Royal Marsden Hospital, London, UK.
Division of Molecular Pathology, Institute of Cancer Research, London, UK; Centre for Molecular Pathology, Royal Marsden Hospital, London, UK.
Ann Oncol. 2018 Dec 1;29(12):2356-2362. doi: 10.1093/annonc/mdy407.
Following neoadjuvant chemotherapy for operable gastroesophageal cancer, lymph node metastasis is the only validated prognostic variable; however, within lymph node groups there is still heterogeneity with risk of relapse. We hypothesized that gene profiles from neoadjuvant chemotherapy treated resection specimens from gastroesophageal cancer patients can be used to define prognostic risk groups to identify patients at risk for relapse.
The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial (n = 202 with high quality RNA) samples treated with perioperative chemotherapy were profiled for a custom gastric cancer gene panel using the NanoString platform. Genes associated with overall survival (OS) were identified using penalized and standard Cox regression, followed by generation of risk scores and development of a NanoString biomarker assay to stratify patients into risk groups associated with OS. An independent dataset served as a validation cohort.
Regression and clustering analysis of MAGIC patients defined a seven-Gene Signature and two risk groups with different OS [hazard ratio (HR) 5.1; P < 0.0001]. The median OS of high- and low-risk groups were 10.2 [95% confidence interval (CI) of 6.5 and 13.2 months] and 80.9 months (CI: 43.0 months and not assessable), respectively. Risk groups were independently prognostic of lymph node metastasis by multivariate analysis (HR 3.6 in node positive group, P = 0.02; HR 3.6 in high-risk group, P = 0.0002), and not prognostic in surgery only patients (n = 118; log rank P = 0.2). A validation cohort independently confirmed these findings.
These results suggest that gene-based risk groups can independently predict prognosis in gastroesophageal cancer patients treated with neoadjuvant chemotherapy. This signature and associated assay may help risk stratify these patients for post-surgery chemotherapy in future perioperative chemotherapy-based clinical trials.
在可手术的胃食管癌患者接受新辅助化疗后，淋巴结转移是唯一经过验证的预后变量；然而，在淋巴结组内仍然存在异质性，存在复发风险。我们假设，从接受新辅助化疗的胃食管癌患者的手术标本中提取的基因谱可用于定义预后风险组，以识别有复发风险的患者。
英国医学研究理事会辅助胃输注化疗（MAGIC）试验（n=202 例，高质量 RNA）的样本接受围手术期化疗治疗，并用 NanoString 平台对一个定制的胃癌基因进行基因谱分析。使用惩罚和标准 Cox 回归确定与总生存（OS）相关的基因，然后生成风险评分，并开发 NanoString 生物标志物检测以将患者分层为与 OS 相关的风险组。一个独立的数据集作为验证队列。
MAGIC 患者的回归和聚类分析定义了一个七基因签名和两个具有不同 OS 的风险组[危险比（HR）为 5.1；P<0.0001]。高风险和低风险组的中位 OS 分别为 10.2 个月（95%置信区间[CI]为 6.5 至 13.2 个月）和 80.9 个月（CI：43.0 个月和无法评估）。多变量分析显示，风险组独立地预测淋巴结转移的预后（阳性淋巴结组 HR 为 3.6，P=0.02；高风险组 HR 为 3.6，P=0.0002），但在仅接受手术的患者中无预后意义（n=118；对数秩检验 P=0.2）。一个验证队列独立地证实了这些发现。
这些结果表明，基于基因的风险组可独立预测接受新辅助化疗的胃食管癌患者的预后。该签名和相关检测可能有助于在未来基于围手术期化疗的临床试验中对这些患者进行术后化疗的风险分层。
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