RESUMO
PURPOSE: There is no agreed-upon standard option for patients with locally advanced head and neck squamous cell carcinoma (LA HNSCC) unfit for cisplatin-based regimens. Therefore, we performed a systematic review to explore alternative options for this population. METHODS: We searched PubMed, Cochrane, and Embase databases for observational studies and clinical trials (CTs) assessing treatment options for LA HNSCC cisplatin-ineligible patients. This study was registered in PROSPERO under the number CRD42023483156. RESULTS: This systematic review included 24 studies (18 observational studies and 6 CTs), comprising 4450 LA HNSCC cisplatin-ineligible patients. Most patients were treated with cetuximab-radiotherapy [RT] (50.3%), followed by carboplatin-RT (31.7%). In seven studies reporting median overall survival (OS) in patients treated with cetuximab-RT, it ranged from 12.8 to 46 months. The median OS was superior to 40 months in two studies assessing carboplatin-RT, and superior to 15 months in two studies assessing RT alone. For other regimens such as nimotuzumab-RT, docetaxel-RT, and carboplatin-RT plus paclitaxel the median OS was 21, 25.5, and 28 months, respectively. CONCLUSIONS: Our systematic review supports the use of a variety of therapy combinations for LA HNSCC cisplatin-ineligible patients. We highlight the urgent need for clinical studies assessing treatment approaches in this population.
Assuntos
Cisplatino , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias de Cabeça e Pescoço/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/métodos , Cetuximab/uso terapêutico , Cetuximab/administração & dosagem , Carboplatina/administração & dosagem , Antineoplásicos/uso terapêuticoRESUMO
The complex evolution of genetic alterations in cancer that occurs in vivo is a selective process involving numerous factors and mechanisms. Chemotherapeutic agents that prevent the growth and spread of cancer cells induce selective pressure, leading to rapid artificial selection of resistant subclones. This rapid evolution is possible because antineoplastic drugs promote alterations in tumorcell metabolism, thus creating a bottleneck event. The few resistant cells that survive in this new environment obtain differential reproductive success that enables them to pass down the newly selected resistant gene pool. The present review aims to summarize key findings of tumor evolution, epithelialmesenchymal transition and resistance to cetuximab therapy in head and neck squamous cell carcinoma.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genéticaRESUMO
INTRODUCCIÓN: Cuadro clínico: El cáncer colorrectal (CCR) es el 4° cáncer más frecuente y es la 3° causa de muerte por cáncer a nivel mundial. En Perú, el CCR es el 5° cáncer más frecuente y la 6° causa de muerte por cáncer a nivel nacional. El 20 % es diagnosticado en etapa metastásica. De los pacientes con CCR en etapa metastásica hasta un 30 % tienen metástasis hepática. A nivel molecular, la presencia de mutaciones RAS se reporta entre el 12 % y 75 % (las proteínas RAS participan en la activación del EGFR que conduce a la tumorigénesis de colon) y a nivel histológico, las características del tumor primario del lado izquierdo son distintas a la del lado opuesto. Sobre la carga de enfermedad, los reportes nacionales informan que el cáncer colorrectal genera 19,955 años de vida saludables perdidos (AVISA). Con respecto al tratamiento, siendo el CCR metastásico (CCRM) una enfermedad incurable, el objetivo del tratamiento es prolongar la vida, maximizando la calidad de vida y seguridad del paciente. Dentro de las opciones de terapias sistemáticas, la quimioterapia sigue siendo una de las alternativas recomendadas, entre ellas el esquema denominado FOLFOX (compuesto por 5-fluorouracilo con leucovorina y oxaliplatino). Tecnología sanitária: El cetuximab un anticuerpo monoclonal quimérico de tipo IgG1, contra el EGFR. En Perú, el cetuximab cuenta con registro sanitario (N°BE00609), otorgado por la
Assuntos
Humanos , Neoplasias Colorretais/tratamento farmacológico , Leucovorina/uso terapêutico , Cetuximab/uso terapêutico , Fluoruracila/uso terapêutico , Oxaliplatina/uso terapêutico , Metástase Neoplásica/tratamento farmacológico , Avaliação em Saúde/economia , Eficácia , Análise Custo-Benefício/economiaRESUMO
BACKGROUND: Epidermal growth factor receptor (EGFR) is frequently activated in head and neck squamous cell carcinoma (HNSCC) and serves as a valuable target for therapy. Despite the availability of the EGFR inhibitors Cetuximab, Afatinib, and Allitinib, there are limited predictive markers for their response. Understanding molecular aberrations in HNSCC could facilitate the identification of new strategies for patient clinical and biological classification, offering novel therapeutic avenues. METHODS: We assessed CCNA1, DCC, MGMT, CDKN2A/p16, and DAPK methylation status in HNSCC cell lines and their association with anti-EGFR treatment response. RESULTS: MGMT methylation status displayed high sensitivity and specificity in distinguishing sensitive and resistant HNSCC cell lines to Afatinib (AUC = 0.955) and Allitinib (AUC = 0.935). Moreover, DAPK methylation status predicted response to Allitinib with high accuracy (AUC = 0.852), indicating their putative predictive biomarker roles. CONCLUSION: These findings hold promise for the development of more personalized and effective treatment approaches for HNSCC patients.
Assuntos
Acrilamidas , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Quinazolinas , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Afatinib , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Receptores ErbB/metabolismo , Linhagem Celular Tumoral , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/uso terapêutico , Proteínas Supressoras de Tumor , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/uso terapêuticoRESUMO
BACKGROUND: Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR), is effective for RAS wild-type metastatic colorectal cancer (mCRC) patients. However, cetuximab resistance often occur and the mechanism has not been fully elucidated. The purpose of this study was to investigate the role of asparaginyl endopeptidase (AEP) in cetuximab resistance. METHODS: Differentially expressed genes between cetuximab responders and non-responders were identified by analyzing the gene expression profile GSE5851, retrieved from Gene Expression Omnibus (GEO). The potential genes were further validated in cetuximab-resistant CRC cell lines. The expression of AEP in the peripheral blood and tumor tissues of mCRC patients in our hospital were detected by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. The survival analysis was carried out by Kaplan-Meier method. The function and associated pathways of AEP were further investigated by lentivirus transfection, CCK8 assay, colony formation assay, real-time polymerase chain reaction (qPCR) and western blot. RESULTS: Through bioinformatics analysis, we found that the expression of AEP gene was related to progress free survival (PFS) of mCRC patients treated with cetuximab alone (P = 0.00133). The expression of AEP was significantly higher in the cetuximab-resistant CRC cell lines, as well as in mCRC patients with shorter PFS treated with cetuximab-containing therapy. Furthermore, AEP could decrease the sensitivity of CRC cells to cetuximab in vitro. And the phosphorylation level of MEK and ERK1/2 was increased in AEP overexpression cells. The downregulation of AEP using specific inhibitors could partially restore the sensitivity of CRC cells to cetuximab. CONCLUSION: The higher expression of AEP could contribute to the shorter PFS of cetuximab treatment in mCRC. The reason might be that AEP could promote the phosphorylation of MEK/ERK protein in the downstream signal pathway of EGFR.
Assuntos
Neoplasias Colorretais , Cisteína Endopeptidases , Resistencia a Medicamentos Antineoplásicos , Humanos , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/genética , Transdução de Sinais , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Sistema de Sinalização das MAP QuinasesRESUMO
PURPOSE: This study sought to determine the R0 resection rate in KRAS wild-type (WT), liver-only metastatic colorectal cancer (CRC) patients initially identified as having unresectable disease who were treated with FOLFOX7 plus cetuximab. Exploratory molecular analyses were undertaken before and after treatment. METHODS: Twenty patients were enrolled. None had prior adjuvant chemotherapy. Cetuximab was added to a FOLFOX7 backbone and administered at 500 mg/m2 every 14 days with dose reductions to 400 and 300 mg/m2 in the event of toxicity. In the absence of toxicity, dose-escalations to 600, 700, and 800 mg/m2 were allowed. The mean dose of cetuximab (mg/m2 /week) throughout the study was 289 mg/m2 . Paired samples were collected for correlative studies, where feasible. RESULTS: We assessed the conversion rates from unresectable to resectable in hepatic-only, KRAS exon 2 WT mCRC. Seventeen of 20 patients undergoing chemotherapy were considered resectable by imaging criteria; R0 resection was achieved in 15/20 patients. Molecular profiling revealed heterogeneity between patients at the gene-expression, pathway signaling, and immune-profile levels. CONCLUSIONS: Although 15/20 (75%) converted to R0 resection, by 2 years, 10/15 R0 resections had recurred. Therefore, chemotherapy plus cetuximab is of limited long-term benefit in this setting. ctDNA analysis may guide additional therapy including immunotherapy.
Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Humanos , Cetuximab/uso terapêutico , Camptotecina , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Fluoruracila , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirurgia , LeucovorinaRESUMO
INTRODUÇÃO: O câncer colorretal (CCR) é a segunda neoplasia maligna mais incidente entre homens e mulheres no Brasil, desconsiderando tumores de pele não melanoma. Para cada ano do triênio de 2020-2022 foram estimadas taxas brutas de incidências de 19,64 e 19,03 casos novos para cada 100 mil homens e mulheres, respectivamente. Para cerca de 20 a 30% dos pacientes acometidos, a doença terá se espalhado do local primário para outras partes do corpo antes da detecção; esses indivíduos apresentam câncer colorretal metastático (CCRm) irressecável no momento do diagnóstico do câncer primário. O prognóstico médio de portadores de CCRm não tratado é de 3 a 6 meses de vida. O tratamento do CCRm pode ser realizado com quimioterapia (QT) citotóxica em monoterapia ou em associação (com outros quimioterápicos ou terapias alvo, como por exemplo com anticorpos monoclonais), em várias combinações e esquemas. TECNOLOGIA: anticorpos monoclonais direcionados ao receptor do fator de crescimento epidérmico Anti-EGFR (cetuximabe e panitumumabe) e direcionados ao receptor do fator de crescimento endot
Assuntos
Humanos , Neoplasias Colorretais/tratamento farmacológico , Bevacizumab/uso terapêutico , Cetuximab/uso terapêutico , Panitumumabe/uso terapêutico , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economiaRESUMO
INTRODUCCIÓN: Según GLOBOCAN, durante el año 2020 aproximadamente 1,428 casos nuevos de cáncer de cabeza y cuello fueron diagnosticados en el Perú. Con respecto a la mortalidad, el cáncer de cabeza y cuello ha sido el responsable de más de 600 muertes en nuestro país. El cáncer de cabeza y cuello se asocia con la infección por PVH, siendo los subtipos 16 y 18 los más frecuentemente detectados, por lo cual esta neoplasia se asocia con mayor frecuencia a poblaciones jóvenes y económicamente activa. El cáncer de cabeza y cuello presenta una alta tasa de recurrencia (30-50%) y se asocia con pobre respuesta a la quimioterapia y una corta sobrevida. TECNOLOGÍA: Cetuximab es un anticuerpo monoclonal dirigido contra el receptor del factor de crecimiento epidermoide (EGFR), cuyo mecanismo de acción permitiría el bloqueo de vías moleculares que inhibirían el desarrollo y progresión del cáncer. Por lo cual, se estableció la siguiente pregunta PICO: "¿En los pacientes con diagnóstico de carcinoma escamoso de cabeza y cuello, no nasofaríngeo, estadio clínico IV o irresecable, ¿Cuál es la eficacia y seguridad de cetuximab asociado a quimioterapia en comparación con quimioterapia?" MÉTODOS: La estrategia de búsqueda sistemática de información científica para el desarrollo del presente informe se realizó siguiendo las recomendaciones de la Pirámide jerárquica de la evidencia propuesta por Haynes y se consideró los siguientes estudios: Sumarios y guías de práctica clínica. Revisiones sistemáticas y/o metanálisis. Ensayos Controlados Aleatorizados (ECA) . Estudios Observacionales (cohortes, caso y control, descriptivos). DISCUSIÓN: Según GLOGOCAN, durante el año 2020 aproximadamente 1,428 casos nuevos de cáncer de cabeza y cuello fueron diagnosticados en el Perú. Con respecto a la mortalidad, el cáncer de cabeza y cuello ha sido el responsable de más de 600 muertes en nuestro país. En Estados Unidos, más de la mitad de neoplasias de cabeza y cuello se originan por el virus del papiloma humano (PVH), siendo los subtipos 16 y 18 los más frecuentemente detectados. El cáncer bucofaríngeo relacionado con PVH se presenta en poblaciones más jóvenes, económicamente activa. El 5-10% de pacientes presentan enfermedad metastásica durante el diagnóstico. Sin embargo, el 30-50% de pacientes con enfermedad regional o localmente avanzada que fueron operadas y/o tratadas localmente presentarán recurrencia de enfermedad durante su evolución. Este grupo de pacientes presenta una duración corta de respuesta a tratamientos citotóxicos, y una pobre supervivencia (6-8 meses). Cetuximab es un anticuerpo monoclonal dirigido contra el receptor del factor de crecimiento epidermoide (EGFR), cuyo mecanismo de acción permitiría el bloqueo de vías moleculares que inhibirían el desarrollo del cáncer. CONCLUSIONES: Los pacientes con cáncer de cabeza y cuello metastásico/recurrente, no nasofaríngeo, corresponden a una población principalmente joven, económicamente activa, con pobre pronóstico y respuesta a quimioterapia convencional. 2. Las guías de práctica clínica internacional (NCCN, ESMO, NICE) recomiendan el uso de Cetuximab-Quimioterapia en esta población de interés. 3. RS/MA reporta mejoría estadísticamente significativa en TRO y SLP, y una tendencia a mejorar significativamente la SG con Cetuximab-Quimioterapia en la población de interés. 4. ECAs fase III reporta mejoría estadísticamente significativa en TRO, SLP y SG con Cetuximab-Platino-5FU en la población de interés. 5. Estudio de Calidad de Vida reporta que añadir Cetuximab no deteriora la calidad de vida de los pacientes tratados. 6. Dos estudios fármaco-económicos catalogan Cetuximab-Quimioterapia como una combinación "no costo-efectiva" en la población de interés. 7. Se estima que el costo de añadir cetuximab al régimen de tratamiento de los pacientes con cáncer de cabeza y cuello metastásico/recurrente es de aproximadamente S/. 19,925.04 por cada paciente. 8. Se discutió la presente evaluación de tecnología sanitaria en reunión de la Unidad Funcional de Tecnología Sanitaria (UFETS), recomendando su uso en los regímenes de quimioterapia estandarizada por 6 cursos en los pacientes con cáncer de cabeza y cuello avanzado, no nasofaríngeo, seguido de terapia como agente único de mantenimiento semanal.
Assuntos
Humanos , Quimioterapia Adjuvante , Cetuximab/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Eficácia , Análise Custo-Benefício/economiaRESUMO
Cetuximab is the sole anti-EGFR monoclonal antibody that is FDA approved to treat head and neck squamous cell carcinoma (HNSCC). However, no predictive biomarkers of cetuximab response are known for HNSCC. Herein, we address the molecular mechanisms underlying cetuximab resistance in an in vitro model. We established a cetuximab resistant model (FaDu), using increased cetuximab concentrations for more than eight months. The resistance and parental cells were evaluated for cell viability and functional assays. Protein expression was analyzed by Western blot and human cell surface panel by lyoplate. The mutational profile and copy number alterations (CNA) were analyzed using whole-exome sequencing (WES) and the NanoString platform. FaDu resistant clones exhibited at least two-fold higher IC50 compared to the parental cell line. WES showed relevant mutations in several cancer-related genes, and the comparative mRNA expression analysis showed 36 differentially expressed genes associated with EGFR tyrosine kinase inhibitors resistance, RAS, MAPK, and mTOR signaling. Importantly, we observed that overexpression of KRAS, RhoA, and CD44 was associated with cetuximab resistance. Protein analysis revealed EGFR phosphorylation inhibition and mTOR increase in resistant cells. Moreover, the resistant cell line demonstrated an aggressive phenotype with a significant increase in adhesion, the number of colonies, and migration rates. Overall, we identified several molecular alterations in the cetuximab resistant cell line that may constitute novel biomarkers of cetuximab response such as mTOR and RhoA overexpression. These findings indicate new strategies to overcome anti-EGFR resistance in HNSCC.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Cetuximab/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Cetuximab/farmacologia , Humanos , Transdução de SinaisRESUMO
OBJECTIVES: Epithelial growth factor receptor (EGFR), as a malignancy marker, is overly expressed in multiple solid tumors including colorectal neoplasms, one of the most prevalent malignancies worldwide. The main objective of this study is to enhance the efficacy of anti-tumor therapy targeting EGFR by constructing a novel EGFR-specific immunotoxin (C-CUS245C) based on Cetuximab and recombinant Cucurmosin (CUS245C). METHODS: E. coli BL21 (DE3) PlysS (E. coli) was used to express CUS245C with a cysteine residue inserting to the C-terminus of Cucurmosin. Then immobilized metal ion affinity chromatography (IMAC) was used to purify CUS245C. The chemical conjugation method was used for the preparation of C-CUS245C. Then dialysis and IMAC were used to purify C-CUS245C. Western blot as well as SDS-PAGE was carried out to characterize the formation of C-CUS245C. At last the anti-colorectal cancer activity of C-CUS245C was investigated in vitro and in vivo. RESULTS: CUS245C with high purity could be obtained from the prokaryotic system. C-CUS245C was successfully constructed and highly purified. The cytotoxicity assays in vitro showed a significant proliferation inhibition of C-CUS245C on EGFR-positive cells for 120 h with IC50 values less than 0.1 pM. Besides, the anti-tumor efficacy of C-CUS245C was remarkably more potent than that of Cetuximab, CUS245C, and C + CUS245C (P < 0.001). Whereas the cytotoxicity of C-CUS245C could hardly be detected on EGFR-null cell line. Our results also showed that C-CUS245C had efficacy of anti-colorectal cancer in mouse xenograft model, indicating the therapeutic potential of C-CUS245C for the targeted therapy of colorectal neoplasms. CONCLUSIONS: C-CUS245C exhibits potent and EGFR-specific cytotoxicity. Insertional mutagenesis technique is worthy to be adopted in the preparation of immunotoxin. Immunotoxin can be highly purified through dialysis followed by IMAC.