Synchronous ground‐glass nodules showed limited response to anti‐PD‐1/PD‐L1 therapy in patients with advanced lung adenocarcinoma

Wu, Fengying; Li, Wei; Zhao, Wencheng; Zhou, Fei; Xie, Huikang; Shi, Jingyun; Yu, Guiping; Fan, Jue; Jiang, Tao

doi:10.1002/ctm2.149

Cited by 25 publications

(28 citation statements)

References 10 publications

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“…Recently, a retrospective study showed limited efficacy of PD-1/PD-L1 checkpoint blockade alone in multiple ground-glass nodules of advanced NSCLC. 33 Altogether, these data suggested that neoadjuvant immunotherapy alone might not be an ideal option for patients with MPLC due to insufficient antitumor response for all subsolid lesions. However, given the genomic and immune microenvironment heterogeneity among MPLCs, neoadjuvant immunotherapy for MPLC with subsolid nodules should be deliberately considered for future clinical trials.…”

Section: Discussionmentioning

confidence: 97%

Multiomics analysis reveals a distinct response mechanism in multiple primary lung adenocarcinoma after neoadjuvant immunotherapy

Zhang

Yin

Liu

et al. 2021

J Immunother Cancer

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Multiple primary lung cancer (MPLC) remains a tough challenge to diagnose and treat. Although neoadjuvant immunotherapy has shown promising results in early stage non-small cell lung cancer, whether such modality can benefit all primary lesions remains unclear. Herein, we performed integrated multiomics analysis in one patient with early stage MPLC with remarkable tumor shrinkage in a solid nodule and no response in two subsolid nodules after treatment with three cycles of neoadjuvant pembrolizumab. Genomic heterogeneity was observed among responding nodules with high levels of infiltrating CD8+ and CD68+ immune cells. Substantially downregulated human leukocyte antigen (HLA)-related genes and impaired T lymphocyte function were observed in non-responding nodules. A larger proportion of infiltrating tissue resident memory T cells (Trm) along with high T cell receptor repertoire clonality in responding nodules were validated as predictive and prognostic biomarkers in multiple cancer types using external public datasets. These results suggested that neoadjuvant programmed death 1 (PD-1)/programmed death ligand 1 inhibitors alone may not be an optimal therapeutic strategy for MPLC due to disparities in genomic alterations and immune microenvironment among different lesions. Additionally, we postulate that increased infiltration of Trm may be a unique marker of early immune responses to PD-1 blockade.

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Section: Discussionmentioning

confidence: 97%

Multiomics analysis reveals a distinct response mechanism in multiple primary lung adenocarcinoma after neoadjuvant immunotherapy

Zhang

Yin

Liu

et al. 2021

J Immunother Cancer

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“…reported based on two cases, that synchronous GGNs may not be sensitive to anti-PD-1/PD-L1 based therapy. In this study, the proportion of CD8+T cells was lower in synchronous GGNs than in primary lung cancers, while tumor-associated macrophages showed significant enrichment in the tumor microenvironment of GGNs ( 9 ). A recently published study further performed multiomics analysis of a consecutive clinical cohort prospective observational cohort study to characterize pulmonary nodules with or without GGO component and found GGO-associated lung cancers with lower mutational burden, less active immune environment, and less ctDNA shedding, revealing that the intrinsic biological features may have contributed to the indolent clinical course of GGO-associated lung cancers.…”

mentioning

confidence: 61%

Editorial: New Trends in Early-Stage Lung Cancer Presenting as Ground-Glass Opacities: Clinical, Pathological and Molecular Aspects

Chen

2021

Front. Oncol.

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Ground-Glass Opacity (GGO)-associated lung cancers are radiologically distinct clinical entities. Consensus or guidelines suggest that the clinical management decision on ground-glass nodules (GGN) should be based on the initial size, percentage of solid portion, and growth rate of GGNs, but are inconsistent in terms of the GGN cutoff size for surgical intervention and low-dose CT scan (LDCT) follow-up frequency (1-3). In addition, the unpredictable aggressive potential and highly heterogeneous characteristics of GGNs add another layer of complexity for GGN management. Thus, effectively treating GGNs remains challenging for clinicians who may have to rely on their individual experiences. To address this knowledge gap, we initiated this Research Topic to further explore the clinical manifestations, pathological features, and genetic changes that will assist in the diagnosis and decision-making of treatment of early-stage lung cancer presenting as GGOs. A number of interesting studies closely related to this field were included.Previous studies have shown that most resected GGNs are histologically atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic predominant adenocarcinoma, which are considered to have a low risk for regional lymph node metastasis, vascular invasion, or pleural invasion. In the WHO 5 th lung cancer TNM clinical classification, AIS has been removed from preinvasive to precursor lesions, companied with AAH (4). Wang et al. reported that using a radiomics prediction model in patients with subcentimeter GGOs to distinguish AAH from early lung adenocarcinomas. The model turns to have the potentiality to improve preoperative prediction accuracy for AAH nodules and may help to avoid unnecessarily aggressive operations for patients with AAH.Prospective multicenter validation with higher accuracy is needed for routine clinical application as surgeons are unwilling to defer surgery based on false-negative predictions that will delay the treatment of invasive lesions. GGNs with a solid component are more likely related to invasive adenocarcinoma with poor prognosis. Xi et al. and Tsutani et al. studies confirmed the solid size of GGNs has a decisive effect on prognosis and provided an accurate solid tumor size cutoff for highrisk patients. Qi et al. reported that in small-sized lung adenocarcinoma, consolidation tumor ratio (CTR) is the best sign for predicting lung cancer spread through air spaces (STAS).

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“…Wu et al. also found in a small-size cohort that even for the same patient, the volume of synchronous GGOs showed no significant change before and after treatment (4,160.2 vs 4,185.5 mm 3 , p = 0.6050) than solid nodules ( 52 ). Therefore, it is predictable that PD-1 treatment is less effective for patients with GGOs.…”

Section: Discussionmentioning

confidence: 89%

“…We clearly showed that the incidence of PD-L1 expression was much lower in GGOs than pure-solid tumors in several articles, which was verified by Suda et al in a clinical experiment including 124 qualified patients (4% vs. 25%, p < 0.01) (32). Wu et al also found in a small-size cohort that even for the same patient, the volume of synchronous GGOs showed no significant change before and after treatment (4,160.2 vs 4,185.5 mm 3 , p = 0.6050) than solid nodules (52). Therefore, it is predictable that PD-1 treatment is less effective for patients with GGOs.…”

Section: Discussionmentioning

confidence: 94%

Molecular Alterations in Lung Adenocarcinoma With Ground-Glass Nodules: A Systematic Review and Meta-Analysis

et al. 2021

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Background and AimsNodular ground-glass lesions have become increasingly common with the increased use of computed tomography (CT), while the genomic features of ground-glass opacities (GGOs) remain unclear. This study aims to comprehensively investigate the molecular alterations of GGOs and their correlation with radiological progression.MethodsStudies from PubMed, Embase, Cochrane Library, and Web of Science, using PCR, targeted panel sequencing, whole exosome sequencing, and immunohistochemistry, and reporting genomic alterations or PD-L1 expressions in lung nodules presenting as GGOs until January 21, 2021 were included in this study. Chi-square test, random-effects model, and Z-test analysis were adopted to analyze the data.ResultsA total of 22 studies describing mutations in lung adenocarcinoma (LUAD) with GGOs were analyzed. EGFR was the most frequently mutative gene (51%, 95%CI 47%–56%), followed by TP53 (18%, 95%CI 6%–31%), HER2 (10%, 95%CI 0%–21%), ROS1 (6%, 95%CI 0%–18%), and KRAS (6%, 95%CI 3%–9%). The correlation between the frequency of EGFR mutation and radiological was observed and the differences were found to be not statistically significant in the subgroups, which are listed as below: radiological: gGGO 47.40%, 95%CI [38.48%; 56.40%]; sGGO 51.94%, 95%CI [45.15%; 58.69%]. The differences of the frequency of KRAS mutation in the different subgroups were also consistent with this conclusion, which are listed as: radiological gGGO 3.42, 95%CI [1.35%; 6.13%]; sGGO 12.27%, 95%CI [3.89%; 23.96%]. The pooled estimated rate of PD-L1 was 8.82%, 95%CI [5.20%–13.23%]. A total of 11.54% (3/26) of the SMGGNs were confirmed to be intrapulmonary spread by WES.ConclusionsSomatic genetic alterations are considered in early-stage GGO patients without distinct changes of the frequency following the progress of the tumor. This review sheds insight on molecular alterations in LUAD with GGOs.

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Synchronous ground‐glass nodules showed limited response to anti‐PD‐1/PD‐L1 therapy in patients with advanced lung adenocarcinoma

Cited by 25 publications

References 10 publications

Multiomics analysis reveals a distinct response mechanism in multiple primary lung adenocarcinoma after neoadjuvant immunotherapy

Multiomics analysis reveals a distinct response mechanism in multiple primary lung adenocarcinoma after neoadjuvant immunotherapy

Editorial: New Trends in Early-Stage Lung Cancer Presenting as Ground-Glass Opacities: Clinical, Pathological and Molecular Aspects

Molecular Alterations in Lung Adenocarcinoma With Ground-Glass Nodules: A Systematic Review and Meta-Analysis

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