Dowlati A, Lipka M B, McColl K, Dabir S, Behtaj M, Kresak A, Miron A, Yang M, Sharma N, Fu P, Wildey G
Division of Hematology and Oncology
Division of Hematology and Oncology.
Ann Oncol. 2016 Apr;27(4):642-7. doi: 10.1093/annonc/mdw005. Epub 2016 Jan 22.
Genomic studies in small-cell lung cancer (SCLC) lag far behind those carried out in nonsmall-cell lung cancer (NSCLC). To date, most SCLC studies have evaluated patients with surgically resectable disease. Here we sought to evaluate the genomic mutation spectrum of 'every-day' SCLC patient tumors with extensive stage disease (ES-SCLC) and to correlate mutations with the main clinical outcomes of response to chemotherapy, progression-free (PFS) and overall (OS) survival.
A total of 50 SCLC patient tumors were examined in this study; targeted exome sequencing was obtained on 42 patients and whole-exome sequencing on 8 patients. Mutated genes were correlated with clinical outcomes using Kaplan-Meier methods (PFS, OS) and logistic regression (chemo-response). RB1 protein expression was detected by either western blotting of cultured cell lysates or immunohistochemistry of tumor specimens.
In all, 39 patients had ES-SCLC; 15 patients had either primary refractory/resistant disease and 21 patients had sensitive disease. The two most frequently mutated genes were TP53 (86%) and RB1 (58%); other frequently mutated genes (>10% patients) were involved in epigenetic regulation as well as the mTOR pathway. We identified a number of low-frequency, targetable mutations, including RICTOR, FGFR1, KIT, PTCH1 and RET. Using multivariate analysis, RB1 was the only significant factor (P = 0.038) in predicting response to first-line chemotherapy, with an odds ratio of 5.58 comparing mutant RB1 with wild-type. Patients with mutant RB1 had both better OS (11.7 versus 9.1 months P = 0.04) and PFS (11.2 versus 8.6 months, P = 0.06) compared with patients with wild-type RB1. Interestingly, ∼25% of SCLC cell lines and tumor specimens expressed RB1 protein, possibly representing the subgroup with wild-type RB1.
We found that SCLC tumors harboring no mutation in RB1 had a poor response to chemotherapy.
小细胞肺癌（SCLC）的基因组研究远远落后于非小细胞肺癌（NSCLC）。迄今为止，大多数SCLC研究评估的是可手术切除疾病的患者。在此，我们试图评估广泛期疾病（ES-SCLC）的“日常”SCLC患者肿瘤的基因突变谱，并将突变与化疗反应、无进展生存期（PFS）和总生存期（OS）等主要临床结局相关联。
本研究共检测了50例SCLC患者的肿瘤；对42例患者进行了靶向外显子组测序，8例患者进行了全外显子组测序。使用Kaplan-Meier方法（PFS、OS）和逻辑回归（化疗反应）将突变基因与临床结局相关联。通过对培养细胞裂解物进行蛋白质印迹或对肿瘤标本进行免疫组织化学检测RB1蛋白表达。
总共39例患者患有ES-SCLC；15例患者患有原发性难治/耐药疾病，21例患者患有敏感疾病。两个最常发生突变的基因是TP53（86%）和RB1（58%）；其他频繁突变的基因（>10%的患者）涉及表观遗传调控以及mTOR通路。我们鉴定出一些低频的、可靶向的突变，包括RICTOR、FGFR1、KIT、PTCH1和RET。使用多变量分析，RB1是预测一线化疗反应的唯一显著因素（P = 0.038），突变型RB1与野生型相比的优势比为5.58。与野生型RB1患者相比，突变型RB1患者的OS（11.7个月对9.1个月，P = 0.04）和PFS（11.2个月对8.6个月，P = 0.06）均更好。有趣的是，约25%的SCLC细胞系和肿瘤标本表达RB1蛋白，可能代表野生型RB1亚组。
我们发现RB1无突变的SCLC肿瘤对化疗反应较差。
