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Abstract：
UNASSIGNED: Neuroendocrine neoplasms (NENs) are a rare group of tumors exceptionally heterogeneous, with clinical presentation ranging from well differentiated more indolent tumors to poorly differentiated very aggressive forms. Both are often diagnosed after the metastatic spread and require appropriate medical treatment. A high priority need in the management of this disease is the identification of effective therapeutic strategies for advanced and metastatic patients. The recent TALENT trial demonstrated the efficacy of lenvatinib, a multi-tyrosine kinase inhibitor, in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with no other treatment indication. Further development of this drug in advanced NETs is warranted.
UNASSIGNED: We investigated potential clinical and molecular determinants of lenvatinib response in human primary cultures derived from patients with GEP-NET of different grades and sites of origin. We correlated response to treatment with patient clinical characteristics, with the mutational status of 161-cancer associated genes and with the expression levels of MKI-related genes.
UNASSIGNED: Lenvatinib exerted a significant antitumor activity in primary GEP-NET cells, with median survival inhibitions similar or higher than those of standard frontline treatments. Of the 11 primary cultures analyzed in our case series, 6 were classified as responder showing a significant survival inhibition, and 5 as non-responder. We observed that the overexpression of HRAS in the original tumor tissue compared to the matched healthy tissue significantly correlated with responsiveness of primary cells to lenvatinib (p=.048). All 5 non-responder cultures showed normal HRAS expression, while of the 6 responder cultures, 4 had HRAS overexpression. Overexpression of HRAS was not associated with gene mutation. None of the other evaluated clinical variables (grade, Ki67, site of origin and syndromic disease) or molecular markers correlated with response.
UNASSIGNED: Lenvatinib appears to be a highly effective drug for the treatment of NETs. The evaluation of HRAS expression in the tumor tissue might improve patient selection and optimize therapeutic outcome.
UNASSIGNED: We investigated potential clinical and molecular determinants of lenvatinib response in human primary cultures derived from patients with GEP-NET of different grades and sites of origin. We correlated response to treatment with patient clinical characteristics, with the mutational status of 161-cancer associated genes and with the expression levels of MKI-related genes.
UNASSIGNED: Lenvatinib exerted a significant antitumor activity in primary GEP-NET cells, with median survival inhibitions similar or higher than those of standard frontline treatments. Of the 11 primary cultures analyzed in our case series, 6 were classified as responder showing a significant survival inhibition, and 5 as non-responder. We observed that the overexpression of HRAS in the original tumor tissue compared to the matched healthy tissue significantly correlated with responsiveness of primary cells to lenvatinib (p=.048). All 5 non-responder cultures showed normal HRAS expression, while of the 6 responder cultures, 4 had HRAS overexpression. Overexpression of HRAS was not associated with gene mutation. None of the other evaluated clinical variables (grade, Ki67, site of origin and syndromic disease) or molecular markers correlated with response.
UNASSIGNED: Lenvatinib appears to be a highly effective drug for the treatment of NETs. The evaluation of HRAS expression in the tumor tissue might improve patient selection and optimize therapeutic outcome.
摘要：
未经证实：神经内分泌肿瘤（NENs）是一组罕见的异常异质性肿瘤，临床表现从分化良好的惰性肿瘤到分化较差的侵袭性肿瘤。两者通常在转移扩散后被诊断出来，需要适当的药物治疗。治疗这种疾病的高度优先需求是确定晚期和转移性患者的有效治疗策略。最近的TALENT试验证明了lenvatinib的疗效，一种多酪氨酸激酶抑制剂，无其他治疗指征的胃肠胰腺神经内分泌肿瘤（GEP-NETs）患者。该药物在先进的NETs中的进一步开发是有必要的。
UNASSIGNED：我们研究了来自不同级别和来源部位的GEP-NET患者的人类原代培养物中lenvatinib反应的潜在临床和分子决定因素。我们将对治疗的反应与患者临床特征相关联，与161个癌症相关基因的突变状态和MKI相关基因的表达水平。
未经证实：Lenvatinib在原代GEP-NET细胞中发挥了显著的抗肿瘤活性，中位生存抑制作用与标准一线治疗相似或更高。在我们的案例系列中分析的11种主要文化中，6个被分类为显示显著存活抑制的应答者，5为无应答者。我们观察到，与匹配的健康组织相比，原始肿瘤组织中HRAS的过表达与原代细胞对乐伐替尼的反应性显着相关（p=.048）。所有5个无反应者培养物显示正常的HRAS表达，而在6种响应者文化中，4具有HRAS过表达。HRAS的过表达与基因突变无关。没有其他评估的临床变量(等级，Ki67，起源和综合征的部位）或与反应相关的分子标记。
未经批准：Lenvatinib似乎是治疗NETs的高效药物。肿瘤组织中HRAS表达的评估可能会改善患者选择并优化治疗结果。
UNASSIGNED：我们研究了来自不同级别和来源部位的GEP-NET患者的人类原代培养物中lenvatinib反应的潜在临床和分子决定因素。我们将对治疗的反应与患者临床特征相关联，与161个癌症相关基因的突变状态和MKI相关基因的表达水平。
未经证实：Lenvatinib在原代GEP-NET细胞中发挥了显著的抗肿瘤活性，中位生存抑制作用与标准一线治疗相似或更高。在我们的案例系列中分析的11种主要文化中，6个被分类为显示显著存活抑制的应答者，5为无应答者。我们观察到，与匹配的健康组织相比，原始肿瘤组织中HRAS的过表达与原代细胞对乐伐替尼的反应性显着相关（p=.048）。所有5个无反应者培养物显示正常的HRAS表达，而在6种响应者文化中，4具有HRAS过表达。HRAS的过表达与基因突变无关。没有其他评估的临床变量(等级，Ki67，起源和综合征的部位）或与反应相关的分子标记。
未经批准：Lenvatinib似乎是治疗NETs的高效药物。肿瘤组织中HRAS表达的评估可能会改善患者选择并优化治疗结果。
