Levels Of Growth Factor Receptor Research Articles

A case report and literature review on a rare subtype of triple-negative breast cancer in children

BackgroundTriple-negative breast cancer (TNBC) is a type of breast tumor with a poor prognosis because it lacks or expresses low levels of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2). TNBC is more common in middle-aged and older women, and cases of TNBC in children are rarely reported. This is the only case of childhood SBC in our hospital in more than 70 years, and the disease is extremely rare internationally. We analyzed and studied the disease and TNBC from both clinical and pathological aspects and found that SBC is very different from TNBC.Case presentationWe report a case of secretory breast cancer (SBC), a subtype of TNBC, in an 8-year-old girl from our institution. The child presented with a single mass in the left breast only, with no skin rupture and no enlargement of the surrounding lymph nodes. The child underwent two surgeries and was followed up for one year with a good prognosis.ConclusionsSBC is highly prevalent among the multiple pathological types of pediatric breast cancer. Almost all pediatric SBC patients are characterized by the ETV6-NTRK3 fusion gene, which has a good prognosis and a 10-year survival rate of more than 90% when compared with other TNBC subtypes. According to the patient, we performed local mass resection and a postoperative pathological diagnosis of SBC (a subtype of BL-TNBC). The TNBC case had a good prognosis and differed from basal TNBC in several aspects, including clinical presentation, treatment, and prognosis. It is necessary to exclude SBC from BL-type TNBC, enhance understanding of the disease, and individualize the treatment plan, so as to avoid medical errors.

RNA-binding protein-regulated fibronectin is essential for EGFR-activated metastasis of head and neck squamous cell carcinoma.

There is a higher expression level of epidermal growth factor receptor (EGFR) in up to 90% of advanced head and neck squamous cell carcinoma (HNSCC) tissue than in normal surrounding tissues. However, the role of RNA-binding proteins (RBPs) in EGFR-associated metastasis of HNSCC remains unclear. In this study, we reveal that RBPs, specifically nucleolin (NCL) and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1), correlated with the mesenchymal phenotype of HNSCC. The depletion of RBPs significantly attenuated EGF-induced HNSCC metastasis. Intriguingly, the EGF-induced EMT markers, such as fibronectin, were regulated by RBPs through the ERK and NF-κB pathway, followed by the enhancement of mRNA stability of fibronectin through the 5' untranslated region (5'-UTR) of the gene. The upregulation of fibronectin triggered the integrin signaling activation to enhance tumor cells' attachment to endothelial cells and increase endothelial permeability. In addition, the concurrence of EGFR and RBPs or EGFR and fibronectin was associated with overall survival and disease-free survival of HNSCC. The in vivo study showed that depletion of NCL, hnRNPA2B1, and fibronectin significantly inhibited EGF-promoted extravasation of tumor cells into lung tissues. The depletion of fibronectin or treatment with integrin inhibitors dramatically attenuated EGF-induced HNSCC metastatic nodules in the lung. Our data suggest that the RBPs/fibronectin axis is essential for EGF-induced tumor-endothelial cell interactions to enhance HNSCC cell metastasis.

Cost-effectiveness of Trastuzumab Deruxtecan for HER2-low Advanced Breast Cancer in the United States

Trastuzumab deruxtecan has been shown to be effective for advanced breast cancer with low levels of human epidermal growth factor receptor 2. To optimize the allocation of limited health care resources, this study evaluated the cost-effectiveness of trastuzumab deruxtecan from the US payer perspective. A partitioned survival model was developed to project the disease course of advanced breast cancer. Clinical efficacy, treatment utilization, safety, and cost data were gathered from the DESTINY-Breast04 (Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer) trial and the Centers for Medicare & Medicaid Services. Transition probabilities were obtained from the reported survival probabilities per DESTINY-Breast04 group. The incremental cost-effectiveness ratio (ICER), the incremental monetary benefit, and the incremental net health benefit were measured. One-way sensitivity analysis, probabilistic sensitivity analysis, and subgroup analysis were performed to explore the uncertainty of the model. Trastuzumab deruxtecan had an ICER of $307,751 per quality-adjusted life-year (QALY) gained, with an incremental net health benefit of -0.317 QALY and an incremental monetary benefit of -$63,313 compared with the physician's choice of alternative chemotherapy agents. Subgroup analysis indicated that trastuzumab deruxtecan had an ICER of $383,776 per QALY gained for the hormone receptor-positive subgroup and an ICER of $194,424 per QALY for the hormone receptor-negative subgroup. One-way sensitivity analysis showed that the cost of trastuzumab deruxtecan had the most impact on model outcomes. The cost-effectiveness acceptability curve projected that the probability of trastuzumab deruxtecan being cost-effective was 5% in the overall population, 2% in the hormone receptor-positive subgroup, and 56% in the hormone receptor-negative subgroup at the willingness-to-pay threshold of $200,000 per QALY. Trastuzumab deruxtecan may be a cost-effective option for hormone receptor-negative patients with advanced breast cancer with low levels of human epidermal growth factor receptor 2.

Multiparametric MRI and Radiomics for the Prediction of HER2-Zero, -Low, and -Positive Breast Cancers.

Background Half of breast cancers exhibit low expression levels of human epidermal growth factor receptor 2 (HER2) and can be targeted by new antibody-drug conjugates. The imaging differences between HER2-zero (immunohistochemistry [IHC] score of 0), HER2-low (IHC score of 1+ or 2+ with negative findings at fluorescence in situ hybridization [FISH]), and HER2-positive (IHC score of 2+ with positive findings at FISH or IHC score of 3+) breast cancers were unknown. Purpose To assess whether multiparametric dynamic contrast-enhanced MRI-based radiomic features can help distinguish HER2 expressions in breast cancer. Materials and Methods This study included women with breast cancer who underwent MRI at two different centers between December 2020 and December 2022. Tumor segmentation and radiomic feature extraction were performed on T2-weighted and dynamic contrast-enhanced T1-weighted images. Unsupervised correlation analysis of reproducible features and least absolute shrinkage and selector operation were used for the selection of features to build a radiomics signature. The area under the receiver operating characteristic curve (AUC) was used to assess the performance of the radiomic signature. Multivariable logistic regression was used to identify independent predictors for distinguishing HER2 expressions in both the training and prospectively acquired external data set. Results The training set included 208 patients from center 1 (mean age, 53 years ± 14 [SD]), and the external test set included 131 patients from center 2 (mean age, 54 years ± 13). In the external test data set, the radiomic signature achieved an AUC of 0.80 (95% CI: 0.71, 0.89) for distinguishing HER2-low and -positive tumors versus HER2-zero tumors and was a significant predictive factor for distinguishing these two groups (odds ratio = 7.6; 95% CI: 2.9, 19.8; P < .001). Among HER2-low or -positive breast cancers, histology type, associated nonmass enhancement, and multiple lesions at MRI had an AUC of 0.77 (95% CI: 0.68, 0.86) in the external test set for the prediction of HER2-positive versus HER2-low cancers. Conclusion The radiomic signature and tumor descriptors from multiparametric breast MRI may predict distinct HER2 expressions of breast cancers with therapeutic implications. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kataoka and Honda in this issue.

Design, Synthesis and Biological Evaluation of Novel Pyrazolotriazolopyrimidine Derivatives as Potential Anticancer Agents

Three novel pyrazolo-[4,3-e][1,2,4]triazolopyrimidine derivatives (1, 2, and 3) were designed, synthesized, and evaluated for their in vitro biological activity. All three compounds exhibited different levels of cytotoxicity against cervical and breast cancer cell lines. However, compound 1 showed the best antiproliferative activity against all tested tumor cell lines, including HCC1937 and HeLa cells, which express high levels of wild-type epidermal growth factor receptor (EGFR). Western blot analyses demonstrated that compound 1 inhibited the activation of EGFR, protein kinase B (Akt), and extracellular signal-regulated kinase (Erk)1/2 in breast and cervical cancer cells at concentrations of 7 and 11 µM, respectively. The results from docking experiments with EGFR suggested the binding of compound 1 at the ATP binding site of EGFR. Furthermore, the crystal structure of compound 3 (7-(4-bromophenyl)-9-(pyridin-4-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine) was determined by single crystal X-ray analysis. Our work represents a promising starting point for the development of a new series of compounds targeting EGFR.

HER3/Akt/mTOR pathway is a key therapeutic target for the reduction of triple‑negative breast cancer metastasis via the inhibition of CXCR4 expression.

Triple‑negative breast cancer (TNBC), a highly metastatic subtype of breast cancer, and it has the worst prognosis among all subtypes of breast cancer. However, no effective systematic therapy is currently available for TNBC metastasis. Therefore, novel therapies targeting the key molecular mechanisms involved in TNBC metastasis are required. The present study examined whether the expression levels of human epidermal growth factor receptor 3 (HER3) were associated with the metastatic phenotype of TNBC, and evaluated the potential of HER3 as a therapeutic target invitro and invivo. A new highly metastatic 4T1 TNBC cell line, termed 4T1‑L8, was established. The protein expression levels in 4T1‑L8 cells were measured using luminex magnetic bead assays and western blot analysis. The HER3 expression levels and distant metastasis‑free survival (DMFS) in TNBC were analyzed using Kaplan‑Meier Plotter. Transwell migration and invasion assays were performed to detect migration and invasion. The anti‑metastatic effects were determined in an experimental mouse model of metastasis. The results revealed that the increased expression of the HER3/Akt/mTOR pathway was associated with a greater level of cell migration, invasion and metastasis of TNBC cells. In addition, it was found that high expression levels of HER3 were associated with a poor DMFS. The inhibition of the HER3/Akt/mammalian target of rapamycin (mTOR) pathway decreased the migration, invasion and metastasis of TNBC cells by decreasing the expression of C‑X‑C chemokine receptor type 4 (CXCR4). Furthermore, treatment of metastatic TNBC cells with everolimus inhibited their migration, invasion and metastasis by decreasing CXCR4 expression. Thus, targeting the HER3/Akt/mTOR pathway opens up a new avenue for the development of therapeutics against TNBC metastasis; in addition, everolimus may prove to be an effective therapeutic agent for the suppression of TNBC metastasis.

The potential roles of lncRNA TINCR in triple negative breast cancer.

Triple negative breast cancer (TNBC) is the most aggressive intrinsic breast cancer subtype characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and low levels of human epidermal growth factor receptor 2 (HER2). The complex nature of TNBC has resulted in little therapeutic progress for the past several decades. The standard of care remains the FEC cocktail (5-fluorouracil (5-FU), epirubicin and cyclophosphamide). However, early relapse and metastasis in TNBC patients persists in causing dismal clinical outcomes. Due to complex heterogeneity features of TNBC, identifying the biomarker associated to the chemoresistance remains a challenge. The emergence of the long non-coding RNA (lncRNA) as a potential signature may have proven to be a new deterrent to diagnostic and treatment options. Previous studies unveiled the associations of lncRNA in the development of TNBCs whereby the aggressiveness and response to therapies may be associated by the abrogation of the molecular mechanism lncRNA. Terminal differentiation induced ncRNA (TINCR) is a lncRNA which have been linked with many cancers including TNBC. The expression and behavior of TINCR may exert unfavorable outcome in TNBCs. Nevertheless, the underlying molecular mechanism of TINCR in driving chemoresistance in TNBC is not well understood. This review will highlight the potential molecular mechanisms of TINCR in TNBC chemoresistance and how it can serve as a future potential prognostic and therapeutic target for a better treatment intervention.

PSMC4 promotes prostate carcinoma progression by regulating the CBX3-EGFR-PI3K-AKT-mTOR pathway.

Proteasome 26S subunit ATPase 4 (PSMC4) could regulate cancer progression. However, the function of PSMC4 in prostate carcinoma (PCa) progression requires further clarification. In the study, PSMC4 and chromobox 3 (CBX3) levels were verified by TCGA data and tissue microarrays. Cell counting kit-8, cell apoptosis, cell cycle, wound healing, transwell and xenograft tumour model assays were performed to verify biological functions of PSMC4 in PCa. RNA-seq, PCR, western blotting and co-IP assays were performed to verify the mechanism of PSMC4. Results showed that PSMC4 level was significantly increased in PCa tissues, and patients with PCa with a high PSMC4 level exhibited shorter overall survival. PSMC4 knockdown markedly inhibited cell proliferation, cell cycle and migration in vitro and in vivo, and significantly promoted cell apoptosis. Then further study revealed that CBX3 was a downstream target of PSMC4. PSMC4 knockdown markedly reduced CBX3 level, and inhibited PI3K-AKT-mTOR signalling. CBX3 overexpression markedly promoted epidermal growth factor receptor (EGFR) level. Finally, PSMC4 overexpression showed reverse effect in DU145 cells, and the effects of PSMC4 overexpression on cell proliferation, migration and clonal formation were rescued by the CBX3 knockdown, and regulated EGFR-PI3K-AKT-mTOR signalling. In conclusion, PSMC4 could regulate the PCa progression by mediating the CBX3-EGFR-PI3K-AKT-mTOR pathway. These findings provided a new target for PCa treatment.

Complement factor H inhibits endothelial cell migration through suppression of STAT3 signaling.

Complement factor H (CFH), a major soluble inhibitor of complement, is a plasma protein that directly interacts with the endothelium of blood vessels. Mutations in the CFH gene lead to diseases associated with excessive angiogenesis; however, the underlying mechanisms are unknown. The present study aimed to determine the effects of CFH on endothelial cells and to explore the underlying mechanisms. The adenoviral plasmid expressing CFH was transduced into HepG2 cells, and the culture medium supernatant was collected and co-cultured with human umbilical vein endothelial cells (HUVECs). Cell proliferation was measured by CCK8 and MTT assays, and cell migration was measured by wound healing and Transwell assays. Reverse transcription-quantitative PCR was performed to detect gene transcription. Western blotting was used to determine protein levels. The results revealed that CFH can inhibit migration, but not viability, of HUVECs. In addition, CFH did not significantly alter MAPK or TGF-β signaling, whereas it decreased STAT3 phosphorylation in HUVECs. Furthermore, CFH failed to reduce migration of HUVECs, with inhibition of STAT3 signaling by STATTIC or activation of STAT3 signaling by overexpression of STAT3 (Y705D) compromising CFH-inhibited HUVEC migration. CFH also decreased the expression levels of vascular endothelial growth factor receptor 2, a downstream effector of STAT3 mediating endothelial cell migration. In conclusion, the present study suggested that CFH may be a potential therapeutic target for angiogenesis-related diseases.

O-141 Combination of gefitinib and methotrexate to treat tubal ectopic pregnancy (GEM3): a multicentre, randomised, double-blind, placebo-controlled trial

Abstract Study question Is a combination of parenteral methotrexate and oral gefitinib more effective than methotrexate alone in the treatment of tubal ectopic pregnancy? Summary answer In women with a tubal ectopic pregnancy, adding oral gefitinib to parental methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions. What is known already Current treatment of tubal ectopic pregnancies is with methotrexate or surgery. Methotrexate treatment fails in ∼30% of women and they require rescue surgery. At the time of the design of the trial, it had been shown in preclinical studies that tubal implantation sites express high levels of epidermal growth factor receptor (EGFR) and that gefitinib (an EGFR antagonist) augments methotrexate-induced regression of pregnancy-like tissue. There was also evidence from uncontrolled phase I and II trials that raised the possibility that combination methotrexate and gefitinib could be a more effective medical treatment than methotrexate alone to treat stable ectopic pregnancies. Study design, size, duration Between 2nd November 2016 and 6th October 2021, we performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Eligible participants were women with a tubal ectopic pregnancy deemed suitable for medical management with methotrexate. Inclusion criteria were: aged 18-50 years; pre-treatment serum hCG level of 1000–5000 IU/L; and either a definite diagnosis of tubal ectopic pregnancy or a clinical judgement of ‘probable’ tubal ectopic pregnancy. Participants/materials, setting, methods Participants were administered a single dose of intramuscular methotrexate (50 mg/m2) and randomised (1:1 ratio) to seven days of additional oral gefitinib (250mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. Main results and the role of chance 328 participants were allocated to methotrexate and gefitinib (n = 165) or methotrexate and placebo (n = 163). Three participants in the placebo group withdrew. Surgical intervention occurred in 30% (50/165) of the gefitinib group and in 29% (47/160) of the placebo group (adjusted risk ratio 1.15, 95% confidence interval [CI] 0.85-1.58; adjusted risk difference -0.01, 95% CI -0.10-0.09; p = 0.37). Without surgical intervention, median time to resolution was 28.0 days in the gefitinib group and 28.0 days in the placebo group (subdistribution hazard ratio 1.03, 95% CI 0.75-1.40). Serious adverse events occurred in 3% (5/165) of the gefitinib group and in 4% (6/162) of the placebo group. Diarrhoea and rash were more common in the gefitinib group. Limitations, reasons for caution Limitations of the trial include the fact that we only tested one dose regimen. It is possible gefitinib may be effective if a different protocol were used, such as a longer period of administration. Also, we did not carry out pharmacodynamic studies to determine optimal drug bioavailability. Wider implications of the findings Our results show that the addition of gefitinib to standard medical management with methotrexate to treat tubal ectopic pregnancy is not clinically effective as it does not reduce subsequent surgical intervention and is associated with higher rates of reported symptoms than placebo. Trial registration number ISRCTN67795930

Altered serum levels of platelet-derived growth factor receptor β and cluster of differentiation 13 suggest a role for pericytes in West syndrome

BackgroundPericytes play a role in the maintenance of the blood–brain barrier and neuroinflammation, attracting attention as to whether they are also involved in the pathogenesis of epilepsy.This study aimed to explore the relationship between West syndrome and pericytes. MethodsEighteen Japanese pediatric West syndrome patients and nine controls aged 2 years or younger were retrospectively enrolled in this study. We assessed theserumlevels of pericyte markers, serum PDGFRβ (platelet-derived growth factor receptorβ),CD13 (aminopeptidase N), and 27 cytokines in 17 pediatric patients with West syndrome and the control group. ResultsPatients with West syndrome exhibited significantly increased CD13 and decreased PDGFRβ levels, compared with controls but not serum cytokine levels. These values did not differ significantly between symptomatic and idiopathic West syndrome. ConclusionPericytes might be implicated in the pathogenesis of West syndrome.

Plasma levels of per- and polyfluoroalkyl substances (PFAS) are associated with altered levels of proteins previously linked to inflammation, metabolism and cardiovascular disease

BackgroundPer- and polyfluoroalkyl substances (PFAS) have been linked to immunotoxic and cardiometabolic effects in both experimental and epidemiological studies, but with conflicting results. AimThe aim of the present study was to investigate potential associations between plasma PFAS levels and plasma levels of preselected proteomic biomarkers previously linked to inflammation, metabolism and cardiovascular disease. MethodsThree PFAS (perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and perfluorohexane sulfonic acid (PFHxS)) were measured by non-targeted metabolomics and 249 proteomic biomarkers were measured by the proximity extension assay (PEA) in plasma from 2,342 individuals within the Epidemiology for Health (EpiHealth) study from Sweden (45–75 years old, 50.6 % men). ResultsAfter adjustment for age and sex, 92% of the significant associations between PFOS concentrations and proteins were inverse (p < 0.0002, Bonferroni-adjusted). The results were not as clear for PFOA and PFHxS, but still with 80% and 64 % of the significant associations with proteins being inverse. After adjustment for age, sex, smoking, education, exercise habits and alcohol consumption, levels of epidermal growth factor receptor (EGFR), and paraoxonase type 3 (PON3) remained positively associated with all three PFAS, while resistin (RETN) and urokinase plasminogen activator surface receptor (uPAR) showed inverse associations with all three PFAS. ConclusionsOur findings imply that PFAS exposure is cross-sectionally linked to altered levels of proteins previously linked to inflammation, metabolism and cardiovascular disease in middle-aged humans.

Brain Metastasis in HER2-Positive Breast Cancer: Case Report and Review of Literature

Introduction: Breast cancer (BC) is one of the most common cancers in women in developed countries. Approximately 15 to 20% of patients with BC have tumors with elevated levels of Human Epidermal Growth Factor Receptor 2 (HER2), which are associated with an aggressive clinical phenotype and poor prognosis. Brain metastases (BM) appears in more than 15% in the HER2-positive breast cancer population, which cause serious decrease in survival.

Exercise-induced endothelial Mecp2 lactylation suppresses atherosclerosis via the Ereg/MAPK signalling pathway

Background and aimsLactylation, a recently identified post-translational modification (PTM), plays a central role in the regulation of multiple physiological and pathological processes. Exercise is known to provide protection against cardiovascular disease. However, whether exercise-generated lactate changes lactylation and is involved in the exercise-induced attenuation of atherosclerotic cardiovascular disease (ASCVD) remains unclear. The purpose of this study was to investigate the effects and mechanisms of exercise-induced lactylation on ASCVD. Methods and ResultsUsing the high-fat diet-induced apolipoprotein-deficient mouse model of ASCVD, we found that exercise training promoted Mecp2 lysine lactylation (Mecp2k271la); it also decreased the expression of vascular cell adhesion molecule 1 (Vcam-1), intercellular adhesion molecule 1 (Icam-1), monocyte chemoattractant protein 1 (Mcp-1), interleukin (IL)-1β, IL-6, and increased the level of endothelial nitric oxide synthase (Enos) in the aortic tissue of mice. To explore the underlying mechanisms, mouse aortic endothelial cells (MAECs) were subjected to RNA-sequencing and CHIP-qPCR, which confirmed that Mecp2k271la repressed the expression of epiregulin (Ereg) by binding to its chromatin, demonstrating Ereg as a key downstream molecule for Mecp2k271la. Furthermore, Ereg altered the mitogen-activated protein kinase (MAPK) signalling pathway through regulating the phosphorylation level of epidermal growth factor receptor, thereby affecting the expression of Vcam-1, Icam-1, Mcp-1, IL-1β, IL-6, and Enos in ECs, which in turn promoted the regression of atherosclerosis. In addition, increasing the level of Mecp2k271la by exogenous lactate administration in vivo also inhibits the expression of Ereg and the MAPK activity in ECs, resulting in repressed atherosclerotic progression. ConclusionsIn summary, this study provides a mechanistic link between exercise and lactylation modification, offering new insight into the anti-atherosclerotic effects of exercise-induced PTM.

Abstract 3607: RNA-binding proteins are essential for EGF-induced fibronectin expression and metastasis of head and neck squamous cell carcinoma

Abstract There is a higher expression level of epidermal growth factor receptor (EGFR) in up to 90% of advanced head and neck squamous cell carcinoma (HNSCC) tissue than in normal surrounding tissues. However, the precise mechanism involved in modulating EGF-associated metastasis in HNSCC remains unclear. In this study, we reveal that the concurrent expression of EGFR and fibronectin (FN1) was highly associated with the stages of HNSCC progression. EGF-induced fibronectin/integrin axis enhanced tumor-endothelial cell interaction and increased endothelial permeability, conferred HNSCC cell metastasis. Mechanistically, we found that ERK and NF-κB pathway activation was essential for EGF-induced fibronectin expression. In addition, EGF-enhanced mRNA stability of fibronectin occurred through the 5’ untranslated region (5’-UTR) of the gene and was mediated by nucleolin (NCL) and hnRNPA2/B1, which were also involved in the regulation of epithelial-mesenchymal transition gene expression. Intriguingly, the in vivo study showed that depletion of NCL, hnRNPA2/B1, and inhibition of the fibronectin/integrin axis significantly inhibited EGF-promoted HNSCC metastasis in the lung. Our data suggests that the nucleolin/hnRNPA2/B1-regulated fibronectin is essential for EGF-induced tumor-endothelial cell interactions to enhance HNSCC cell metastasis. Citation Format: Ting-Wei Chang, Wen-Chang Chang, Ben-Kuen Chen. RNA-binding proteins are essential for EGF-induced fibronectin expression and metastasis of head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3607.

Nanoproteomics deciphers the prognostic value of EGFR family proteins-based liquid biopsy

Monitoring tumor-associated protein status in serum can effectively track tumors and avoid time-consuming, costly, and invasive tissue biopsy. Epidermal growth factor receptor (EGFR) family proteins are often recommended in the clinical management of multiple solid tumors. However, the low-abundance of serum EGFR (sEGFR) family proteins hinders the depth-understanding of their function and tumor management. Herein, a nanoproteomics approach coupling with aptamer-modified MOFs (NMOFs-Apt) with mass spectrometry was developed for the enrichment and quantitative analysis of sEGFR family proteins. This nanoproteomics approach exhibited high sensitivity and specificity for sEGFR family protein quantification, with the limit of quantification as low as 1.00 nM. After detecting 626 patients’ sEGFR family proteins with various malignant tumors, we concluded that the levels of serum proteins had a moderate concordance with tissue counterparts. Metastatic breast cancer patients with a high level of serum human epidermal growth factor receptor 2 (sHER2) and a low level of sEGFR had a poor prognosis, and patients with a sHER2 decrease of more than 20% had longer disease-free time after receiving chemotherapy. This nanoproteomics method provided a simple and effective approach for low-abundant serum protein detection and our results clarified the potential of sHER2 and sEGFR as cancer markers.

Effects of oleanolic acid on hair growth in mouse dorsal skin mediated via regulation of inflammatory cytokines.

Oleanolic acid (OA) is a pentacyclic triterpenoid with favourable physiological activity. It is widely distributed in more than 200 species of plants. OA has garnered significant interest because of its potential biological activities, such as antioxidant, bacteriostatic, and hair growth-promoting effects. To study the effect of OA on hair growth and related mechanisms, we investigated hair growth in mice with testosterone-induced androgenetic alopecia (AGA) that were treated with three different concentrations of OA. The antioxidant, bacteriostatic, and cytotoxic effects of OA were evaluated. We found that mice with testosterone-induced AGA treated with 1% or 0.5% OA showed significantly enhanced hair growth and increased vascular endothelial growth factor/glyceraldehyde-3-phosphate dehydrogenase ratio and levels of fibroblast growth factor receptor and insulin-like growth factor 1. Using an immunofluorescence staining assay, we demonstrated that β-catenin, a key Wnt signalling transducer, was highly expressed in the OA-treated groups. These results suggest that OA may promote hair growth by stimulating hair matrix cell proliferation via the Wnt/β-catenin pathway and lowering the levels of tumour necrosis factor-alpha, and transforming growth factor-beta 1, dihydrotestosterone, and 5α-reductase.

Correlation between 18F-FDG PET/MR parameters with the expression level of epidermal growth factor receptor and the diagnostic value of PET/MR in head and neck squamous cell carcinoma

ObjectiveTo investigate the correlation between parameters of PET/MR and the expression level of epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinoma (HNSCC) and to evaluate diagnostic efficacy of independent and combined PET/MR parameters for the expression level of EGFR. Materials and methods21 patients who had undergone PET/MR and been proven HNSCC pathologically were included in this retrospective study. The PET/MR sequences included 18-flurodeoxyglucose (18F-FDG) PET, T1, T2-weighted imaging, DWI, ADC and DCE. Parameters including ADCmean from DWI, Ktrans, Ve, Kep from DCE, and SUVmean, SUVmax from PET were obtained. Immunohistochemical method was used to detect the expression level of EGFR. The associations between parameters of PET/MR and EGFR expression level were analyzed by Spearman's analysis. Logistic regression was utilized to establish the diagnostic model of EGFR expression level with PET/MR parameters. The efficacy of the independent and combined diagnostic model for EGFR expression level in HNSCC was analyzed by ROC curve. P value ≤ 0.05 was considered statistically significant. Results(1) Expression level of EGFR was correlated to SUVmean with correlation coefficient of 0.47 (p = 0.05). (2) There was significant difference of SUVmean between the EGFR high- and low-expression groups (p = 0.02). (3) Combination of PET/MR improved the diagnostic efficacy for expression level of EGFR, with AUC = 0.93. ConclusionThere were different degrees of correlation between PET/MR parameters and EGFR expression level in HNSCC. Combination of PET/MR might improve diagnostic efficacy of EGFR expression level.

A SERS/fluorescence dual-mode immuno-nanoprobe for investigating two anti-diabetic drugs on EGFR expressions.

A surface-enhanced Raman scattering (SERS)/fluorescence dual-mode nanoprobe was proposed to assess anti-diabetic drug actions from the expression level of the epidermal growth factor receptor (EGFR), which is a significant biomarker of breast cancers. The nanoprobe has a raspberry shape, prepared by coating a dye-doped silica nanosphere with a mass of SERS tags, which gives high gains in fluorescence imaging and SERS measurement. The in situ detection of EGFR on the cell membrane surfaces after drug actions was achieved by using this nanoprobe, and the detection results agree with the enzyme-linked immunosorbent assay (ELISA) kit. Our study suggests that rosiglitazone hydrochloride (RH) may be a potential drug for diabetic patients with breast cancer, while the anti-cancer effect of metformin hydrochloride (MH) is debatable since MH slightly promotes the EGFR expression of MCF-7 cells in this study. This sensing platform endows more feasibility for highly sensitive and accurate feedback of pesticide effects at the membrane protein level.

Abstract P5-02-43: Incidence of HER2-low Expression in HR-positive/HER2-negative and Triple-Negative Breast Cancers in the Integra Connect Database

Abstract Approximately half of primary breast cancers exhibit low levels of human epidermal growth factor receptor 2 (HER2), defined as a score of 1+ on immunohistochemical (IHC) analysis or a score of 2+ on IHC and lack of HER2 gene amplification on in situ hybridization (ISH). Tumors classified as HER2-low represent a target for novel antibody-drug conjugates. In addition, HER2-low expression accounts for about 60% of HER2-negative breast cancers (BC). Real-world studies noted that HER2-low represents 47-54% of hormone positive (HR-positive)/HER2-negative breast cancers, a percentage higher than in the triple negative subgroup, reported at 35%. The goal of this study was to determine the frequency of HER2-low expression in patients with HR-positive/HER2-negative and triple-negative breast cancers (TNBCs) in the real-world and compare it with the published literature. The IntegraConnect (IC) real-world database of 330 thousand breast cancer patients was used for this analysis. Within the IC database, a subgroup of 387 patients with HR-positive/HER2-negative breast cancer and 618 patients with TNBC were abstracted with medical chart curation. The mean age at diagnosis for each group was 56 years and most patients had an ECOG performance status of 0-1. The statistical tests used were the Mann-Whitney test for age at diagnosis and the Chi-squared test for race, major stage, and ECOG at diagnosis. Differences were considered significant at P &amp;lt; .05. In the HR-positive/HER2-negative subgroup (n=387), 327 patients were tested by IHC and ISH. Sixty patients were tested by ISH only and were removed as they did not fit the definition of HER2-low. Of the 327 HER2-negative patients, 199 patients exhibited low HER2 expression (IHC1+, n=138 patients; IHC2+/ISH-negative, n=61), accounting for 61% (199/327) of HR-positive/HER2-negative breast cancers. In this group, numerically more patients were HER2-low than HER2-negative across all race subgroups. In the TNBC patient group (n=618), 546 patients tested HER2-negative by ICH and ISH. Patients testing HER2-negative by ISH only were removed (n=72) from the analysis. Of 546 patients with TNBC, HER2-low expression accounted for 42% (227/546) [IHC1+, n=168; IHC2+/ISH-negative, n=59]. In the Black or AA patients with TNBC subgroup, 37.2% (N=129) were HER2-low compared with 44% (N=353) in White patients. In all TNBC race subgroups, numerically more patients were HER2-negative compared with HER2-low. In addition, the proportion of HER2-low expression was higher in the HR+/HER2-negative subgroup (N=327) than in TNBC (N=546) (61% vs 42%, respectively), corroborating literature reports. In conclusion, analysis of the IC database showed HER2-low expression in 61% of HR-positive/HER2-negative breast cancers and in 42% of TNBC patients. Approximately 37% of Black or African Americans (AA) patients with TNBC expressed low levels of HER2. The frequency of HER2-low expression in TNBC in the IC database at 42% is slightly higher than previous studies that estimate HER2-low expression at 35% of TNBC. The percentage of HER2-low in HR+/HER2-negative breast cancers at 61% is higher than previous reports, which estimate low HER2 expression in patients with primary and recurrent HR+/HER2-negative breast cancers at 47 and 54%, respectively. Citation Format: Marielle Fares, Mike Gart, Simon Blanc, Jia Zheng, William Saunders, Robert Smith, Anupama Vasudevan, Sandy English. Incidence of HER2-low Expression in HR-positive/HER2-negative and Triple-Negative Breast Cancers in the Integra Connect Database [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-43.