Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer

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Abstract

Despite neoadjuvant/conversion chemotherapy, the prognosis of cT4a/bN+ gastric cancer is poor. Immune checkpoint inhibitors (ICIs) and antiangiogenic agents have shown activity in late-stage gastric cancer, but their efficacy in the neoadjuvant/conversion setting is unclear. In this single-armed, phase II, exploratory trial (NCT03878472), we evaluate the efficacy of a combination of ICI (camrelizumab), antiangiogenesis (apatinib), and chemotherapy (S-1 ± oxaliplatin) for neoadjuvant/conversion treatment of cT4a/bN+ gastric cancer. The primary endpoints are pathological responses and their potential biomarkers. Secondary endpoints include safety, objective response, progression-free survival, and overall survival. Complete and major pathological response rates are 15.8% and 26.3%. Pathological responses correlate significantly with microsatellite instability status, PD-L1 expression, and tumor mutational burden. In addition, multi-omics examination reveals several putative biomarkers for pathological responses, including RREB1 and SSPO mutation, immune-related signatures, and a peripheral T cell expansion score. Multi-omics also demonstrates dynamic changes in dominant tumor subclones, immune microenvironments, and T cell receptor repertoires during neoadjuvant immunotherapy. The toxicity and post-surgery complications are limited. These data support further validation of ICI- and antiangiogenesis-based neoadjuvant/conversion therapy in large randomized trials and provide candidate biomarkers.

Abstract

Immune checkpoint inhibitors and antiangiogenic agents have shown some activity in patients with late-stage gastric cancer. Here the authors report the results of a phase II trial of neoadjuvant anti-PD1 (camrelizumab), antiangiogenic agent (apatinib), and chemotherapy (S-1 ± Oxaliplatin) in stage T4a/bN + M0 gastric cancer patients.

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

Michael Love, Wolfgang Huber, Simon Anders (2014)

In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0550-8) contains supplementary material, which is available to authorized users.

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A global reference for human genetic variation

Lachlan Coin, Robert Garry, Oleksyk Taras (2018)

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

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Author and article information

Contributors

Lian Liu:

ORCID: http://orcid.org/0000-0001-5868-4482

lianliu@sdu.edu.cn

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 3 January 2023

Publication date PMC-release: 3 January 2023

Publication date Collection: 2023

Volume: 14

Electronic Location Identifier: 8

Affiliations

[1 ]GRID grid.27255.37, ISNI 0000 0004 1761 1174, Department of Medical Oncology, Qilu Hospital, , Cheeloo College of Medicine, Shandong University, ; Jinan, 250012 Shandong China

[2 ]GRID grid.27255.37, ISNI 0000 0004 1761 1174, Department of General Surgery, Qilu Hospital, , Cheeloo College of Medicine, Shandong University, ; Jinan, 250012 Shandong China

[3 ]GRID grid.27255.37, ISNI 0000 0004 1761 1174, Department of Pharmacy, Qilu Hospital, , Cheeloo College of Medicine, Shandong University, ; Jinan, 250012 Shandong China

[4 ]Shenzhen Yucebio Technology Co., Ltd., Shenzhen, 518000 Guangdong, China

[5 ]GRID grid.440653.0, ISNI 0000 0000 9588 091X, Department of General Surgery, , Zibo Municipal Central Hospital, Binzhou Medical College, ; Zibo, 255036 Shandong China

[6 ]GRID grid.27255.37, ISNI 0000 0004 1761 1174, Department of Radiology, Qilu Hospital, , Cheeloo College of Medicine, Shandong University, ; Jinan, 250012 Shandong China

[7 ]GRID grid.27255.37, ISNI 0000 0004 1761 1174, Department of Pathology, Qilu Hospital, , Cheeloo College of Medicine, Shandong University, ; Jinan, 250012 Shandong China

[8 ]GRID grid.460018.b, ISNI 0000 0004 1769 9639, Department of Medical Oncology, , Shandong Provincial Hospital of Traditional Chinese Medicine, ; Jinan, 250012 China

Author information

Song Li http://orcid.org/0000-0002-5023-9111

Dexin Yu http://orcid.org/0000-0001-7462-3153

Peng Gao http://orcid.org/0000-0002-4721-0887

Lian Liu http://orcid.org/0000-0001-5868-4482

Article

Publisher ID: 35431

DOI: 10.1038/s41467-022-35431-x

PMC ID: 9810618

PubMed ID: 36596787

SO-VID: e92e961e-f82f-44ff-834f-9c935956ad5b

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 11 March 2022

Date accepted : 2 December 2022

Funding

Funded by: Foundation of Shandong University Clinical Research Center (2020SDUCRCC011)

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 82173305

Award Recipient : Lian Liu

Funded by: FundRef https://doi.org/10.13039/501100007129, Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation);

Award ID: ZR2017MH005

Award Recipient : Lian Liu

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Keywords: gastric cancer,cancer immunotherapy

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ScienceOpen disciplines: Uncategorized

Keywords: gastric cancer, cancer immunotherapy

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Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer

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Cancer Immunotherapy

Most cited references 80

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

A global reference for human genetic variation

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Cited by 36

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