Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York;
Department of Radiology, Weill Cornell Medical College, New York, New York.
J Nucl Med. 2023 Apr;64(4):567-573. doi: 10.2967/jnumed.122.264363. Epub 2022 Nov 17.
Reliable biomarkers for neuroendocrine tumor (NET) management during peptide receptor radionuclide therapy (PRRT) are lacking. We validated the role of 2 circulating biomarkers: the PRRT prediction quotient (PPQ) as a predictive marker for response and the NETest as a monitoring biomarker. Furthermore, we evaluated whether tissue-based genetic alterations are effective in predicting progression-free survival (PFS). Data were prospectively collected on patients at the Memorial Sloan Kettering Cancer Center with Lu-DOTATATE-treated somatostatin receptor (SSTR)-positive gastroenteropancreatic and lung NETs ( = 67; median age, 66 y; 52% female; 42% pancreatic, 39% small-bowel; 78% grade 1 or 2). All cases were metastatic (89% liver) and had received 1-8 prior treatments (median, 3), including somatostatin analogs (91%), surgery (55%), or chemotherapy (49%). Treatment response included PFS. According to RECIST, version 1.1, responders had stable disease or a partial response (disease-control rate) and nonresponders had progression. Blood was collected before each cycle and at follow-up. Samples were deidentified and assayed and underwent masked analyses. The gene expression assays included RNA isolation, real-time quantitative polymerase chain reaction, and multialgorithm analyses. The PPQ (positive predicts a responder; negative predicts a nonresponder) at baseline was determined. The NETest (0-100 score) was performed. Statistics were analyzed using Mann-Whitney testing (2-tailed) or Kaplan-Meier survival testing (PFS). In patients with archival tumor tissue, next-generation sequencing was performed through an institutional platform (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets). Forty-one patients (61%) were responders. PPQ accurately predicted 96% (64/67). The hazard ratio for prediction was 24.4 (95% CI, 8.2-72.5). Twelve-month disease control was 97% for PPQ-positive patients versus 26% for PPQ-negative patients ( < 0.0001). Median progression-free survival was not reached in those predicted to respond (PPQ-positive, = 40) but was 8 mo in those predicted not to respond (PPQ-negative, = 27). The NETest result in responders was 67 ± 25 at baseline and significantly ( < 0.05) decreased (-37 ± 44%) at follow-up. The NETest result in nonresponders was 44 ± 23 at baseline and significantly ( < 0.05) increased (+76% ± 56%) at progression. Overall, the NETest changes (increases or decreases) were 90% accurate. Thirty patients underwent next-generation sequencing. Tumors were microsatellite-stable, and the median mutational burden was 1.8. Alterations involved mainly the mTOR/PTEN/TSC pathway (30%). No relationship was associated with PRRT response. Our interim analysis confirmed that PPQ is an accurate predictor of Lu-DOTATATE responsiveness (radiosensitivity) and that NETest changes accurately correlated with treatment response. Tissue-based molecular genetic information had little value in PRRT prediction. Blood-based gene signatures may improve the management of patients undergoing Lu-DOTATATE by providing information on tumor radiosensitivity and disease course, thus allowing individualized strategies.
用于神经内分泌肿瘤 (NET) 管理的肽受体放射性核素治疗 (PRRT) 的可靠生物标志物仍然缺乏。我们验证了两种循环生物标志物的作用：PRRT 预测商 (PPQ) 作为预测反应的标志物和 NETest 作为监测生物标志物。此外，我们评估了组织中遗传改变是否能有效预测无进展生存期 (PFS)。数据是前瞻性收集的，来自纪念斯隆凯特琳癌症中心的 Lu-DOTATATE 治疗的 somatostatin 受体 (SSTR) 阳性胃肠胰和肺 NET 患者（ = 67；中位年龄 66 岁；52%为女性；42%为胰腺，39%为小肠；78%为 1 级或 2 级）。所有病例均为转移性（89%为肝脏），并接受了 1-8 次先前治疗（中位数 3 次），包括 somatostatin 类似物（91%）、手术（55%）或化疗（49%）。治疗反应包括 PFS。根据 RECIST 1.1 版，应答者为疾病稳定或部分缓解（疾病控制率），无应答者为进展。在每个周期之前和随访时采集血液。样本被去识别并进行检测，并进行了盲法分析。基因表达检测包括 RNA 分离、实时定量聚合酶链反应和多算法分析。基线时确定了 PPQ（阳性预测应答者；阴性预测无应答者）。进行了 NETest（0-100 分）。使用 Mann-Whitney 检验（双侧）或 Kaplan-Meier 生存检验（PFS）进行统计分析。在有存档肿瘤组织的患者中，通过机构平台（纪念斯隆凯特琳综合行动癌症靶基因突变分析）进行了下一代测序。41 例（61%）患者为应答者。PPQ 准确预测 96%（64/67）。预测的风险比为 24.4（95%CI，8.2-72.5）。PPQ 阳性患者的 12 个月疾病控制率为 97%，而 PPQ 阴性患者为 26%（ < 0.0001）。预测为应答者的患者无进展生存期未达到（PPQ 阳性， = 40），而预测为无应答者的患者为 8 个月（PPQ 阴性， = 27）。应答者的 NETest 结果在基线时为 67±25，随访时显著（ < 0.05）下降（-37±44%）。无应答者的 NETest 结果在基线时为 44±23，在进展时显著（ < 0.05）增加（+76%±56%）。总体而言，NETest 变化（增加或减少）的准确率为 90%。30 名患者接受了下一代测序。肿瘤为微卫星稳定，中位突变负担为 1.8。改变主要涉及 mTOR/PTEN/TSC 通路（30%）。与 PRRT 反应无关联。我们的中期分析证实，PPQ 是 Lu-DOTATATE 反应性（放射敏感性）的准确预测指标，NETest 变化与治疗反应准确相关。组织分子遗传信息在 PRRT 预测中价值有限。基于血液的基因特征可能通过提供肿瘤放射敏感性和疾病过程的信息，从而允许个体化的策略，从而改善接受 Lu-DOTATATE 治疗的患者的管理。
