Integrated genomic analysis identifies a genetic mutation model predicting response to immune checkpoint inhibitors in melanoma

Jiang, Junjie; Ding, Yongfeng; Wu, Mengjie; Chen, Yanyan; Lyu, Xiadong; Lü, Jun; Wang, Haiyong; Teng, Lisong

doi:10.1002/cam4.3481

Cited by 26 publications

(22 citation statements)

References 55 publications

(149 reference statements)

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“…Nevertheless, all of these mutations are weighted the same in TMB scoring systems, highlighting the limitations of TMB as a predictive biomarker for ICI. Recently, it has been reported that TMB-based survival prediction can be improved by optimizing the TMB algorithm 20 or by establishing gene mutation-based signatures 21 , 22 . We therefore investigated the genomic determinants of ICIs benefits in gastrointestinal cancer and developed a gene mutation-based risk model containing the most decisive prognosis-related genes to better predict the clinical outcomes of immunotherapy in patients with gastrointestinal cancer.…”

Section: Introductionmentioning

confidence: 99%

A genomic mutation signature predicts the clinical outcomes of immunotherapy and characterizes immunophenotypes in gastrointestinal cancer

Wei

et al. 2021

npj Precis. Onc.

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The association between genetic variations and immunotherapy benefit has been widely recognized, while such evidence in gastrointestinal cancer remains limited. We analyzed the genomic profile of 227 immunotherapeutic gastrointestinal cancer patients treated with immunotherapy, from the Memorial Sloan Kettering (MSK) Cancer Center cohort. A gastrointestinal immune prognostic signature (GIPS) was constructed using LASSO Cox regression. Based on this signature, patients were classified into two subgroups with distinctive prognoses (p < 0.001). The prognostic value of the GIPS was consistently validated in the Janjigian and Pender cohort (N = 54) and Peking University Cancer Hospital cohort (N = 92). Multivariate analysis revealed that the GIPS was an independent prognostic biomarker. Notably, the GIPS-high tumor was indicative of a T-cell-inflamed phenotype and immune activation. The findings demonstrated that GIPS was a powerful predictor of immunotherapeutic survival in gastrointestinal cancer and may serve as a potential biomarker guiding immunotherapy treatment decisions.

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Section: Introductionmentioning

confidence: 99%

A genomic mutation signature predicts the clinical outcomes of immunotherapy and characterizes immunophenotypes in gastrointestinal cancer

Wei

et al. 2021

npj Precis. Onc.

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“…The clinical outcome of immunotherapy is not easy to predict and, in some cases, is not positive for patients. Indeed, unlike targeted therapy, which has predictive response markers, such as the BRAF mutation, validated biomarkers for the immunotherapeutic agents still need to be approved [45,46]. In recent years, gene sequencing studies have shown that the TMB, neoantigen load (NL) or PDL1 expression degree are often associated with an increased response to immunotherapy [47,48].…”

Section: Genomics Approachesmentioning

confidence: 99%

“…In recent years, gene sequencing studies have shown that the TMB, neoantigen load (NL) or PDL1 expression degree are often associated with an increased response to immunotherapy [47,48]. However, undefined cut-off and weak reliability of prediction have not given significant results [46,49]. Thus, in melanoma, the research of new predictive biomarkers appears fundamental to discriminate the patients and to avoid unnecessary and sometimes dangerous treatments.…”

Section: Genomics Approachesmentioning

confidence: 99%

“…The authors have produced this model by sequencing whole exomes, and have observed an increased response to treatments and prolonged survival in patients, with high levels of ITS. ITS is not only a good isolated predictive factor, indeed, in association with TMB and plasmatic value of lactate dehydrogenase (LDH), it seems to be, in terms of response to immunotherapy, the best biomarker compared to single factors [46]. A new possible marker of response to immunotherapy in metastatic melanoma is the activation of nuclear factor kappa-lightchain-enhancer of activated B cells (NF-kB) signaling.…”

Section: Genomics Approachesmentioning

confidence: 99%

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Precision Medicine and Melanoma: Multi-Omics Approaches to Monitoring the Immunotherapy Response

Valenti¹,

Falcone

Ungania

et al. 2021

IJMS

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The treatment and management of patients with metastatic melanoma have evolved considerably in the “era” of personalized medicine. Melanoma was one of the first solid tumors to benefit from immunotherapy; life expectancy for patients in advanced stage of disease has improved. However, many progresses have yet to be made considering the (still) high number of patients who do not respond to therapies or who suffer adverse events. In this scenario, precision medicine appears fundamental to direct the most appropriate treatment to the single patient and to guide towards treatment decisions. The recent multi-omics analyses (genomics, transcriptomics, proteomics, metabolomics, radiomics, etc.) and the technological evolution of data interpretation have allowed to identify and understand several processes underlying the biology of cancer; therefore, improving the tumor clinical management. Specifically, these approaches have identified new pharmacological targets and potential biomarkers used to predict the response or adverse events to treatments. In this review, we will analyze and describe the most important omics approaches, by evaluating the methodological aspects and progress in melanoma precision medicine.

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“…RTK/RAS pathway gene alterations showed a tendency for higher TMB, with every TMB-high patient being in the RTK/RAS pathway alteration group also (Extended Data Fig 6e-f). Indeed, the RTK/RAS pathway is related to enhanced response to immunotherapy through stabilization or overexpression of PD-L1 [29][30][31] .…”

mentioning

confidence: 99%

First-line pembrolizumab, trastuzumab, and chemotherapy in advanced HER2-positive gastric cancer with sequential genomic profiling

Chung

Lee

Rha

et al. 2021

Preprint

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Combining programmed cell death 1 (PD-1) and human epidermal receptor 2 (HER2) targeting agents has shown synergy in HER2-positive preclinical cancer models. Here, we describe a single-arm multi-institutional phase Ib/II trial combining pembrolizumab, trastuzumab, and chemotherapy (capecitabine plus cisplatin) as first-line therapy for HER2-positive advanced gastric cancer (AGC). With a median follow-up of 18.2 months, 3 out of 43 enrolled patients remained in the treatment and 7 finished 2-year treatment without progression. Objective response rate was 76.7% (complete response 16.3%, partial response 60.5%, conversion surgery 4.6%), with 26 patients (56.6%) showing tumor reduction of more than 50%. Median progression-free survival was 8.6 months (95% confidence interval [CI] 7.2–16.4) and median overall survival was 19.3 months (95% CI 16.5–not reached). There was no patient with microsatellite instability-high or Epstein–Barr virus-positive tumor. No patient discontinued pembrolizumab because of immune-related adverse events. Programmed death ligand-1 (PD-L1) status, metastatic organ, or baseline tumor burden were not related to survival. Molecular analyses of pre-treatment tumor samples using next-generation panel sequencing (NGS) showed that HER2 amplification, RTK/RAS pathway alteration, and neoantigen load corrected by HLA-B were related to survival. Comparison analyses of sequentially biopsied samples identified sensitive and resistant sub-clones with spatial and longitudinal tumor heterogeneity. This study provided insight into potentially relevant NGS-based genomic changes to identify patients who may benefit from quadruplet regimen (pembrolizumab, trastuzumab, capecitabine, and cisplatin), which was active and safe for HER2-positive AGC.

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Integrated genomic analysis identifies a genetic mutation model predicting response to immune checkpoint inhibitors in melanoma

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 26 publications

References 55 publications

A genomic mutation signature predicts the clinical outcomes of immunotherapy and characterizes immunophenotypes in gastrointestinal cancer

A genomic mutation signature predicts the clinical outcomes of immunotherapy and characterizes immunophenotypes in gastrointestinal cancer

Precision Medicine and Melanoma: Multi-Omics Approaches to Monitoring the Immunotherapy Response

First-line pembrolizumab, trastuzumab, and chemotherapy in advanced HER2-positive gastric cancer with sequential genomic profiling

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