heterogeneity in metastatic tissues, which are more critical to inhibit tumor progression. Here, we aimed to explore the expression of potential ADC-related genes, including HER2, HER3, Nectin4 and Trop2 in advanced urothelial cancers between primary tumors and metastatic lymph nodes (mLN) in pairs. Methods: A large cohort of 306 urothelial cancer patients (292 patients, pN+), including 65 renal pelvis, 38 ureter, 179 bladder and 24 urethral cancer patients (10 patients, pN+), from SYSUCC was enrolled. Paraffin-embedded primary tumors and corresponding mLN sections were subjected to immunohistochemistry (IHC) to detect ADC-related gene expression. HER2 IHC scores of 2/3+ were defined as high expression as previously described. HER3, Nectin4 and Trop2 were evaluated by H-scores (range 0-300, rank 0 to 3+) multiplied by the extent and intensity of the staining, and H-scores &gt;15 were considered positive. Results: A total of 74.8% of advanced urothelial cancer patients were HER2 positive (1-3+), and 49.4% had high HER2 expression. High HER2 expression was detected in 33.8%, 42.2%, 56.5% and 50% of renal pelvis, ureter, bladder and urethral primary tumors, respectively. The rate of high HER2 expression in mLNs slightly decreased to 30.1%, 41.7%, 51.9% and 50%, and the concordance rate of HER2 expression between primary and mLNs was 71.9%. Similarly, 27.7%, 42.1%, 52%, and 66.7% of primary tumors were positive for HER3 expression; 72.3%, 89.5%, 77.7%, and 87.5% were positive for Nectin4; and 89.2%, 94.7%, 83.2%, and 95.8% were positive for Trop2 in renal pelvis, ureter, bladder and urethral cancers, respectively. Overall, 71.9%, 50.7%, and 65.3% of patients had consistent expression of HER3, Nectin4 and Trop2 in mLNs, respectively. Survival analysis indicated that the overexpression of HER2, HER3 and Trop2 in advanced urothelial cancers was associated with poor OS (p=0.001, 0.025 and 0.022, respectively). More importantly, we found that patients with higher HER2 expression in mLNs at primary sites had a worse prognosis (p=0.006). Conclusions: We first investigated the heterogeneity of ADC-related marker expression in primary urothelial tumors and mLNs in a large single cohort, especially in patients who underwent radical lymphadenectomy. Therapy targeting HER2-ADCs might show better homogeneity in advanced disease, but it is more recommended to detect IHC staining both in primary and metastatic tissues if possible.

Effect of HER2-low status on brain metastasis-free survival and survival after brain metastasis in patients with breast cancer.

The discovery of novel human epidermal growth factor receptor 2 (HER2)-directed antibody‒drug conjugates has accelerated the identification of the HER2-low subtype. However, the biological significance of low HER2 expression in breast cancer brain metastasis (BCBM) is unclear. Patients with HER2-negative BC and brain metastasis were retrospectively screened between February 2012 and November 2023. Brain metastasis-free survival (BMFS) and survival after brain metastasis (SABM) were analyzed according to HER2 expression. A total of 201 female patients, 84 of whom were HER2-low and 117 of whom were HER2-zero, were evaluated. The median BMFS in the entire cohort was 35.6months (95% CI 29.8-41.4). Although HER2-low patients had numerically longer median BMFS than HER2-zero patients (43.7m vs. 30.1m, p = 0.025), multivariate analysis revealed that the difference was not significant (p = 0.167). BMFS between the HER2-low and HER2-zero groups was similar in the hormone receptor (HR)-positive (52.8m vs. 47.6m, p = 0.276) and HR-negative (15.3m vs. 19.7m, p = 0.930) cohorts. The median SABM in the entire cohort was 6.0months (95% CI 3.8-8.1). HER2-low and HER2-zero patients had similar median SAMB (5.4m vs. 6.1m, p = 0.816). The SABM between the HER2-low and HER2-zero groups was similar in the HR-positive (6.3m vs. 8.7m, p = 0.375) and HR-negative (3.3m vs. 4.2m, p = 0.783) cohorts. Low HER2 expression does not affect BMFS or SAMB in brain metastatic breast cancer patients in this real-world population.