Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.
Department of Pathology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.
Oncologist. 2020 Jul;25(7):e1021-e1030. doi: 10.1634/theoncologist.2019-0419. Epub 2020 Feb 14.
The use of microsatellite instability (MSI) and mismatch repair (MMR) as predictive biomarkers for fluorouracil-based adjuvant chemotherapy in colorectal cancer has been a paradigm shift. However, whether this applies to gastric cancer is questionable. Furthermore, we herein investigated whether and how autophagy plays a role in MSI-relevant chemoresistance.
A total of 929 patients with deficient MMR (dMMR) and proficient MMR (pMMR) gastric cancers who underwent curative-intent gastrectomy were enrolled. We compared clinicopathological variables and survival among dMMR and pMMR cohorts and tested the responses of MSI-high and microsatellite stable (MSS) gastric cancer cell lines to 5-fluorouracil (5-FU) with or without chloroquine, an autophagy inhibitor.
We identified an 8.9% prevalence of dMMR cases (83 out of 929) in our cohort. This was associated with old age, tumor site at the distal stomach, an intestinal phenotype, fewer nodal metastasis, and early pathological stages. MMR was an independent prognostic factor after multivariate adjustment. Overall survival (OS) of dMMR patients was better than that of the pMMR patients but was only applicable to stage III patients. There was no difference in OS between dMMR patients treated with or without adjuvant chemotherapy, although the latter showed more medical morbidities. The MSI-high gastric cancer cell lines, versus the MSS counterparts, displayed increased resistance to 5-FU and increased autophagy. Interestingly, autophagy inhibition abrogated the chemoresistance.
Our data show that fluorouracil-based adjuvant chemotherapy does not work for dMMR cases, if not worse. Autophagy inhibition and/or immune checkpoint inhibition might be promising alternative strategies for gastric cancer treatment.
The use of microsatellite instability (MSI) and mismatch repair (MMR) as predictive biomarkers for adjuvant chemotherapy in colorectal cancer has caused a paradigm shift in cancer therapy, although its implications in gastric cancer are still questionable. The data obtained in the current study indicate that MSI-MMR is an independent prognostic factor for gastric cancer. Standard fluorouracil-based adjuvant chemotherapy did not work for deficient MMR cases, and was likely worse. Instead, strategies like autophagy inhibition and/or immune checkpoint inhibition should be taken into consideration in the future.
将微卫星不稳定性（MSI）和错配修复（MMR）作为结直肠癌氟尿嘧啶辅助化疗的预测生物标志物已经是一个范式转变。然而，这是否适用于胃癌仍存在疑问。此外，我们在此研究了自噬在 MSI 相关化疗耐药中的作用机制。
共纳入 929 例经根治性胃切除术治疗的缺陷型 MMR（dMMR）和功能型 MMR（pMMR）胃癌患者。我们比较了 dMMR 和 pMMR 两组的临床病理变量和生存情况，并检测了 MSI 高和微卫星稳定（MSS）胃癌细胞系对氟尿嘧啶（5-FU）的反应，以及是否存在氯喹（一种自噬抑制剂）。
我们在队列中发现了 8.9%的 dMMR 病例（929 例中有 83 例）。这与老年、远端胃肿瘤部位、肠型表型、较少的淋巴结转移和较早的病理分期有关。在多变量调整后，MMR 是一个独立的预后因素。dMMR 患者的总生存期（OS）优于 pMMR 患者，但仅适用于 III 期患者。dMMR 患者接受或不接受辅助化疗的 OS 无差异，尽管后者的医疗并发症更多。MSI 高的胃癌细胞系与 MSS 细胞系相比，对 5-FU 的耐药性增加，自噬增加。有趣的是，自噬抑制消除了耐药性。
我们的数据表明，如果不是更糟的话，氟尿嘧啶为基础的辅助化疗对 dMMR 病例无效。自噬抑制和/或免疫检查点抑制可能是胃癌治疗的有前途的替代策略。
将微卫星不稳定性（MSI）和错配修复（MMR）作为结直肠癌辅助化疗的预测生物标志物已经在癌症治疗中引起了范式转变，尽管其在胃癌中的意义仍存在疑问。本研究获得的数据表明，MSI-MMR 是胃癌的一个独立预后因素。标准的氟尿嘧啶为基础的辅助化疗对 dMMR 病例无效，而且可能更糟。相反，未来应该考虑自噬抑制和/或免疫检查点抑制等策略。
