RESUMO
BACKGROUND: Nivolumab, a programmed cell death protein 1 (PD-1) inhibitor, showed promising activity for the treatment of advanced esophageal squamous-cell carcinoma in a phase II study (ONO-4538-07; JapicCTI-No.142422). We explored serum microRNA (miRNA) candidate predictive markers of the response to nivolumab. METHODS: In the phase II study, 19 patients received nivolumab (3 mg/kg IV Q2W) at National Cancer Center Hospital. The expression of 2565 serum miRNAs before and during treatment was analyzed using a 3D-Gene Human miRNA Oligo Chip (Toray Industries, Inc.). Immune-related response evaluation criteria used to evaluate response and miRNA expression were compared between responders and non-responders. The top 20 miRNAs by accuracy in receiver operating characteristic curve analysis were identified by leave-one-out cross-validation, and those with the area under curve values > 0.8, cross-validated accuracy > 0.8, and a 0.5 difference in the average log2 expression level between responders and non-responders were further analyzed. RESULTS: Of the 19 patients, five responded to nivolumab. We identified miRNAs related to the response to nivolumab, including one detected in the serum before treatment (miR-1233-5p; AUC = 0.895) and three present after treatment (miR-6885-5p, miR-4698 and miR-128-2-5p; AUC = 0.93, 0.97 and 0.93, respectively). CONCLUSIONS: Candidate miRNAs capable of predicting the response to nivolumab were identified in the serum of patients with advanced esophageal squamous-cell carcinoma in ONO-4538-07.
Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , MicroRNAs/classificação , Nivolumabe/farmacologia , Idoso , Área Sob a Curva , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , MicroRNAs/sangue , MicroRNAs/genética , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Curva ROCRESUMO
OBJECTIVE: CD133 has been recently identified as a marker of putative cancer stem cells in colorectal tumors. The ability of cancer stem cells to resist chemotherapy was clinically highlighted; however, whether CD133 expression can predict chemoresistance remains controversial. The objective of the study was to determine the relationship between clinical benefits of adjuvant chemotherapy and CD133 expression status in colorectal cancer. METHODS: We enrolled 234 patients with Stage III colorectal cancer who underwent curative resection. Among them, 149 received 5-fluorouracil-based adjuvant chemotherapy (chemotherapy group) and 85 did not (surgery-alone group). We immunohistochemically stained the specimens for CD133 on specimens evaluated the benefits of adjuvant chemotherapy according to CD133 expression using the Kaplan-Meier method and log-rank test. RESULTS: A comparison of disease-free survival between both the groups revealed a significant 3-year disease-free survival benefit of adjuvant chemotherapy in CD133-negative (92.2% versus 74.5%; P = 0.004), but not in CD133-positive patients (46.8% versus 52.9%; P = 0.67). Multivariate analysis corroborated the benefits of adjuvant chemotherapy in CD133-negative (P = 0.003, hazard ratio = 0.26), but not in CD133-positive patients. CONCLUSIONS: CD133-positive patients showed resistance to 5-FU-based chemotherapy, while CD133-negative patients experienced significant survival benefits from adjuvant chemotherapy not shared by CD133-positive patients.
Assuntos
Antígenos CD/análise , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Glicoproteínas/análise , Peptídeos/análise , Antígeno AC133 , Adulto , Idoso , Quimioterapia Adjuvante , Neoplasias Colorretais/cirurgia , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Prognóstico , Resultado do TratamentoRESUMO
Irinotecan is a key drug in second- or further-line chemotherapy for patients with advanced gastric cancer. Continuous administration of trastuzumab beyond first progression is expected to contribute to the benefit of chemotherapy for human epidermal growth factor receptor 2-positive gastric cancer. The aim of this trial is to evaluate the efficacy and safety of combination chemotherapy with trastuzumab and irinotecan in Japanese patients with advanced human epidermal growth factor receptor 2-positive chemo-refractory gastric cancer. The primary endpoint is the disease control rate. The secondary endpoints are adverse events, overall response rate, time to treatment failure, progression-free survival, overall survival and response rate stratified by prior trastuzumab use. A total of 30 patients will be enrolled in this Osaka Gastrointestinal Cancer Chemotherapy Study Group trial.