Salgia Ravi, Weaver R Waide, McCleod Michael, Stille John R, Yan S Betty, Roberson Stephanie, Polzer John, Flynt Amy, Raddad Eyas, Peek Victoria L, Wijayawardana Sameera R, Um Suzane L, Gross Steve, Connelly Mark C, Morano Carrie, Repollet Madeline, Sanders Renouard, Baeten Kurt, D'Haese David, Spigel David R
City of Hope Comprehensive Cancer Center, 1500 E. Duarte Road, Duarte, CA, 91010-3000, USA.
Florida Cancer Specialists, St. Petersburg, FL, USA.
Invest New Drugs. 2017 Jun;35(3):334-344. doi: 10.1007/s10637-017-0446-z. Epub 2017 Mar 15.
Background Circulating tumor cells (CTCs) and chemokine (C-X-C motif) receptor 4 (CXCR4) expression in CTCs and tumor tissue were evaluated as prognostic or predictive markers of CXCR4 peptide antagonist LY2510924 plus carboplatin-etoposide (CE) versus CE in extensive-stage disease small cell lung cancer (ED-SCLC). Methods This exploratory analysis of a phase II study evaluated CXCR4 expression in baseline tumor tissue and peripheral blood CTCs and in post-treatment CTCs. Optimum cutoff values were determined for CTC counts and CXCR4 expression in tumors and CTCs as predictors of survival outcome. Kaplan-Meier estimates and hazard ratios were used to determine biomarker prognostic and predictive values. Results There was weak positive correlation at baseline between CXCR4 expression in tumor tissue and CTCs. Optimum cutoff values were H-score ≥ 210 for CXCR4 tumor, ≥7% CTCs with CXCR4 expression (CXCR4 CTCs), and ≥6 CTCs/7.5 mL blood. Baseline H-score for CXCR4 tumor was not prognostic of progression-free survival (PFS) or overall survival (OS). Baseline CXCR4 CTCs ≥7% was prognostic of shorter PFS. CTCs ≥6 at baseline and cycle 2, day 1 were prognostic of shorter PFS and OS. None of the biomarkers at their respective optimum cutoffs was predictive of treatment response of LY2510924 plus CE versus CE. Conclusions In patients with ED-SCLC, baseline CXCR4 expression in tumor tissue was not prognostic of survival or predictive of LY2510924 treatment response. Baseline CXCR4 CTCs ≥7% was prognostic of shorter PFS. CTC count ≥6 at baseline and after 1 cycle of treatment were prognostic of shorter PFS and OS.
评估循环肿瘤细胞（CTC）以及CTC和肿瘤组织中趋化因子（C-X-C基序）受体4（CXCR4）的表达，作为CXCR4肽拮抗剂LY2510924联合卡铂-依托泊苷（CE）与单纯CE治疗广泛期小细胞肺癌（ED-SCLC）的预后或预测标志物。方法：这项II期研究的探索性分析评估了基线肿瘤组织和外周血CTC以及治疗后CTC中的CXCR4表达。确定了肿瘤和CTC中CTC计数及CXCR4表达的最佳临界值，作为生存结果的预测指标。采用Kaplan-Meier估计值和风险比来确定生物标志物的预后和预测价值。结果：肿瘤组织和CTC中CXCR4表达在基线时呈弱正相关。CXCR4肿瘤的最佳临界值为H评分≥210，CXCR4表达的CTC≥7%（CXCR4 CTC），以及≥6个CTC/7.5 mL血液。CXCR4肿瘤的基线H评分对无进展生存期（PFS）或总生存期（OS）无预后价值。基线CXCR4 CTC≥7%对较短的PFS具有预后价值。基线及第2周期第1天CTC≥6对较短的PFS和OS具有预后价值。在各自的最佳临界值下，没有一个生物标志物能够预测LY2510924联合CE与单纯CE治疗的反应。结论：在ED-SCLC患者中，肿瘤组织中基线CXCR4表达对生存无预后价值，也不能预测LY2510924的治疗反应。基线CXCR4 CTC≥7%对较短的PFS具有预后价值。基线及1周期治疗后CTC计数≥6对较短的PFS和OS具有预后价值。
