Department of Endocrinology and Nutrition, Germans Trias i Pujol University Hospital, Badalona, Spain.
Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain.
Endocr Relat Cancer. 2020 Jun;27(6):375-389. doi: 10.1530/ERC-18-0565.
Pharmacologic treatment of acromegaly is currently based upon assay-error strategy, the first-generation somatostatin receptor ligands (SRL) being the first-line treatment. However, about 50% of patients do not respond adequately to SRL. Our objective was to evaluate the potential usefulness of different molecular markers as predictors of response to SRL. We used somatotropinoma tissue obtained after surgery from a national cohort of 100 acromegalic patients. Seventy-one patients were treated with SRL during at least 6 months under maximal therapeutic doses according to IGF1 values. We analyzed the expression of SSTR2, SSTR5, AIP, CDH1 (E-cadherin), MKI67 (Ki-67), KLK10, DRD2, ARRB1, GHRL, In1-Ghrelin, PLAGL1 and PEBP1 (RKIP) by RT-qPCR and mutations in GNAS gene by Sanger sequencing. The response to SRL was categorized as complete response (CR), partial (PR) or non-response (NR) if IGF1 was normal, between >2<3 SDS or >3 SDS IGF1 at 6 months of follow-up, respectively. From the 71 patients treated, there were 27 CR (38%), 18 PR (25%) and 26 NR (37%). SSTR2, Ki-67 and E-cadherin were associated with SRL response (P < 0.03, P < 0.01 and P < 0.003, respectively). E-cadherin was the best discriminator for response prediction (AUC = 0.74, P < 0.02, PPV of 83.7%, NPV of 72.6%), which was validated at protein level. SSTR5 expression was higher in patients pre-treated with SRL before surgery. We conclude that somatotropinomas showed heterogeneity in the expression of genes associated with SRL response. E-cadherin was the best molecular predictor of response to SRL. Thus, the inclusion of E-cadherin in subsequent treatment-decision after surgical failure may be useful in acromegaly.
肢端肥大症的药物治疗目前基于检测误差策略，第一代生长抑素受体配体（SRL）是一线治疗药物。然而，约 50%的患者对 SRL 反应不充分。我们的目的是评估不同分子标志物作为 SRL 反应预测因子的潜在有用性。我们使用了来自全国肢端肥大症患者队列的 100 例患者的手术获得的生长激素瘤组织。71 例患者在 IGF1 值的最大治疗剂量下接受 SRL 治疗至少 6 个月。我们通过 RT-qPCR 分析了 SSTR2、SSTR5、AIP、CDH1（E-钙黏蛋白）、MKI67（Ki-67）、KLK10、DRD2、ARRB1、GHRL、In1-Ghrelin、PLAGL1 和 PEBP1（RKIP）的表达，并通过 Sanger 测序分析了 GNAS 基因突变。如果 IGF1 正常、6 个月随访时 IGF1 介于>2<3 SDS 或 >3 SDS，则将 SRL 反应分为完全缓解（CR）、部分缓解（PR）或无反应（NR）。在接受治疗的 71 例患者中，有 27 例 CR（38%）、18 例 PR（25%）和 26 例 NR（37%）。SSTR2、Ki-67 和 E-钙黏蛋白与 SRL 反应相关（P < 0.03、P < 0.01 和 P < 0.003）。E-钙黏蛋白是预测反应的最佳鉴别器（AUC = 0.74，P < 0.02，PPV 为 83.7%，NPV 为 72.6%），并在蛋白质水平上得到验证。SSTR5 的表达在手术前接受过 SRL 预处理的患者中更高。我们得出结论，生长激素瘤在与 SRL 反应相关的基因表达方面存在异质性。E-钙黏蛋白是 SRL 反应的最佳分子预测因子。因此，在手术失败后，将 E-钙黏蛋白纳入后续治疗决策中可能对肢端肥大症有用。
