Background: The randomized phase III study (WJOG4407G) showed equivalent efficacy between FOLFOX and FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (mCRC). We studied whole genome copy number profiles using array-based comparative genomic hybridization (aCGH) analysis of tumor tissue samples obtained in this study. The aim of this study was to identify gene copy number alterations that could aid in selecting either FOLFOX or FOLFIRI in combination with bevacizumab for patients with mCRC.
Materials and methods: DNA was purified from 154 pretreatment formalin-fixed paraffin-embedded tissue samples (75 from the FOLFOX arm and 79 from the FOLFIRI arm) of 395 patients enrolled in the WJOG4407G trial and analyzed by aCGH. Genomic regions greater than 1.2-fold were regarded as copy number gain (CNG).
Results: Patient characteristics between the treatment arms were well balanced except for tumor laterality (left side; 64% in FOLFOX arm and 80% in FOLFIRI arm, p = .07). FOLFIRI showed a trend toward better response rate (RR), progression-free survival (PFS) and overall survival (OS) than FOLFOX in the patients with CNG of chromosome 8q24.1 (Fisher's exact test, p = .134 for RR; interaction test, p = .102 for PFS and p = .003 for OS) and 8q24.2 (Fisher's exact test, p = .179 for RR; interaction test, p = .144 for PFS and p = .002 for OS).
Conclusion: Chromosome 8q24.1-q24.2 may contain genes that could potentially serve as predictive markers for selecting either FOLFOX or FOLFIRI in combination with bevacizumab for treatment of patients with mCRC.
Implications for practice: Bevacizumab has been used as a standard first-line treatment for patients with metastatic colorectal cancer (mCRC) in combination with either oxaliplatin-based or irinotecan-based chemotherapy. Until now, there has been no predictive marker to choose between the two combination chemotherapies. This array-based comparative genomic hybridization analysis revealed that the difference in therapeutic effect between the two combination chemotherapies is prominent in patients with mCRC with gene copy number gain in chromosome 8p24.1-p24.2. Such patients showed more favorable response and survival when treated with irinotecan-based combination chemotherapy. Overlapping genes commonly found in this region may be predictive biomarkers of the efficacy of the combination chemotherapy with bevacizumab.
摘要
背景。随机 III 期研究(WJOG4407G)显示 FOLFOX 和 FOLFIRI 联合贝伐珠单抗作为转移性结直肠癌(mCRC)的一线治疗具有相同的疗效。我们使用在该研究中获得的肿瘤组织样本的基于阵列的比较基因组杂交(aCGH)分析研究全基因组拷贝数分布图。本研究的目的是确定基因拷贝数的改变，这有助于为 mCRC 患者选择 FOLFOX 或 FOLFIRI 联合贝伐珠单抗。
材料和方法。从参与 WJOG4407G 试验的 395 名患者的 154 个治疗前福尔马林固定的石蜡包埋的组织样本(75 个来自 FOLFOX 组，79 个来自 FOLFIRI 组)中纯化 DNA，并进行 aCGH 分析。大于 1.2 倍的基因组区域被认为是拷贝数增加(CNG)。
结果。除肿瘤位置(左侧；FOLFOX 组为 64%，FOLFIRI 组为 80%，p = 0.07)外，治疗组之间的患者特征良好均衡。在染色体 8q24.1 [Fisher 精确检验，反应率(RR) 的 p 值 = 0.134；交互测试，无进展生存期(PFS) 的 p 值 = 0.102，总生存期(OS) 的 p 值 = 0.003]和 8q24.2(Fisher 精确检验，RR 的 p 值 = 0.179；交互测试，PFS 的 p 值 = 0.144 ，OS 的 p 值 = 0.002)的 CNG 患者中，FOLFIRI 显示出比 FOLFOX 更好的RR、PFS和OS的趋势。
结论。染色体 8q24.1 ‐ q24.2 含有可能作为预测标志物的基因，用于选择 FOLFOX 或 FOLFIRI 与贝伐珠单抗联合以治疗mCRC 患者。
对实践的启示:贝伐珠单抗已被用作转移性结直肠癌(mCRC)患者的标准一线治疗，与基于奥沙利铂或基于伊立替康的化学疗法相结合。到目前为止，还没有预测标志物可以在两种联合化疗之间进行选择。这种基于阵列的比较基因组杂交分析显示，在具有染色体 8p24.1‐p24.2 的基因拷贝数增加的 mCRC 患者中，两种联合化疗之间的治疗效果差异显著。当使用基于伊立替康的联合化疗治疗时，这些患者表现出更有利的反应和生存率。通常在该区域中发现的重叠基因可能是贝伐珠单抗联合化疗的功效的预测性生物标志物。
Keywords: Bevacizumab; Colorectal cancer; Irinotecan; Oxaliplatin; aCGH analysis.
© AlphaMed Press 2018.