Thoracic Oncology, Aberdeen Royal Infirmary, University of Aberdeen, Aberdeen, United Kingdom.
J Thorac Oncol. 2013 Jul;8(7):930-9. doi: 10.1097/JTO.0b013e318292c500.
In retrospective analyses of patients with nonsquamous non-small-cell lung cancer treated with pemetrexed, low thymidylate synthase (TS) expression is associated with better clinical outcomes. This phase II study explored this association prospectively at the protein and mRNA-expression level.
Treatment-naive patients with nonsquamous non-small-cell lung cancer (stage IIIB/IV) had four cycles of first-line chemotherapy with pemetrexed/cisplatin. Nonprogressing patients continued on pemetrexed maintenance until progression or maximum tolerability. TS expression (nucleus/cytoplasm/total) was assessed in diagnostic tissue samples by immunohistochemistry (IHC; H-scores), and quantitative reverse-transcriptase polymerase chain reaction. Cox regression was used to assess the association between H-scores and progression-free/overall survival (PFS/OS) distribution estimated by the Kaplan-Meier method. Maximal χ² analysis identified optimal cutpoints between low TS- and high TS-expression groups, yielding maximal associations with PFS/OS.
The study enrolled 70 patients; of these 43 (61.4%) started maintenance treatment. In 60 patients with valid H-scores, median (m) PFS was 5.5 (95% confidence interval [CI], 3.9-6.9) months, mOS was 9.6 (95% CI, 7.3-15.7) months. Higher nuclear TS expression was significantly associated with shorter PFS and OS (primary analysis IHC, PFS: p < 0.0001; hazard ratio per 1-unit increase: 1.015; 95%CI, 1.008-1.021). At the optimal cutpoint of nuclear H-score (70), mPFS in the low TS- versus high TS-expression groups was 7.1 (5.7-8.3) versus 2.6 (1.3-4.1) months (p = 0.0015; hazard ratio = 0.28; 95%CI, 0.16-0.52; n = 40/20). Trends were similar for cytoplasm H-scores, quantitative reverse-transcriptase polymerase chain reaction and other clinical endpoints (OS, response, and disease control).
The primary endpoint was met; low TS expression was associated with longer PFS. Further randomized studies are needed to explore nuclear TS IHC expression as a potential biomarker of clinical outcomes for pemetrexed treatment in larger patient cohorts.
在接受培美曲塞治疗的非鳞状非小细胞肺癌患者的回顾性分析中，低胸苷酸合成酶（TS）表达与更好的临床结局相关。这项 II 期研究前瞻性地在蛋白质和 mRNA 表达水平上探讨了这种相关性。
未经治疗的非鳞状非小细胞肺癌（III B/IV 期）患者接受培美曲塞/顺铂一线化疗 4 个周期。无进展的患者继续接受培美曲塞维持治疗，直至进展或达到最大耐受。采用免疫组织化学（IHC；H 评分）评估诊断组织样本中的 TS 表达（核/胞质/总），并进行定量逆转录聚合酶链反应。Cox 回归用于评估 H 评分与 Kaplan-Meier 法估计的无进展/总生存（PFS/OS）分布之间的关联。最大 χ²分析确定低 TS-和高 TS-表达组之间的最佳截断点，从而与 PFS/OS 产生最大关联。
该研究纳入了 70 例患者；其中 43 例（61.4%）开始维持治疗。在 60 例具有有效 H 评分的患者中，中位（m）PFS 为 5.5 个月（95%置信区间[CI]，3.9-6.9），mOS 为 9.6 个月（95%CI，7.3-15.7）。核 TS 表达越高，PFS 和 OS 越短（主要分析 IHC，PFS：p < 0.0001；每增加 1 个单位的危险比：1.015；95%CI，1.008-1.021）。在核 H 评分的最佳截断点（70）处，低 TS-组与高 TS-组的 mPFS 分别为 7.1 个月（5.7-8.3）和 2.6 个月（1.3-4.1）（p = 0.0015；危险比=0.28；95%CI，0.16-0.52；n = 40/20）。细胞质 H 评分、定量逆转录聚合酶链反应和其他临床终点（OS、反应和疾病控制）也存在类似的趋势。
主要终点达到；低 TS 表达与更长的 PFS 相关。需要进一步的随机研究来探索核 TS IHC 表达作为培美曲塞治疗更大患者队列的潜在临床结局生物标志物。
