Genomic Landscape and Tumor Mutational Burden Determination of Circulating Tumor DNA in Over 5,000 Chinese Patients with Lung Cancer

2021 ◽  
Author(s):  
Jie Shi ◽  
Zhiyu Wang ◽  
Junping Zhang ◽  
Yaping Xu ◽  
Xiao Xiao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Circulating Tumor Dna ◽  
Chinese Patients ◽  
Mutational Burden ◽  
Genomic Landscape ◽  
Tumor Mutational Burden ◽  
Tumor Dna

Real-world concordance between tumor mutational burden (TMB) from blood (circulating tumor DNA) and tissue in lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20522-e20522
Author(s):  
Inae Park ◽  
Jin Young Hwang ◽  
William Bae ◽  
Grace Lee ◽  
Leeseul Kim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Squamous Cell ◽  
Circulating Tumor Dna ◽  
Mutational Burden ◽  
Significant Difference ◽  
Discordant Group ◽  
Tumor Mutational Burden ◽  
Group B ◽  
Metastatic Sites ◽  
Tumor Dna

e20522 Background: Tumor mutational burden (TMB) level is associated with response to immunotherapy in lung cancer. However, tissue TMB can be difficult to obtain, as tissue samples obtained from biopsies may be insufficient. Circulating tumor DNA-based TMB has been developed in order to complement or replace tissue TMB, but there is limited real-world data on their concordance. Here, we investigate the landscape and concordance between blood and tissue TMB, along with clinical traits of the concordant and discordant groups. Methods: Tumor mutational burden (TMB) was calculated using Tempus (tissue) and Guardant Health (blood) next generation sequencing (NGS) platforms from October 2020 to January 2021. There were 33 patients who had both Tempus and Guardant TMB data. Under the assumption that tissue TMB (tTMB) correlates with blood TMB (bTMB) at a ratio of 1:1.6, the patients were divided into concordant and discordant groups. The concordant group patients had bTMB/tTMB ratios between 1.3 and 1.9. The discordant group was divided into two subgroups: over 1.9 (Group B) and less than 1.3 (Group C). Among the 33 patients, 9 patients were excluded due to their non-evaluable bTMB levels. Treatment response was evaluated using RECIST criteria. Results: Of the remaining 24 patients, 7 patients in the concordant group and 21 patients in the discordant group were analyzed according to their clinical manifestations [Blood TMB (n = 24): range [1.46, 44.01], median = 9.57], [Tissue TMB (n = 24), range [1.3, 18.4], median = 4.5]. We compared the clinical presentations (number of metastatic organs and metastatic sites) between the two discordant groups (Groups B and C). Among the 24 patients, 13% (n = 3) had small cell lung cancer, 50% (n = 12) had adenocarcinoma, and 29% (n = 7) had squamous cell lung carcinoma. Patients with higher bTMB than tTMB (Group B) had more squamous cell carcinoma cases (71%, n = 5) compared to remaining groups (Groups A and C) (29%, n = 2). Among the discordant group, 6% of the patients (n = 1) had small cell lung cancer, 47% (n = 8) had adenocarcinoma, and 35% (n = 6) had squamous cell carcinoma. Further, 58% (n = 14) of the patients had higher bTMB than tTMB levels. Among the concordant and discordant groups, tumor burden as reflected by the number of metastatic sites and metastatic lesions and the sum of the largest diameters of tumor lesions using RECIST had no significant difference (p = 0.10, 0.68, 0.54, respectively). The concordant and discordant groups showed no significant difference in objective response (33% vs. 20%, p = 0.60) or clinical benefit rate (100% vs. 60%, p = 0.33). Conclusions: The majority of the patients had higher blood TMB than tissue TMB (Group A), with a concordance rate as low as 28%. Further studies are warranted to understand the biology behind the difference between blood and tissue TMB, including intertumoral heterogeneity.

scholarly journals Clinical Implications of Circulating Tumor DNA Tumor Mutational Burden (ctDNA TMB) in Non‐Small Cell Lung Cancer

2019 ◽  
Vol 24 (6) ◽  
pp. 820-828 ◽  
Author(s):  
Young Kwang Chae ◽  
Andrew A. Davis ◽  
Sarita Agte ◽  
Alan Pan ◽  
Nicholas I. Simon ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Circulating Tumor Dna ◽  
Small Cell ◽  
Clinical Implications ◽  
Small Cell Lung ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Tumor Dna

scholarly journals Pan-cancer circulating tumor DNA detection in over 10,000 Chinese patients

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yongliang Zhang ◽  
Yu Yao ◽  
Yaping Xu ◽  
Lifeng Li ◽  
Yan Gong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Circulating Tumor Dna ◽  
Small Cell ◽  
Chinese Patients ◽  
Plasma Samples ◽  
Small Cell Lung ◽  
Pan Cancer ◽  
Tumor Dna

AbstractCirculating tumor DNA (ctDNA) provides a noninvasive approach to elucidate a patient’s genomic landscape and actionable information. Here, we design a ctDNA-based study of over 10,000 pan-cancer Chinese patients. Using parallel sequencing between plasma and white blood cells, 14% of plasma cell-free DNA samples contain clonal hematopoiesis (CH) variants, for which detectability increases with age. After eliminating CH variants, ctDNA is detected in 73.5% of plasma samples, with small cell lung cancer (91.1%) and prostate cancer (87.9%) showing the highest detectability. The landscape of putative driver genes revealed by ctDNA profiling is similar to that in a tissue-based database (R2 = 0.87, p < 0.001) but also shows some discrepancies, such as higher EGFR (44.8% versus 25.2%) and lower KRAS (6.8% versus 27.2%) frequencies in non-small cell lung cancer, and a higher TP53 frequency in hepatocellular carcinoma (53.1% versus 28.6%). Up to 41.2% of plasma samples harbor drug-sensitive alterations. These findings may be helpful for identifying therapeutic targets and combined treatment strategies.

IFNγ mRNA signature (IFNγ sig), circulating tumor DNA (ctDNA), and survival in NSCLC or urothelial cancer (UC) treated with durvalumab (D).

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 51-51 ◽  
Author(s):  
Brandon W. Higgs ◽  
Chris Morehouse ◽  
Michael Kuziora ◽  
Philip Z. Brohawn ◽  
Sriram Sridhar ◽  
...  
Keyword(s):  
Liver Metastases ◽  
Urothelial Cancer ◽  
Progressive Disease ◽  
Phase 1 ◽  
Circulating Tumor Dna ◽  
Mutational Burden ◽  
Dna Variants ◽  
Tumor Mutational Burden ◽  
Tumor Dna ◽  
Clinical Trial Information

51 Background: Associations between early reduction in plasma ctDNA, pretreatment tumoral IFNγ sig, liver metastases and outcomes, and between tumor mutational burden (TMB) and CD274 (PD-L1) mRNA or IFNγ sig in TCGA were evaluated in NSCLC and UC pts treated with D. Methods: Pts received 10 mg/kg Q2W of D in a Phase 1/2 study in advanced solid tumors. RNAseq measured a 4-gene IFNγ sig; top tertile was IFNγ sig+. Pts with PD-L1 expression (Ventana SP263) ≥ 25% tumor cells in NSCLC or ≥ 25% tumor or immune cells in UC were PD-L1+. 70 genes were assayed for DNA variants (Guardant360) in plasma ctDNA pre/posttreatment. TCGA was used to calculate TMB; ≥ median TMB was high. Results: IFNγ sig+ NSCLC or UC pts had higher response and longer median PFS and OS compared with PD-L1+, PD-L1- and IFNγ sig- pts (Table). Responders showed significant decreases in ctDNA mean variant allele frequency (VAF) posttreatment with D; pts with progressive disease showed increased VAF. Pts with decreased VAF at week 6 had longer median PFS and OS compared with those with VAF increases. VAF changes were not associated with IFNγ sig. NSCLC without liver metastases had higher IFNγ sig (P < 0.001) than pts with liver metastases. In TCGA NSCLC and UC, IFNγ sig+ correlated with high TMB; CD274 mRNA did not. Conclusions: IFNγ sig correlated with outcomes and with TMB in NSCLC and UC. CtDNA VAFs were reduced in NSCLC or UC responders after treatment and correlated with longer survival, suggesting utility as an early indicator of clinical benefit. Clinical trial information: NCT01693562. [Table: see text]

Comprehensive analysis of genomic alterations detected by next-generation sequencing-based tissue and circulating tumor DNA assays in Chinese patients with non-small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20534-e20534
Author(s):  
Hua Yang ◽  
Junjie Zhang ◽  
Lemeng Zhang ◽  
Xiaoping Wen ◽  
Yongzhong Luo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Next Generation Sequencing ◽  
Circulating Tumor Dna ◽  
Small Cell ◽  
Chinese Patients ◽  
Small Cell Lung ◽  
Genomic Alterations ◽  
Nsclc Patients ◽  
Tumor Dna ◽  
Generation Sequencing

e20534 Background: While tumor genotyping is the standard treatment for patients with non-small cell lung cancer (NSCLC), spatial and temporal tumor heterogeneity and insufficient specimens can lead to limitations in the use of tissue-based sequencing. Circulating tumor DNA (ctDNA) fully encompasses tumor-specific sequence alterations and offers an alternative to tissue sample biopsies. The aim of the study was to evaluate whether the frequency of multiple genomic alterations observed following ctDNA sequencing was similar to that observed following tissue sequencing in NSCLC. Methods: A total of 99 NSCLC patients were enrolled in this study, including 40 tissue and 59 plasma samples. All kinds of variants of oncogenic drivers in NSCLC were identified by next-generation sequencing (NGS) with Acornmed panel. Results: The frequencies of genetic alterations detected in ctDNA were significantly correlated to those detected via tissue profiling (Spearman’s r = 0.812, P = 0.022). Genomic data revealed significant mutual exclusivity between alterations in epidermal growth factor receptor ( EGFR) and tumor protein 53 ( TP53; P = 0.020) and between those in EGFR and Kirsten rat sarcoma viral oncogene homolog ( KRAS; P = 0.008), as well as potential mutual exclusivity between alterations in EGFR and Erb-B2 receptor tyrosine kinase 2 ( ERBB2; P = 0.059). Furthermore, the EGFR mutant allele frequency (MAF) was strongly correlated with the TP53 MAF in individual tumors (Spearman’s r = 0.773, P = 0.005), and there was a marked difference in the EGFR MAF between patients with and without the TP53 mutation (P = 0.001). Levels of the tumor serum marker CA242 in patients with ctDNA-detectable mutations were higher than those in patients without ctDNA-detectable mutations. Conclusions: This study provides a better understanding of the spectra of genomic alterations detected by tissue and plasma ctDNA assays in Chinese patients with NSCLC. The present data also highlights the importance of tissue and plasma ctDNA screening by NGS to guide personalized therapy and promote the clinical management of NSCLC patients.

scholarly journals Assessing tumor heterogeneity: integrating tissue and circulating tumor DNA (ctDNA) analysis in the era of immuno-oncology - blood TMB is not the same as tissue TMB

2021 ◽  
Vol 9 (8) ◽  
pp. e002551
Author(s):  
Stanislav Fridland ◽  
Jaeyoun Choi ◽  
Myungwoo Nam ◽  
Samuel Joseph Schellenberg ◽  
Eugene Kim ◽  
...  
Keyword(s):  
Tumor Heterogeneity ◽  
Predictive Power ◽  
Composite Index ◽  
Circulating Tumor Dna ◽  
Small Cell Lung ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Ctdna Analysis ◽  
Tumor Dna ◽  
Predict Treatment Response

Tissue tumor mutational burden (tTMB) is calculated to aid in cancer treatment selection. High tTMB predicts a favorable response to immunotherapy in patients with non-small cell lung cancer. Blood TMB (bTMB) from circulating tumor DNA is reported to have similar predictive power and has been proposed as an alternative to tTMB. Across many studies not only are tTMB and bTMB not concordant but also as reported previously by our group predict conflicting outcomes. This implies that bTMB is not a substitute for tTMB, but rather a composite index that may encompass tumor heterogeneity. Here, we provide a thorough overview of the predictive power of TMB, discuss the use of tumor heterogeneity alongside TMB to predict treatment response and review several methods of tumor heterogeneity assessment. Furthermore, we propose a hypothetical method of estimating tumor heterogeneity and touch on its clinical implications.

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