Medical Prognosis Institute A/S, Hoersholm, Denmark.
Section for Molecular Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
PLoS One. 2018 Mar 22;13(3):e0194609. doi: 10.1371/journal.pone.0194609. eCollection 2018.
Effective predictive biomarkers for selection of patients benefiting from adjuvant platinum-based chemotherapy in non-small cell lung cancer (NSCLC) are needed. Based on a previously validated methodology, molecular profiles of predicted sensitivity in two patient cohorts are presented.
The profiles are correlations between in vitro sensitivity to cisplatin and vinorelbine and baseline mRNA expression of the 60 cell lines in the National Cancer Institute panel. An applied clinical samples filter focused the profiles to clinically relevant genes. The profiles were tested on 1) snap-frozen tumors from 133 patients with completely resected stage 1B-2 NSCLC randomized to adjuvant cisplatin and vinorelbine (ACV, n = 71) or no adjuvant treatment (OBS, n = 62) and 2) formalin-fixed paraffin-embedded (FFPE) tumors from 95 patients with completely resected stage 1A-3B NSCLC receiving adjuvant cisplatin and vinorelbine.
The combined cisplatin and vinorelbine profiles showed: 1) univariate Hazard Ratio (HR) for sensitive versus resistant of 0.265 (95% CI:0.079-0.889, p = 0.032) in the ACV cohort and a HR of 0.28 in a multivariate model (95% CI:0.08-1.04, p = 0.0573); 2) significant prediction at 3 year survival from surgery in univariate (HR = 0.138 (95% CI:0.035-0.537), p = 0.004) and multivariate analysis (HR = 0.14 (95% CI:0.030-0.6), p = 0.0081). No discrimination was found in the OBS cohort (HR = 1.328, p = 0.60). The cisplatin predictor alone had similar figures with 1) univariate HR of 0.37 (95% CI:0.12-1.15, p = 0.09) in the ACV cohort and 2) univariate HR of 0.14 (95% CI:0.03-0.59, p = 0.0076) to three years. Functional analysis on the cisplatin profile revealed a group of upregulated genes related to RNA splicing as a part of DNA damage repair and apoptosis.
Profiles derived from snap-frozen and FFPE NSCLC tissue were prognostic and predictive in the patients that received cisplatin and vinorelbine but not in the cohort that did not receive adjuvant treatment.
需要有效的预测生物标志物来选择从非小细胞肺癌（NSCLC）辅助铂类化疗中获益的患者。基于以前验证的方法，呈现了两个患者队列中预测敏感性的分子谱。
这些谱是体外顺铂和长春瑞滨敏感性与国家癌症研究所小组中 60 个细胞系的基线 mRNA 表达之间的相关性。应用临床样本筛选器将谱聚焦于临床相关基因。在 1）接受完全切除的 1B-2 期 NSCLC 随机分配至辅助顺铂和长春瑞滨（ACV，n = 71）或无辅助治疗（OBS，n = 62）的 133 名患者的冷冻肿瘤和 2）接受完全切除的 1A-3B 期 NSCLC 并接受辅助顺铂和长春瑞滨的 95 名患者的福尔马林固定石蜡包埋（FFPE）肿瘤上测试了这些谱。
联合顺铂和长春瑞滨的图谱显示：1）在 ACV 队列中，敏感与耐药的单变量风险比（HR）为 0.265（95%CI：0.079-0.889，p = 0.032），多变量模型中的 HR 为 0.28（95%CI：0.08-1.04，p = 0.0573）；2）在单变量（HR = 0.138（95%CI：0.035-0.537），p = 0.004）和多变量分析（HR = 0.14（95%CI：0.030-0.6），p = 0.0081）中，手术 3 年生存的显著预测。在 OBS 队列中未发现差异（HR = 1.328，p = 0.60）。单独的顺铂预测因子也具有类似的结果，在 ACV 队列中，1）单变量 HR 为 0.37（95%CI：0.12-1.15，p = 0.09），2）单变量 HR 为 0.14（95%CI：0.03-0.59，p = 0.0076）至 3 年。对顺铂图谱的功能分析显示，一组上调的基因与 RNA 剪接有关，这是 DNA 损伤修复和细胞凋亡的一部分。
从冷冻和 FFPE NSCLC 组织中得出的图谱在接受顺铂和长春瑞滨治疗的患者中具有预后和预测价值，但在未接受辅助治疗的患者中则没有。
