Prognostic implication of molecular subtypes and response to neoadjuvant chemotherapy in 760 gastric carcinomas: role of Epstein-Barr virus infection and high- and low-microsatellite instability
Prognostic implication of molecular subtypes and response to neoadjuvant chemotherapy in 760 gastric carcinomas: role of Epstein-Barr virus infection and high- and low-microsatellite instability
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DOI：
10.1002/cjp2.137
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发表时间：
2019-10-01
影响因子：
4.1
通讯作者：
Keller, Gisela
中科院分区：
文献类型：
--
作者：
Kohlruss, Meike;Grosser, Bianca;Keller, Gisela
EB病毒阳性（EBV（+））和高微卫星不稳定性（MSI-H）是胃癌的分子亚型。我们研究的目的是确定这些亚组在铂/5-氟尿嘧啶（5-FU）为基础的术前化疗（CTx）的背景下的预后和预测相关性。此外，我们研究了低MSI（MSI-L）表型的临床相关性。我们分析了760例胃腺癌或胃食管交界处腺癌，包括143例CTx前活检和617例切除肿瘤（291例未切除，326例CTx后切除）。用PCR和原位杂交方法检测EB病毒。利用5个微卫星标记对MSI进行PCR分析，并将其分为MSI-H和MSI-L。CTx前活检标本中EBV（+）、MSI-H和MSI-L的频率分别为4.2%、10.5%和4.9%。EBV（+）或MSI-H与缓解无关，但MSI-L与更好的缓解相关（p = 0.011）。在切除的肿瘤中，EBV（+）、MSI-H和MSI-L的频率分别为3.9%、9.6%和4.5%。非CTx组的总生存期（OS）显著不同（p = 0.014）。EBV（+）肿瘤患者的OS最好，其次是MSI-H。MSI-L与OS恶化显著相关（风险比[HR]，2.21; 95%置信区间[CI]，1.21-4.04，p = 0.01）。在CTx后切除的肿瘤中，MSI-H也与OS增加相关（HR，0.54; 95% CI，0.26-1.09，p = 0.085）。在多变量分析中，分子分类是完全切除（R 0）非CTx组的独立预后因素（p = 0.035）。总之，MSI-H和EBV（+）不能预测新辅助铂类/5-FU CTx的应答，但它们表明预后良好。特别是，MSI-H表明无论用CTx治疗如何都有良好的预后。MSI-L预测对CTx的良好反应，其对单独接受手术治疗的患者的负面预后影响表明MSI-L可能有助于识别从术前CTx中潜在高获益的患者。
Epstein-Barr virus positivity (EBV(+)) and high-microsatellite instability (MSI-H) have been identified as molecular subgroups in gastric carcinoma. The aim of our study was to determine the prognostic and predictive relevance of these subgroups in the context of platinum/5-fluorouracil (5-FU) based preoperative chemotherapy (CTx). Additionally, we investigated the clinical relevance of the low-MSI (MSI-L) phenotype. We analysed 760 adenocarcinomas of the stomach or the gastro-oesophageal junction encompassing 143 biopsies before CTx and 617 resected tumours (291 without and 326 after CTx). EBV was determined by PCR and in situ hybridisation for selected cases. MSI was analysed by PCR using five microsatellite markers and classified as MSI-H and MSI-L. Frequencies of EBV(+), MSI-H and MSI-L in the biopsies before CTx were 4.2, 10.5 and 4.9% respectively. EBV(+) or MSI-H did not correlate with response, but MSI-L was associated with better response (p = 0.011). In the resected tumours, frequencies of EBV(+), MSI-H and MSI-L were 3.9, 9.6 and 4.5% respectively. Overall survival (OS) was significantly different in the non-CTx group (p = 0.014). Patients with EBV(+) tumours showed the best OS, followed by MSI-H. MSI-L was significantly associated with worse OS (hazard ratio [HR], 2.21; 95% confidence interval [CI], 1.21-4.04, p = 0.01). In the resected tumours after CTx, MSI-H was also associated with increased OS (HR, 0.54; 95% CI, 0.26-1.09, p = 0.085). In multivariable analysis, molecular classification was an independent prognostic factor in the completely resected (R0) non-CTx group (p = 0.035). In conclusion, MSI-H and EBV(+) are not predictive of response to neoadjuvant platinum/5-FU based CTx, but they are indicative of a good prognosis. In particular, MSI-H indicates a favourable prognosis irrespective of treatment with CTx. MSI-L predicts good response to CTx and its negative prognostic effect for patients treated with surgery alone suggests that MSI-L might help to identify patients with potentially high-benefit from preoperative CTx.