Yale University School of Medicine, New Haven, CT, USA.
Wren Laboratories, Branford, CT, USA.
Ann Surg Oncol. 2021 Nov;28(12):7506-7517. doi: 10.1245/s10434-021-10021-1. Epub 2021 May 18.
Surgery is the only cure for neuroendocrine tumors (NETs), with R0 resection being critical for successful tumor removal. Early detection of residual disease is key for optimal management, but both imaging and current biomarkers are ineffective post-surgery. NETest, a multigene blood biomarker, identifies NETs with >90% accuracy. We hypothesized that surgery would decrease NETest levels and that elevated scores post-surgery would predict recurrence.
This was a multicenter evaluation of surgically treated primary NETs (n = 153). Blood sampling was performed at day 0 and postoperative day (POD) 30. Follow-up included computed tomography/magnetic resonance imaging (CT/MRI), and messenger RNA (mRNA) quantification was performed by polymerase chain reaction (PCR; NETest score: 0-100; normal ≤20). Statistical analyses were performed using the Mann-Whitney U-test, Chi-square test, Kaplan-Meier survival, and area under the receiver operating characteristic curve (AUROC), as appropriate. Data are presented as mean ± standard deviation.
The NET cohort (n = 153) included 57 patients with pancreatic cancer, 62 patients with small bowel cancer, 27 patients with lung cancer, 4 patients with duodenal cancer, and 3 patients with gastric cancer, while the surgical cohort comprised patients with R0 (n = 102) and R1 and R2 (n = 51) resection. The mean follow-up time was 14 months (range 3-68). The NETest was positive in 153/153 (100%) samples preoperatively (mean levels of 68 ± 28). In the R0 cohort, POD30 levels decreased from 62 ± 28 to 22 ± 20 (p < 0.0001), but remained elevated in 30% (31/102) of patients: 28% lung, 29% pancreas, 27% small bowel, and 33% gastric. By 18 months, 25/31 (81%) patients with a POD30 NETest >20 had image-identifiable recurrence. An NETest score of >20 predicted recurrence with 100% sensitivity and correlated with residual disease (Chi-square 17.1, p < 0.0001). AUROC analysis identified an AUC of 0.97 (p < 0.0001) for recurrence-prediction. In the R1 (n = 29) and R2 (n = 22) cohorts, the score decreased (R1: 74 ± 28 to 45 ± 24, p = 0.0012; R2: 72 ± 24 to 60 ± 28, p = non-significant). At POD30, 100% of NETest scores were elevated despite surgery (p < 0.0001).
The preoperative NETest accurately identified all NETs (100%). All resections decreased NETest levels and a POD30 NETest score >20 predicted radiologically recurrent disease with 94% accuracy and 100% sensitivity. R0 resection appears to be ineffective in approximately 30% of patients. NET mRNA blood levels provide early objective genomic identification of residual disease and may facilitate management.
手术是神经内分泌肿瘤（NETs）的唯一治愈方法，R0 切除对于成功切除肿瘤至关重要。早期发现残留疾病是最佳管理的关键，但影像学和当前的生物标志物在手术后均无效。NETest 是一种多基因血液生物标志物，其对 NETs 的识别准确率超过 90%。我们假设手术后 NETest 水平会降低，手术后升高的分数会预测复发。
这是一项对接受手术治疗的原发性 NETs（n=153）的多中心评估。在手术当天和术后第 30 天（POD30）进行采血。随访包括计算机断层扫描/磁共振成像（CT/MRI），通过聚合酶链反应（PCR）进行信使 RNA（mRNA）定量（NETest 评分：0-100；正常范围≤20）。使用 Mann-Whitney U 检验、卡方检验、Kaplan-Meier 生存分析和接受者操作特征曲线（AUROC）下的面积进行适当的统计分析。数据以平均值±标准差表示。
NET 队列（n=153）包括 57 例胰腺癌患者、62 例小肠癌患者、27 例肺癌患者、4 例十二指肠癌患者和 3 例胃癌患者，而手术队列包括 R0（n=102）和 R1 和 R2（n=51）切除患者。中位随访时间为 14 个月（范围 3-68）。NETest 在术前 153/153（100%）样本中呈阳性（平均水平为 68±28）。在 R0 队列中，POD30 水平从 62±28 降至 22±20（p<0.0001），但仍有 30%（31/102）的患者升高：28%的肺癌、29%的胰腺癌、27%的小肠癌和 33%的胃癌。到 18 个月时，31 例（81%）POD30 NETest>20 的患者有影像学可识别的复发。NETest 评分>20 预测复发的敏感性为 100%，与残留疾病相关（卡方检验 17.1，p<0.0001）。AUROC 分析确定了 0.97（p<0.0001）的复发预测 AUC。在 R1（n=29）和 R2（n=22）队列中，评分下降（R1：74±28 降至 45±24，p=0.0012；R2：72±24 降至 60±28，p=无显著性差异）。在 POD30，尽管进行了手术，但 100%的 NETest 评分仍升高（p<0.0001）。
术前 NETest 准确识别了所有 NETs（100%）。所有切除均降低了 NETest 水平，POD30 的 NETest 评分>20 预测影像学复发性疾病的准确率为 94%，敏感性为 100%。R0 切除在大约 30%的患者中似乎无效。NET mRNA 血液水平可早期提供残留疾病的客观基因组识别，并可能有助于管理。
