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1.
Sci Rep ; 14(1): 2628, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38297001

RESUMO

In clinical trials evaluating antibody-conjugated drugs (ADCs), HER2-low breast cancer is defined through protein immunohistochemistry scoring (IHC) 1+ or 2+ without gene amplification. However, in daily practice, the accuracy of IHC is compromised by inter-observer variability. Herein, we aimed to identify HER2-low breast cancer primary tumors by leveraging gene expression profiling. A discovery approach was applied to gene expression profile of institutional INT1 (n = 125) and INT2 (n = 84) datasets. We identified differentially expressed genes (DEGs) in each specific HER2 IHC category 0, 1+, 2+ and 3+. Principal Component Analysis was used to generate a HER2-low signature whose performance was evaluated in the independent INT3 (n = 95), and in the publicly available TCGA and GSE81538 datasets. The association between the HER2-low signature and HER2 IHC categories was evaluated by Kruskal-Wallis test with post hoc pair-wise comparisons. The HER2-low signature discriminatory capability was assessed by estimating the area under the receiver operating characteristic curve (AUC). Gene Ontology and KEGG analyses were performed to evaluate the HER2-low signature genes functional enrichment. A HER2-low signature was computed based on HER2 IHC category-specific DEGs. The twenty genes included in the signature were significantly enriched with lipid and steroid metabolism pathways, peptidase regulation, and humoral immune response. The HER2-low signature values showed a bell-shaped distribution across IHC categories (low values in 0 and 3+; high values in 1+ and 2+), effectively distinguishing HER2-low from 0 (p < 0.001) to 3+ (p < 0.001). Notably, the signature values were higher in tumors scored with 1+ as compared to 0. The HER2-low signature association with IHC categories and its bell-shaped distribution was confirmed in the independent INT3, TCGA and GSE81538 datasets. In the combined INT1 and INT3 datasets, the HER2-low signature achieved an AUC value of 0.74 (95% confidence interval, CI 0.67-0.81) in distinguishing HER2-low vs. the other categories, outperforming the individual ERBB2 mRNA AUC value of 0.52 (95% CI 0.43-0.60). These results represent a proof-of-concept for an observer-independent gene-expression-based classifier of HER2-low status. The herein identified 20-gene signature shows promise in distinguishing between HER2 0 and HER2-low expressing tumors, including those scored as 1+ at IHC, and in developing a selection approach for ADCs candidates.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , Receptor ErbB-2/metabolismo , Genes erbB-2 , Imuno-Histoquímica , Expressão Gênica , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo
2.
Urology ; 184: 75-78, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38052324

RESUMO

In bladder urothelial carcinoma, ERBB2 mutations have been associated with favorable response to platinum-based neoadjuvant chemotherapy. However, this association has not been reported in upper tract urothelial carcinoma (UTUC). We describe an excellent response to cisplatin-based chemotherapy in metastatic UTUC with an ERBB2 mutation. Our patient is a 54-year-old female with metastatic UTUC who received systemic cisplatin and gemcitabine. Postchemotherapy imaging demonstrated decreased size of pyelocaliceal mass and decreased retroperitoneal adenopathy compared to initial imaging. Surgical pathology from consolidative resection showed 3 mm residual renal tumor and no viable lymph node disease. Genomic testing demonstrated an ERBB2 gain of function mutation.


Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Feminino , Humanos , Pessoa de Meia-Idade , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/genética , Platina , Cisplatino/uso terapêutico , Genes erbB-2 , Mutação , Neoplasia Residual , Receptor ErbB-2/genética
3.
Mol Biol Rep ; 51(1): 1, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38040921

RESUMO

BACKGROUND: Colorectal cancer (CRC) is a widespread malignancy characterized by uncontrolled growth in the colon or rectum and remains a leading cause of cancer-related mortality globally. Various genes polymorphisms have been linked with the risk of CRC, but our study aimed to investigate the association between HER1 (rs11543848) and HER2 (rs1136201) polymorphisms with the risk of CRC in the Khyber Pakhtunkhwa (KPK) population of Pakistan. The association of the selected polymorphisms (rs11543848 and rs1136201) with CRC risk has been investigated in various ethnic groups, but their impact remains unexplored in Pakistan, particularly within the KPK population, highlighting the need of the study in this region. METHODS: In this study 120 CRC patients and 120 healthy controls were enrolled. The DNA was extracted from the blood by salting-out method and genotyping was done using ARMS-PCR. RESULTS: Our investigations provided convincing evidence of a strong association between HER1 (rs11543848) and the risk of CRC. Both the genotypes heterozygous GA (OR = 2.07, CI = 1.18 to 3.64, P = 0.01) and homozygous AA (OR = 6.22, CI = 2.56 to 15.08, P = 0.0001) showed higher risk and significant association with the CRC risk. Similarly, heterozygous genotype AG of HER2 (rs1136201) was significantly associated (OR = 3.16, 95% CI = 1.78 to 5.58, P = 0.0001) while mutant genotype GG showed higher risk but non-significant association (OR = 3.23, 95% CI = 0.84 to 12.43, P = 0.08) with CRC patients. HER1 (rs11543848) demonstrated a significant association (P = 0.003) with the age at diagnosis in CRC patients, while HER2 (rs1136201) showed a non-significant association (P = 0.434). Both the SNPs were non-significantly associated with gender (P = 0.793 and 0.117), metastasis (P = 0.582 and 0.129), location of the tumor (P = 0.555 and 0.993), tumor grade (P = 0.290 and 0.920), tumor size (P = 0.535 and 0.289) and stages of cancer (P = 0.892 and 0.352). CONCLUSION: In conclusion, both the polymorphisms rs11543848 and rs1136201 displayed susceptibility with CRC in the KPK population. However, further investigations are recommended while using whole exome sequencing on a larger sample size for more precise results.


Assuntos
Neoplasias Colorretais , Predisposição Genética para Doença , Humanos , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Genótipo , Paquistão , Polimorfismo de Nucleotídeo Único/genética , Genes erbB-2
4.
Biomark Med ; 17(17): 711-721, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-38085163

RESUMO

Background: The aim of this study was to explore whether the Lung Immune Prognostic Index (LIPI) is associated with clinical outcomes in patients with metastatic gastric cancer (MGC) treated with anti-PD-1 and chemotherapy. Methods: Patients with MGC treated with an anti-PD-1 therapy or chemotherapy were enrolled. This study was composed of two cohorts including 266 patients in the anti-PD-1-treated group and 139 patients in the chemotherapy-treated group. Results: Patients treated with anti-PD-1 therapy that also showed a good LIPI showed a longer median progression-free survival and median overall survival in patients with an intermediate or poor LIPI. These outcomes were not observed in the chemotherapy cohort. Conclusion: Good LIPI correlated with better outcomes for patients with MGC in the anti-PD-1-treated group but not in the chemotherapy-treated group.


Assuntos
Neoplasias Gástricas , Humanos , Prognóstico , Intervalo Livre de Progressão , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Tórax , Genes erbB-2/genética , Inibidores de Checkpoint Imunológico/uso terapêutico
7.
Oral Oncol ; 146: 106541, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37595449

RESUMO

BACKGROUND: Carcinoma ex pleomorphic adenoma (CXPA) is a neoplasm of the salivary gland that causes 3.6% of salivary gland tumors and 12% of salivary gland malignancies. Its prognosis is determined by the histological progression beyond the adenoma capsule. CXPA is thought to be a malignant transformation of a primary or recurrent pleomorphic adenoma and is associated with both benign and malignant lesions. Salivary gland cancers represent a rare heterogeneous group of neoplasms with complex clinicopathological characteristics and distinct biological behavior. CASE DESCRIPTION: This case report summarizes the treatment of a 57-year-old male patient with CXPA of the left parotid gland, harboring HER2 amplification with poor prognosis. The overall survival of the patient has been > 3.5 years. The application and outcome of an immune checkpoint inhibitor and targeted therapy combination regimens in the treatment of CXPA carcinoma are discussed. CONCLUSION: Targeted therapy combined with immunotherapy has long-term clinical benefits and targeted therapy which has a high clinical response rate (immunotherapy + dual-targeting three-drug regimens) may present an ideal choice for the treatment of patients with rare and/or refractory tumors without compromising patient safety.


Assuntos
Adenocarcinoma , Adenoma Pleomorfo , Neoplasias das Glândulas Salivares , Humanos , Masculino , Pessoa de Meia-Idade , Adenoma Pleomorfo/genética , Adenoma Pleomorfo/terapia , Adenoma Pleomorfo/patologia , Mutação , Cuidados Paliativos , Neoplasias das Glândulas Salivares/tratamento farmacológico , Neoplasias das Glândulas Salivares/genética , Genes erbB-2/genética
8.
Int J Mol Sci ; 24(12)2023 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-37373090

RESUMO

The main goal of the present study was to examine if the RNA-sequencing (RNAseq)-based ERBB2/HER2 expression level in malignant plasma cells from multiple myeloma (MM) patients has clinical significance for treatment outcomes and survival. We examined the relationship between the RNAseq-based ERBB2 messenger ribonucleic acid (mRNA) levels in malignant plasma cells and survival outcomes in 787 MM patients treated on contemporary standard regimens. ERBB2 was expressed at significantly higher levels than ERBB1 as well as ERBB3 across all three stages of the disease. Upregulated expression of ERBB2 mRNA in MM cells was correlated with amplified expression of mRNAs for transcription factors (TF) that recognize the ERBB2 gene promoter sites. Patients with higher levels of ERBB2 mRNA in their malignant plasma cells experienced significantly increased cancer mortality, shorter progression-free survival, and worse overall survival than other patients. The adverse impact of high ERBB2 expression on patient survival outcomes remained significant in multivariate Cox proportional hazards models that accounted for the effects of other prognostic factors. To the best of our knowledge, this is the first demonstration of an adverse prognostic impact of high-level ERBB2 expression in MM patients. Our results encourage further evaluation of the prognostic significance of high-level ERBB2 mRNA expression and the clinical potential of ERBB2-targeting therapeutics as personalized medicines to overcome cancer drug resistance in high-risk as well as relapsed/refractory MM.


Assuntos
Neoplasias da Mama , Mieloma Múltiplo , Humanos , Feminino , Genes erbB-2 , Mieloma Múltiplo/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Resultado do Tratamento , Sequência de Bases , Neoplasias da Mama/genética
9.
Clin Genitourin Cancer ; 21(4): 508.e1-508.e10, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37183125

RESUMO

Introduction/Background To determine the clinical significance of micropapillary urothelial carcinoma (MPUC) of the upper urinary tract (UTUC) and a potential therapeutic strategy. Patients and Methods A retrospective cohort study was conducted to examine the incidence of micropapillary UTUC from 2010 to 2018 and its clinicopathological characteristics. Clinical outcomes and cancer-specific survival (CSS) were compared between MPUC and conventional UTUC matched by stage within a 6-month variation of receiving surgery. Results A total of 24 MPUC cases were identified out of 901 cases (2.7%) of urothelial carcinoma (UC) of the renal pelvis and ureter. MPUC was significantly smaller (<3 cm) and associated with nodal metastasis compared with conventional UTUC (P = .017 & 0.021, respectively); however, no significant difference was observed for lymphovascular invasion, distant metastasis, or CSS (P > 0.50, respectively) compared with match controls. Six MPUC patients (25%) developed metastasis to the liver, lymph nodes, and lung during follow-up. Patients with HER2-positive MPUC (3 of 4) had a significantly higher risk of metastasis compared with HER2-negative MPUC (3 of 20; P = 0.035). Conclusions MPUC is an aggressive variant of UTUC and usually presents as a small locally advanced disease. HER2 immunohistochemistry may identify the subset of patients with micropapillary UTUC that are candidates for targeted therapy.


Assuntos
Terapia de Alvo Molecular , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/fisiopatologia , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/tratamento farmacológico , Carcinoma Papilar/fisiopatologia , Genes erbB-2/genética , Estudos de Casos e Controles , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Regulação Neoplásica da Expressão Gênica , Invasividade Neoplásica/genética , Imuno-Histoquímica , Biomarcadores Tumorais/metabolismo
10.
Int J Mol Sci ; 24(8)2023 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-37108234

RESUMO

Therapeutic oligonucleotides are powerful tools for the inhibition of potential targets involved in cancer. We describe the effect of two Polypurine Reverse Hoogsteen (PPRH) hairpins directed against the ERBB2 gene, which is overexpressed in positive HER-2 breast tumors. The inhibition of their target was analyzed by cell viability and at the mRNA and protein levels. The combination of these specific PPRHs with trastuzumab was also explored in breast cancer cell lines, both in vitro and in vivo. PPRHs designed against two intronic sequences of the ERBB2 gene decreased the viability of SKBR-3 and MDA-MB-453 breast cancer cells. The decrease in cell viability was associated with a reduction in ERBB2 mRNA and protein levels. In combination with trastuzumab, PPRHs showed a synergic effect in vitro and reduced tumor growth in vivo. These results represent the preclinical proof of concept of PPRHs as a therapeutic tool for breast cancer.


Assuntos
Neoplasias da Mama , Genes erbB-2 , Humanos , Feminino , Trastuzumab/farmacologia , Trastuzumab/genética , Oncogenes , Células MCF-7 , RNA Mensageiro/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Receptor ErbB-2/genética
11.
Breast Cancer Res ; 25(1): 48, 2023 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-37101199

RESUMO

BACKGROUND: Recent genomics studies of breast cancer in Asian cohorts have found a higher prevalence of TP53 mutations in Asian breast cancer patients relative to Caucasian patients. However, the effect of TP53 mutations on Asian breast tumours has not been comprehensively studied. METHODS: Here, we report an analysis of 492 breast cancer samples from the Malaysian Breast Cancer cohort where we examined the impact of TP53 somatic mutations in relation to PAM50 subtypes by comparing whole exome and transcriptome data from tumours with mutant and wild-type TP53. RESULTS: We found that the magnitude of impact of TP53 somatic mutations appears to vary between different subtypes. TP53 somatic mutations were associated with higher HR deficiency scores as well as greater upregulation of gene expression pathways in luminal A and luminal B tumours compared to the basal-like and Her2-enriched subtypes. The only pathways that were consistently dysregulated when comparing tumours with mutant and wild-type TP53 across different subtypes were the mTORC1 signalling and glycolysis pathways. CONCLUSION: These results suggest that therapies that target TP53 or other downstream pathways may be more effective against luminal A and B tumours in the Asian population.


Assuntos
Neoplasias da Mama , Feminino , Humanos , Povo Asiático/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Genômica , Mutação , Transcriptoma , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Genes erbB-2
12.
Breast Cancer ; 30(3): 506-517, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36977973

RESUMO

BACKGROUND: This AMEERA-2 study evaluated the pharmacokinetics, efficacy, and safety of the oral selective estrogen receptor degrader amcenestrant as a monotherapy with dose escalation in Japanese postmenopausal women with advanced estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer. METHODS: In this open-label, nonrandomized, phase I study, patients received amcenestrant 400 mg once daily (QD) (n = 7) and 300 mg twice daily (BID) (n = 3). The incidence of dose-limiting toxicities (DLT), recommended dose, maximum tolerated dose (MTD), pharmacokinetics, efficacy, and safety were assessed. RESULTS: No DLTs were observed and MTD was not reached in the 400 mg QD group. One DLT (grade 3 maculopapular rash) was reported in a patient treated with 300 mg BID. After repeated oral administration of either dosing regimen, steady state reached before day 8, without accumulation. Four out of 5 response-evaluable patients from 400 mg QD group achieved clinical benefit and showed tumor shrinkage. No clinical benefit was reported in the 300 mg BID group. Overall, most patients (8/10) experienced a treatment-related adverse event (TRAE), with skin and subcutaneous tissue disorders most commonly reported (4/10 patients). No ≥ grade 3 TRAE in 400 mg QD group and 1 grade 3 TRAE in 300 mg BID group were reported. CONCLUSIONS: Amcenestrant 400 mg QD has a favorable safety profile and has been selected as the recommended Phase II dose for monotherapy for evaluating the safety and efficacy of amcenestrant in a larger, global, randomized clinical trial of patients with metastatic breast cancer. TRIAL REGISTRATION: Clinical trial registration NCT03816839.


Assuntos
Neoplasias da Mama , Antagonistas de Estrogênios , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , População do Leste Asiático , Antagonistas de Estrogênios/administração & dosagem , Antagonistas de Estrogênios/farmacocinética , Antagonistas de Estrogênios/uso terapêutico , Dose Máxima Tolerável , Receptores de Estrogênio/genética , Genes erbB-2/genética , Administração Oral , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico
13.
Am J Clin Pathol ; 159(5): 464-473, 2023 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-36857635

RESUMO

OBJECTIVES: Human epidermal growth factor receptor 2 (HER2) status in endometrial cancer is usually determined by immunohistochemistry and/or in situ hybridization. We employed a novel HER2 gene protein assay (GPA) to simultaneously assesses HER2 gene amplification and protein expression in high-grade endometrial cancers. METHODS: We performed GPA in 180 endometrial cancers, including 106 serous carcinomas, 34 carcinosarcomas, and 40 mixed epithelial carcinomas. HER2 status was determined using the 2018 HER2 guidelines for breast carcinoma, and HER2 intratumoral heterogeneity (ITH) was examined. Clinicopathologic characteristics were collected and correlated with HER2 status. RESULTS: HER2 positivity was noted in 32% of serous carcinomas, significantly higher than in carcinosarcomas (5.9%) and mixed carcinomas (12.5%). HER2 ITH was detected in 32% of serous carcinomas, significantly greater than in carcinosarcomas (8.8%) and mixed carcinomas (10%). Patients with carcinosarcoma had a significantly lower overall survival than patients with serous or mixed epithelial carcinoma, but HER2 status caused no difference in survival in patients with serous carcinoma. CONCLUSIONS: HER2 GPA can be used to accurately determine HER2 status in endometrial cancers and is a highly valuable tool for identifying HER2 heterogeneity.


Assuntos
Carcinossarcoma , Cistadenocarcinoma Seroso , Neoplasias do Endométrio , Feminino , Humanos , Genes erbB-2 , Amplificação de Genes , Receptor ErbB-2/metabolismo , Neoplasias do Endométrio/patologia , Carcinossarcoma/genética , Biomarcadores Tumorais/genética
14.
Mod Pathol ; 36(1): 100032, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36788069

RESUMO

The HercepTest was approved 20+ years ago as the companion diagnostic test for trastuzumab in human epidermal growth factor 2 (HER2) or ERBB2 gene-amplified/overexpressing breast cancers. Subsequent HER2 immunohistochemistry (IHC) assays followed, including the now most common Ventana 4B5 assay. Although this IHC assay has become the clinical standard, its reliability, reproducibility, and accuracy have largely been approved and accepted on the basis of concordance among small numbers of pathologists without validation in a real-world setting. In this study, we evaluated the concordance and interrater reliability of scoring HER2 IHC in 170 breast cancer biopsies by 18 breast cancer-specialized pathologists from 15 institutions. We used the Observers Needed to Evaluate Subjective Tests method to determine the plateau of concordance and the minimum number of pathologists needed to estimate interrater agreement values for large numbers of raters, as seen in the real-world setting. We report substantial discordance within the intermediate categories (<1% agreement for 1+ and 3.6% agreement for 2+) in the 4-category HER2 IHC scoring system. The discordance within the IHC 0 cases is also substantial with an overall percent agreement (OPA) of only 25% and poor interrater reliability metrics (0.49 Fleiss' kappa, 0.55 intraclass correlation coefficient). This discordance can be partially reduced by using a 3-category system (28.8% vs 46.5% OPA for 4-category and 3-category scoring systems, respectively). Observers Needed to Evaluate Subjective Tests plots suggest that the OPA for the task of determining a HER2 IHC score 0 from not 0 plateaus statistically around 59.4% at 10 raters. Conversely, at the task of scoring HER2 IHC as 3+ or not 3+ pathologists' concordance was much higher with an OPA that plateaus at 87.1% with 6 raters. This suggests that legacy HER2 IHC remains valuable for finding the patients in whom the ERBB2 gene is amplified but unacceptably discordant in assigning HER2-low or HER2-negative status for the emerging HER2-low therapies.


Assuntos
Neoplasias da Mama , Receptor ErbB-2 , Humanos , Feminino , Imuno-Histoquímica , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Genes erbB-2 , Reprodutibilidade dos Testes , Patologistas , Hibridização in Situ Fluorescente , Neoplasias da Mama/metabolismo , Biomarcadores Tumorais/genética
15.
London; NICE; Feb. 1, 2023. 22 p.
Não convencional em Inglês | BIGG - guias GRADE | ID: biblio-1415982

RESUMO

Evidence-based recommendations on trastuzumab deruxtecan (Enhertu) for treating HER2-positive unresectable or metastatic breast cancer after 1 or more anti-HER2 treatments in adults. Commercial arrangement There is a managed access agreement, which includes a patient access scheme, for trastuzumab deruxtecan. NHS organisations can get details on the Commercial Access and Pricing (CAP) Portal. Non-NHS organisations can contact commercialaccess@daiichi-sankyo.co.uk for details.


Assuntos
Humanos , Neoplasias da Mama/terapia , Genes erbB-2/efeitos dos fármacos , Metástase Neoplásica/prevenção & controle , Anticorpos Monoclonais/uso terapêutico
16.
Asian Pac J Cancer Prev ; 24(1): 157-162, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36708564

RESUMO

BACKGROUND: The polymorphisms Arg72Pro in the TP53 gene (rs1042522) and Ile655Val in the HER2 gene (rs1136201) have been related to susceptibility to several types of cancer. Different studies show the association of these polymorphisms with breast cancer, so our aim in this study was to investigate whether the Arg72Pro and Ile655Val polymorphisms have any influence on the risk of developing breast cancer in women from the city of Macapá, Amapá, located in the brazilian amazon region. METHODS AND RESULTS: We then analyzed 80 DNA samples from women with breast cancer and 83 DNA samples from women without the disease, by the Restriction Fragment Length Polymorphism - Polymerase Chain Reaction (PCR-RFLP) technique. The genotype frequencies for rs1042522 were Ar/Arg 23.7%, Arg/Pro 47.5% and Pro/Pro 28.5% in patients and in controls Ar/Arg 69.8%, Arg/Pro 19.2% and Pro/Pro 10.8%. For the HER-2 gene the frequency of Ile/Ile, Ile/Val and Val/Val genotypes was 82.5%, 17.5% and 0% in the patients and 75.9%, 20.4% and 3.6% in the controls. The presence of at least one altered allele in rs1042522 and rs1136201 polymorphisms was found in 91.25% of patient samples. CONCLUSION: This study found a significant association between the Arg/Pro and Pro/Pro genotypes in the TP53 gene and the Ile/Val genotype in the HER-2 gene and breast cancer risk, however, we emphasize that more studies need to be carried out in the investigated population to consolidate our results.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Genes p53 , Brasil/epidemiologia , Genes erbB-2 , Genótipo , Predisposição Genética para Doença , Proteína Supressora de Tumor p53/genética , Estudos de Casos e Controles , Fatores de Risco , Polimorfismo de Nucleotídeo Único
17.
J Cancer Res Clin Oncol ; 149(6): 2437-2450, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35737089

RESUMO

PURPOSE: Several approaches have so far been employed to establish anti-tumor immunity by targeting HER2 protein. Active immunization with recombinant HER2 subdomains has previously been demonstrated to induce potent immune response and tumor growth inhibition. In the present study, we investigated the immunogenicity and tumor inhibitory effect of a fusion protein consisting of human HER2 extracellular subdomain (ECD-DI + II) together with T-helper cell epitopes of Tetanus toxin (p2 and p30). METHODS: BALB/c mice were immunized with two recombinant proteins (DI + II and p2p30-DI + II) emulsified in 4 different adjuvants. Anti-DI + II antibody response, cytokine profile, frequency of splenic CD25+FOXP3+ regulatory T cells (Tregs) and CD8+CD107a+ cytotoxic T lymphocytes (CTLs) were assessed in the immunized mice. To assess the anti-tumor effect, the immunized mice were subcutaneously challenged with HER2-overexpressing tumor cells and the tumor growth was determined. RESULTS: Both recombinant proteins were able to induce comparable levels of ECD-DI + II-specific antibodies. Immunization with p2p30-DI + II resulted in a significant increase in the level of Interferon-gamma (IFN-γ) secretion compared to DI + II protein and significantly higher frequency of CTLs and lower frequency of Tregs. The number of mice that remained tumor-free until day 120 was significantly higher in p2p30-DI + II vaccinated groups. CONCLUSIONS: Our data suggest that the p2p30-DI + II fusion protein together with CpG adjuvant induces more potent anti-tumor immune responses in a mouse tumor model. Accordingly, this formulation might be considered as a potential immunotherapeutic approach in HER2+ cancers.


Assuntos
Genes erbB-2 , Neoplasias , Receptor ErbB-2 , Animais , Humanos , Camundongos , Adjuvantes Imunológicos , Anticorpos , Imunidade , Camundongos Endogâmicos BALB C , Receptor ErbB-2/metabolismo , Proteínas Recombinantes
18.
Anal Bioanal Chem ; 415(4): 725-733, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36571590

RESUMO

Accurate measurement of human epidermal growth factor receptor 2 (HER2) copy number variation (CNV) is very important for guiding the tumor target therapy in breast cancer. Digital PCR (dPCR) is a sensitive and an absolute quantitative method, which can be used to detect HER2 CNV. Three HER2 exon-specific digital PCR assays along with three new reference genes assays (homo sapiens ribonuclease P RNA component H1 (RPPH1), glucose-6-phosphate isomerase (GPI), and chromosome 1 open reading frame 43 (C1ORF43), on different chromosomes) were established and validated by using standard reference material, 8 different cell lines and 110 clinical Formalin-fixed and paraffin-embedded (FFPE) samples. DPCR can achieve precise quantification of HER2 CNV by calculating the ratio of HER2/reference gene. The positive and negative coincidence rates were 98% (53/54) and 95% (53/56), respectively, compared with fluorescence in situ hybridization (FISH) diagnostic result 110 of FFPE samples. The common reference gene CEP17 used for FISH diagnostic was not suitable as single reference gene for HER2 CNV measurements by dPCR. The best practice of HER2 CNV determination by dPCR is to conduct the three duplex assays of H1 (HER2 exon 4) with the proposed three new reference genes, with a positive cut-off value of H1/RPPH1 ≥ 2.0 or H1/averaged reference gene ≥ 2.0. The proposed dPCR method in our study can accurately provide absolute copy number of HER2 and reference gene on an alternative chromosome, thus avoiding false negative caused by polysomy of chromosome 17. The improved molecular typing and diagnosis of breast cancer will better guide clinical medication.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Variações do Número de Cópias de DNA , Hibridização in Situ Fluorescente , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Reação em Cadeia da Polimerase/métodos , Genes erbB-2
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