Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Endocr Relat Cancer. 2018 Apr;25(4):471-480. doi: 10.1530/ERC-17-0404. Epub 2018 Feb 12.
Small intestinal neuroendocrine tumors (SI-NETs) are generally considered resistant to systemic treatment. To date, predictive markers for drug activity are lacking. Tumor samples from 27 patients with SI-NETs were analyzed for sensitivity to a panel of cytotoxic drugs and targeted agents using a short-term total cell kill assay. Samples of renal cancer, colorectal cancer (CRC), ovarian cancer and chronic lymphocytic leukemia (CLL) were included for comparison. For the SI-NET subset, drug sensitivity was analyzed in relation to clinicopathological variables and pre-treatment biomarkers. For cytotoxic drugs, SI-NETs demonstrated similar or higher sensitivity to 5-FU, platinum, gemcitabine and doxorubicin compared with CRC. For several of the targeted kinase inhibitors, SI-NET was among the most sensitive solid tumor types. CLL and ovarian cancer were generally the most sensitive tumor types to both cytotoxic drugs and protein kinase inhibitors. SI-NET was more sensitive to the mTOR inhibitor sirolimus than the other solid tumor types tested. Individual SI-NET samples demonstrated great variability in sensitivity for most drugs. Cross-resistance between different drugs also varied considerably, being higher among protein kinase inhibitors. Age, stage, grade, peritoneal carcinomatosis and extra-abdominal metastases as well as serum chromogranin A and urine 5-HIAA concentrations at diagnosis did not correlate to drug sensitivity SI-NETs exhibit intermediate sensitivity to cytotoxic and targeted drugs. Clinicopathological factors and currently used biomarkers are not clearly associated to sensitivity, challenging these criteria for treatment decisions in SI-NET. The great variability in drug sensitivity calls for individualized selection of therapy.
小肠神经内分泌肿瘤（SI-NETs）通常被认为对全身治疗具有抗性。迄今为止，缺乏用于预测药物活性的生物标志物。使用短期总细胞杀伤测定法，分析了 27 名 SI-NET 患者的肿瘤样本，以评估其对一系列细胞毒性药物和靶向药物的敏感性。纳入了肾细胞癌、结直肠癌（CRC）、卵巢癌和慢性淋巴细胞白血病（CLL）的样本作为比较。对于 SI-NET 亚组，根据临床病理变量和治疗前生物标志物分析药物敏感性。对于细胞毒性药物，与 CRC 相比，SI-NET 对 5-FU、铂类、吉西他滨和阿霉素的敏感性相似或更高。对于几种靶向激酶抑制剂，SI-NET 是最敏感的实体肿瘤类型之一。CLL 和卵巢癌通常是对细胞毒性药物和蛋白激酶抑制剂最敏感的肿瘤类型。与其他测试的实体肿瘤类型相比，SI-NET 对 mTOR 抑制剂依维莫司更敏感。大多数药物的个别 SI-NET 样本显示出很大的敏感性差异。不同药物之间的交叉耐药性也有很大差异，蛋白激酶抑制剂之间的交叉耐药性更高。年龄、分期、分级、腹膜种植和腹外转移以及诊断时的血清嗜铬粒蛋白 A 和尿液 5-HIAA 浓度与药物敏感性无关。SI-NETs 对细胞毒性和靶向药物具有中等敏感性。临床病理因素和当前使用的生物标志物与敏感性没有明确关联，这对 SI-NET 的治疗决策提出了挑战。药物敏感性的巨大差异需要个体化选择治疗方法。
