The correlations of tumor mutational burden among single-region tissue, multi-region tissues and blood in non-small cell lung cancer

Zhang, Yaxiong; Chang, Lianpeng; Yang, Yunpeng; Fang, Wenfeng; Guan, Yanfang; Wu, Aiwei; Hong, Shaodong; Zhou, Huaqiang; Chen, Gang; Chen, Xi; Zhao, Shen; Zheng, Qiufan; Hui, Pei; Zhang, Lanjun; Long, Hao; Yang, Hao‐Xian; Wang, Xin; Wen, Zhesheng; Wang, Junye; Yang, Hong; Xia, Xuefeng; Zhao, Yuanyuan; Hou, Xue; Ma, Yuxiang; Zhou, Ting; Zhang, Zhonghan; Zhan, Jie; Huang, Yan; Zhao, Hongyun; Zhou, Ningning; Yi, Xin; Zhang, Li

doi:10.1186/s40425-019-0581-5

Cited by 56 publications

(49 citation statements)

References 6 publications

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“…Moreover, the cut-off for the bTMB and the exact panel of genes may be questionable and need further validation and standardization [52]. Furthermore, bTMB seems to be independent of tissue TMB and thus new thresholds would need to be evaluated for the stratification of patients [102][103][104].…”

Section: Analysis Of Circulating Free Ctdnamentioning

confidence: 99%

Liquid biopsy in the era of immuno-oncology: is it ready for prime-time use for cancer patients?

2019

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The emergence of immunotherapy in oncology requires the discovery, validation and subsequent adoption of robust, sensitive and specific predictive and prognostic biomarkers for daily practice. Until now, anti-PD-L1 immunohistochemistry (IHC) on tissue sections has been the only validated companion diagnostic test for first-line immunotherapy for advanced and metastatic cancer, notably non-small-cell lung cancer (NSCLC). However, detection of this biomarker presents limitations that have stimulated the development of other biomarkers and other approaches. Within this context, the use of a liquid biopsy (LB) could provide an important complementary or alternative added value to PD-L1 IHC. In this review, we discuss how LBs have been used in the field of immuno-oncology (I-O) to predict response, relapse or adverse advents for patients undergoing immune-checkpoint inhibitor (ICI) therapy (anti-PD-1/PD-L1 and CTLA-4) and we highlight recent developments. Circulating tumor cells (CTCs), cell-free DNA (cfDNA), proteins and cytokines detected in plasma as well as circulating T-lymphocytes are discussed as potential sources for developing new I-O biomarkers. The quantification of cfDNA as a predictive biomarker, as well as its sequencing for the determination of tumor mutational burden, is already well advanced. Additionally, the quantification of PD-L1 from CTCs, bound on exosomes or free in plasma, as well as the determination of cytokines, are also being actively investigated with promising results having recently been published. Lastly, analysis of T-lymphocytes, especially by analyzing the T-cell receptor, has recently emerged as a valuable biomarker that might become relevant for the prediction of response to ICIs. While LBs have not yet been implemented in routine I-O clinical practice, recent promising data and rapidly advancing technologies indicate that this approach has the potential to soon personalize the clinical management of cancer patients receiving ICIs.

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Section: Analysis Of Circulating Free Ctdnamentioning

confidence: 99%

Liquid biopsy in the era of immuno-oncology: is it ready for prime-time use for cancer patients?

2019

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“…All final candidate variants were verified with the integrative genomics viewer browser. TMB was defined as the number of somatic nonsynonymous mutations per megabase including SNVs, insertions, and deletions of the panel region [22].…”

Section: Sequencing Data Analysismentioning

confidence: 99%

Association of genetic and immuno-characteristics with clinical outcomes in patients with RET-rearranged non-small cell lung cancer: a retrospective multicenter study

Dong

Zhao

et al. 2020

J Hematol Oncol

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Background: Rearranged during transfection (RET) has been proven to be a tumorigenic target in non-small cell lung cancers (NSCLCs). In RET-rearranged NSCLCs, molecular features and their impact on prognosis were not well illustrated, and the activity of mainstay therapeutics has not currently been well compared. Methods: Patients diagnosed with NSCLCs with RET rearrangements were analyzed for concomitant mutations, tumor mutation burden (TMB), PD-L1 expression, T cell receptor repertoire and clinical outcomes with chemotherapy, immune checkpoint inhibitors (ICIs), and multikinase inhibitors (MKIs). Results: Among 129 patients with RET-rearranged NSCLC who were analyzed, 41.1% (53/129) had co-occurring genetic alterations by next-generation sequencing, and concomitant TP53 mutation appeared most frequently (20/ 53, 37.7%). Patients with concurrent TP53 mutation (n = 15) had shorter overall survival than those without (n = 30; median, 18.4 months [95% CI, 8.6-39.1] vs 24.8 months [95% CI, 11.7-52.8]; P < 0.05). Patients with lower peripheral blood TCR diversity (n = 5) had superior overall survival compared with those with higher diversity (n = 6; median, 18.4 months [95% CI,.9] vs 4.8 months [95% CI, 4.5-5.3]; P = 0.035). An association with overall survival was not observed for PD-L1 expression nor for tumor mutation burden level. Median progression-free survival was not significantly different across chemotherapy, ICIs, and MKIs (median, 3.5 vs 2.5 vs 3.8 months). For patients treated with ICIs, the disease control rate was 60% (6/10) and the objective response rate was 20% (2/10).Conclusions: RET-rearranged lung cancers can be heterogeneous in terms of concomitant genetic alterations. Patients with concurrent TP53 mutation or high peripheral blood TCR repertoire diversity have relatively inferior overall survival in this series. Outcomes with traditional systemic therapies in general are suboptimal.

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“…All final candidate variants were verified with the integrative genomics viewer browser. Tumor mutational burden was defined as the number of somatic non-synonymous mutations per megabase including SNVs, insertions, and deletions of the panel region [19].…”

Section: Next-generation Sequencingmentioning

confidence: 99%

The Genomic Profiling in Chinese Head and Neck Cancer and Incidence of NTRK Fusion

Xu¹,

R²,

Wang³

et al. 2020

Preprint

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Background Head and neck cancers are aggressive epithelial tumors and well recognized as a particularly challenging class of tumors to treat. Comprehensive molecular profiling is leading to the development of “personalized” or “precision” medicine. Here we report the genomic profiling of Chinese head and neck cancers and the incidence of NTRK aberrations. Methods We retrospectively analyzed the genetic aberrations in 127 patients of Chinese head and neck cancer. All the patients were detected by 1021-gene panel (including NTRK1, NTRK2, NTRK3) of hybridization capture-based next-generation sequencing with tumor tissue and matched peripheral blood control samples. Results This studied was inspired by the outcome benefit of a parotid cancer patient harboring ETV6-NTRK3 fusion, who received crizotinib treatment and achieved a 2-year progression-free survival (PFS). Then, we reviewed 127 cases of head and neck cancer in our database. The most common histology type was HNSCC (79.5%). The genomic profiling indicated that both in our Chinese cohort and TCGA database, TP53 is the most frequently mutated gene in head and neck cancer. The incidence of NTRK genetic aberrations was 7.9% (10/127) including NTRK fusion (n = 4, 3.1%) and NTRK mutation (n = 6, 4.7%). The most common fusion was ETV6-NTRK3 (n = 3, 2.4%). Compared to NTRK-wt group, NTRK aberration group had more APC and PTPRD aberrations (p < 0.05). The association of genetic aberrations with tumor mutation burden (TMB) had been analyzed. NTRK fusion-group had a lower TMB compared to the NTRK-wt group (p = 0.034). TP53 and LRP1B showed significant association with higher TMB (both p < 0.01), which may be potential markers of immunotherapy in head and neck cancer patients. Conclusions Our data is the first study to report the genomic profiling in Chinese head and neck cancers and the incidence of NTRK fusion. About 3% of Chinese head and neck patients may benefit from targeted therapy of NTRK inhibitors. An ETV6-NTRK3 fusion patient reached a long-term response with crizotinib treatment,indicating crizotinib might be an alternative treatment option for patients with NTRK fusions.

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The correlations of tumor mutational burden among single-region tissue, multi-region tissues and blood in non-small cell lung cancer

Cited by 56 publications

References 6 publications

Liquid biopsy in the era of immuno-oncology: is it ready for prime-time use for cancer patients?

Liquid biopsy in the era of immuno-oncology: is it ready for prime-time use for cancer patients?

Association of genetic and immuno-characteristics with clinical outcomes in patients with RET-rearranged non-small cell lung cancer: a retrospective multicenter study

The Genomic Profiling in Chinese Head and Neck Cancer and Incidence of NTRK Fusion

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