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Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer.
文献信息
| DOI | 10.1038/s41591-018-0101-z |
|---|---|
| PMID | 30013197 |
| 期刊 | Nature medicine |
| 影响因子 | 50.0 |
| JCR 分区 | Q1 |
| 发表年份 | 2018 |
| 被引次数 | 946 |
| 关键词 | PD-1抑制, 转移性胃癌, 分子特征, 循环肿瘤DNA, 生物标志物 |
| 文献类型 | Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't |
| ISSN | 1078-8956 |
| 页码 | 1449-1458 |
| 期号 | 24(9) |
| 作者 | Seung Tae Kim, Razvan Cristescu, Adam J Bass, Kyoung-Mee Kim, Justin I Odegaard, Kyung Kim, Xiao Qiao Liu, Xinwei Sher, Hun Jung, Mijin Lee, Sujin Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Hyuk Lee, Mingew Choi, AmirAli Talasaz, Peter Soonmo Kang, Jonathan Cheng, Andrey Loboda, Jeeyun Lee, Won Ki Kang |
一句话小结
本研究分析了61名接受帕博利珠单抗治疗的转移性胃癌患者的组织和循环肿瘤DNA，发现微卫星不稳定性高和埃布斯坦-巴尔病毒阳性患者对治疗反应显著，且PD-L1阳性患者的反应率高于阴性患者。此外，治疗后ctDNA水平的变化可以预测患者的反应和无进展生存期，这为转移性胃癌的个性化治疗提供了重要的生物标志物依据。
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PD-1抑制 · 转移性胃癌 · 分子特征 · 循环肿瘤DNA · 生物标志物
摘要
临床研究支持针对程序性细胞死亡1（PD-1）的靶向治疗在一部分转移性胃癌（mGC）患者中的疗效。为了识别反应的决定因素，我们对61名在前瞻性第二阶段临床试验中接受帕博利珠单抗作为救治治疗的mGC患者的组织和循环肿瘤DNA（ctDNA）进行了分子特征分析。在具有微卫星不稳定性高和埃布斯坦-巴尔病毒阳性肿瘤的患者中，观察到对帕博利珠单抗的显著反应（微卫星不稳定性高的mGC整体反应率（ORR）为85.7%，埃布斯坦-巴尔病毒阳性的mGC整体反应率为100%）。对于55名有程序性死亡配体1（PD-L1）联合阳性评分（combined positive score）数据的患者（联合阳性评分截止值≥1%），PD-L1阳性胃癌的ORR显著高于PD-L1阴性肿瘤（50.0%对0.0%，P值<0.001）。治疗后六周ctDNA水平的变化能够预测反应和无进展生存期，ctDNA的减少与改善的结果相关。我们的研究结果为转移性胃癌患者对帕博利珠单抗反应的分子特征提供了见解，并提供了潜在相关的生物标志物，以便在选择可能从PD-1抑制中受益更大的患者时使用。
英文摘要
Clinical studies support the efficacy of programmed cell death 1 (PD-1) targeted therapy in a subset of patients with metastatic gastric cancer (mGC). With the goal of identifying determinants of response, we performed molecular characterization of tissues and circulating tumor DNA (ctDNA) from 61 patients with mGC who were treated with pembrolizumab as salvage treatment in a prospective phase 2 clinical trial. In patients with microsatellite instability-high and Epstein-Barr virus-positive tumors, which are mutually exclusive, dramatic responses to pembrolizumab were observed (overall response rate (ORR) 85.7% in microsatellite instability-high mGC and ORR 100% in Epstein-Barr virus-positive mGC). For the 55 patients for whom programmed death-ligand 1 (PD-L1) combined positive score positivity was available (combined positive score cut-off value ≥1%), ORR was significantly higher in PD-L1(+) gastric cancer when compared to PD-L1(-) tumors (50.0% versus 0.0%, P value <0.001). Changes in ctDNA levels at six weeks post-treatment predicted response and progression-free survival, and decreased ctDNA was associated with improved outcomes. Our findings provide insight into the molecular features associated with response to pembrolizumab in patients with mGC and provide biomarkers potentially relevant for the selection of patients who may derive greater benefit from PD-1 inhibition.
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主要研究问题
- 在研究中，如何评估微卫星不稳定性（MSI）与PD-1抑制剂反应之间的关系？
- 除了ctDNA水平，是否还有其他生物标志物可以预测对PD-1抑制剂的反应？
- 针对不同类型的肿瘤，PD-L1阳性与阴性患者的治疗方案有何不同？
- 研究中提到的Epstein-Barr病毒阳性肿瘤患者的反应机制是什么？
- 在临床试验中，如何选择适合接受PD-1抑制治疗的患者群体？
核心洞察
1. 研究背景和目的
本研究聚焦于转移性胃癌（mGC）患者对PD-1抑制剂治疗的临床反应，特别是针对抗PD-1疗法（如pembrolizumab）的有效性进行深入探讨。尽管已有临床研究显示PD-1抑制剂对部分患者有效，但目前尚缺乏对反应的分子机制和生物标志物的全面理解。研究的主要目的是通过对患者组织和循环肿瘤DNA（ctDNA）的分子特征分析，识别影响治疗反应的关键因素，以期为临床提供更为准确的患者筛选依据。
2. 主要方法和发现
研究共纳入61名接受pembrolizumab作为救治治疗的mGC患者，进行前瞻性2期临床试验。研究分析了患者的组织样本及ctDNA，重点考察了微卫星不稳定性（MSI-H）和EB病毒阳性肿瘤的反应情况。结果显示，MSI-H mGC患者的总体反应率（ORR）达到85.7%，而EB病毒阳性患者的ORR则高达100%。在55名可获得PD-L1联合阳性评分（CPS）的患者中，PD-L1阳性肿瘤的ORR显著高于PD-L1阴性肿瘤（50%对0%，P值<0.001）。此外，治疗后六周ctDNA水平的变化能够预测患者的反应和无进展生存期，ctDNA水平降低与临床结果改善呈相关性。
3. 核心结论
研究表明，MSI-H和EB病毒阳性肿瘤患者对pembrolizumab具有显著的治疗反应。此外，PD-L1阳性标记对治疗反应的预示作用也得到了验证。ctDNA的动态监测提供了新的生物标志物，可能成为评估治疗效果的重要工具。这些发现有助于在临床实践中更精准地筛选出可能从PD-1抑制剂中获益的患者。
4. 研究意义和影响
本研究不仅加深了对转移性胃癌患者对PD-1抑制剂反应机制的理解，还为临床个体化治疗提供了潜在的生物标志物。这对提高治疗效果、优化患者管理及制定个性化治疗方案具有重要意义。随着对生物标志物的深入研究，未来可能在更广泛的人群中推广PD-1抑制剂，改善转移性胃癌的治疗预后。
引用本文的文献
- What's New in Gastric Cancer: The Therapeutic Implications of Molecular Classifications and Future Perspectives. - Giuseppe Tirino;Luca Pompella;Angelica Petrillo;Maria Maddalena Laterza;Annalisa Pappalardo;Marianna Caterino;Michele Orditura;Fortunato Ciardiello;Gennaro Galizia;Ferdinando De Vita - International journal of molecular sciences (2018)
- Computational measurement of tumor immune microenvironment in gastric adenocarcinomas. - Young Hwan Chang;You Jeong Heo;Junhun Cho;Sang Yong Song;Jeeyun Lee;Kyoung-Mee Kim - Scientific reports (2018)
- EBV-associated gastric cancer evades T-cell immunity by PD-1/PD-L1 interactions. - Sho Sasaki;Jun Nishikawa;Kohei Sakai;Hisashi Iizasa;Hironori Yoshiyama;Masashi Yanagihara;Takuya Shuto;Kanami Shimokuri;Teru Kanda;Yutaka Suehiro;Takahiro Yamasaki;Isao Sakaida - Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association (2019)
- Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8+ T cells in the tumor microenvironment. - Yasuko Tada;Yosuke Togashi;Daisuke Kotani;Takeshi Kuwata;Eichi Sato;Akihito Kawazoe;Toshihiko Doi;Hisashi Wada;Hiroyoshi Nishikawa;Kohei Shitara - Journal for immunotherapy of cancer (2018)
- In the literature: October 2018. - Desamparados Roda;Valentina Gambardella;Andrés Cervantes - ESMO open (2018)
- PD-L1 expression and the prognostic significance in gastric cancer: a retrospective comparison of three PD-L1 antibody clones (SP142, 28-8 and E1L3N). - Jing Ma;Jianhui Li;Meirui Qian;Weili Han;Miaomiao Tian;Zengshan Li;Zhe Wang;Shuixiang He;Kaichun Wu - Diagnostic pathology (2018)
- The role of neoantigen in immune checkpoint blockade therapy. - Ming Yi;Shuang Qin;Weiheng Zhao;Shengnan Yu;Qian Chu;Kongming Wu - Experimental hematology & oncology (2018)
- Genomics of response to immune checkpoint therapies for cancer: implications for precision medicine. - Jake R Conway;Eric Kofman;Shirley S Mo;Haitham Elmarakeby;Eliezer Van Allen - Genome medicine (2018)
- Clinical significance of the mutational landscape and fragmentation of circulating tumor DNA in renal cell carcinoma. - Yoshiyuki Yamamoto;Motohide Uemura;Masashi Fujita;Kazuhiro Maejima;Yoko Koh;Makoto Matsushita;Kosuke Nakano;Yujiro Hayashi;Cong Wang;Yu Ishizuya;Toshiro Kinouchi;Takuji Hayashi;Kyosuke Matsuzaki;Kentaro Jingushi;Taigo Kato;Atsunari Kawashima;Takeshi Ujike;Akira Nagahara;Kazutoshi Fujita;Ryoichi Imamura;Hidewaki Nakagawa;Norio Nonomura - Cancer science (2019)
- Clinical efficacy of immune checkpoint inhibitors in the treatment of unresectable advanced or recurrent gastric cancer: an evidence-based review of therapies. - Kazuhiro Togasaki;Yasutaka Sukawa;Takanori Kanai;Hiromasa Takaishi - OncoTargets and therapy (2018)
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