Transient appearance of circulating tumor DNA associated with de novo treatment

Kato, Kikuya; Uchida, Junji; Kukita, Yoji; Kumagai, Toru; Nishino, Kazumi; Inoue, Tomio; Kimura, Masashi; Imamura, Fumio

doi:10.1038/srep38639

Cited by 12 publications

(7 citation statements)

References 31 publications

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“…Given the clinical implications of tumor heterogeneity, one of the most significant unanswered questions in ctDNA analysis is whether ctDNA observed during therapy is more representative of resistant or responsive tumor cell populations. In a study of lung cancer patients undergoing EGFR tyrosine kinase inhibitor (TKI) therapy, ctDNA sampled 2 weeks after treatment initiation revealed activating mutations not previously detected in the tumor biopsies ( 112 ). Another study of lung cancer patients on TKIs found that clearing of ctDNA within days of treatment was associated with response, whereas sudden increases in ctDNA load later in treatment correlated with rapid tumor progression and poor outcome ( 113 ).…”

Section: The Effect Of Treatment On Circulating Tumor Dna Abundancementioning

confidence: 99%

Blood, Toil, and Taxoteres: Biological Determinants of Treatment-Induced ctDNA Dynamics for Interpreting Tumor Response

Boniface¹,

Spellman²

2022

Pathol. Oncol. Res.

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Collection and analysis of circulating tumor DNA (ctDNA) is one of the few methods of liquid biopsy that measures generalizable and tumor specific molecules, and is one of the most promising approaches in assessing the effectiveness of cancer care. Clinical assays that utilize ctDNA are commercially available for the identification of actionable mutations prior to treatment and to assess minimal residual disease after treatment. There is currently no clinical ctDNA assay specifically intended to monitor disease response during treatment, partially due to the complex challenge of understanding the biological sources of ctDNA and the underlying principles that govern its release. Although studies have shown pre- and post-treatment ctDNA levels can be prognostic, there is evidence that early, on-treatment changes in ctDNA levels are more accurate in predicting response. Yet, these results also vary widely among cohorts, cancer type, and treatment, likely due to the driving biology of tumor cell proliferation, cell death, and ctDNA clearance kinetics. To realize the full potential of ctDNA monitoring in cancer care, we may need to reorient our thinking toward the fundamental biological underpinnings of ctDNA release and dissemination from merely seeking convenient clinical correlates.

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Section: The Effect Of Treatment On Circulating Tumor Dna Abundancementioning

confidence: 99%

Blood, Toil, and Taxoteres: Biological Determinants of Treatment-Induced ctDNA Dynamics for Interpreting Tumor Response

Boniface¹,

Spellman²

2022

Pathol. Oncol. Res.

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“…2 Line graphs depicting the VAF of mutations (labelled on each graph) detected in patients 1 to 5 (a-e, respectively) at baseline, 3 days and 7 days mid-treatment exhibited a transient rise prior to the eventual decrease (3/14 [23] and 2 /10 [24]). In addition, transient rises in ctDNA have been observed following systemic therapy, such as immunotherapy in melanoma [39], neoadjuvant combined cytotoxic/biologic combination therapy in breast carcinoma [40] and tyrosine kinase inhibition in EGFR-mutant NSCLC [41]. This pilot study demonstrates the feasibility of applying ctDNA-optimised NGS protocols through specified time-points in a small, homogenous cohort of patients treated with modern radiotherapy planning for locally advanced NSCLC.…”

Section: Discussionmentioning

confidence: 87%

Early circulating tumour DNA kinetics measured by ultra-deep next-generation sequencing during radical radiotherapy for non-small cell lung cancer: a feasibility study

Walls

McConnell²,

McAleese

et al. 2020

Radiat Oncol

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Background: The evaluation of circulating tumour DNA (ctDNA) from clinical blood samples, liquid biopsy, offers several diagnostic advantages compared with traditional tissue biopsy, such as shorter processing time, reduced patient risk and the opportunity to assess tumour heterogeneity. The historically poor sensitivity of ctDNA testing, has restricted its integration into routine clinical practice for non-metastatic disease. The early kinetics of ctDNA during radical radiotherapy for localised NSCLC have not been described with ultra-deep next generation sequencing previously. Materials and methods: Patients with CT/PET-staged locally advanced, NSCLC prospectively consented to undergo serial venepuncture during the first week of radical radiotherapy alone. All patients received 55Gy in 20 fractions. Plasma samples were processed using the commercially available Roche AVENIO Expanded kit (Roche Sequencing Solutions, Pleasanton, CA, US) which targets 77 genes. Results: Tumour-specific mutations were found in all patients (1 in 3 patients; 2 in 1 patient, and 3 in 1 patient). The variant allele frequency of these mutations ranged from 0.05-3.35%. In 2 patients there was a transient increase in ctDNA levels at the 72 h timepoint compared to baseline. In all patients there was a non-significant decrease in ctDNA levels at the 7-day timepoint in comparison to baseline (p = 0.4627). Conclusion: This study demonstrates the feasibility of applying ctDNA-optimised NGS protocols through specified time-points in a small homogenous cohort of patients with localised lung cancer treated with radiotherapy. Studies are required to assess ctDNA kinetics as a predictive biomarker in radiotherapy. Priming tumours for liquid biopsy using radiation warrants further exploration.

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“…5 ). Previously, early spike in ctDNA has been regarded to reflect cell death and treatment efficacy [ 18 , 19 ]. In terms of tumor detection and diagnosis, the current study might be helpful for patients with small tumors, in whom ctDNA might not otherwise be detected [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

Targeted Liquid Biopsy Using Irradiation to Facilitate the Release of Cell-Free DNA from a Spatially Aimed Tumor Tissue

et al. 2022

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We investigated the feasibility of using an anatomically localized, target-enriched liquid biopsy (TLB) in mouse models of lung cancer. Materials and MethodsAfter irradiating xenograft mouse with human lung-cancer cell lines, H1299 (NRAS protooncogene, GTPase (NRAS) Q61K) and HCC827 (EGFR E746-750del), ctDNA levels were monitored with quantitative PCR (qPCR) on human long interspersed nuclear element-1 (LINE-1) and cell line-specific mutations. We checked dose-dependency at 6, 12, or 18 Gy to each tumor-bearing mouse leg using 6-MV photon beams. We also analyzed ctDNA of lung cancer patients by LiquidSCAN, a targeted deep sequencing to validated the clinical performances of TLB method. ResultsIrradiation could enhance the detection sensitivity of NRAS Q61K in the plasma sample of H1299-xenograft mouse to 4.5-fold. While cell-free DNA (cfDNA) level was not changed at 6 Gy, ctDNA level was increased upon irradiation. Using double-xenograft mouse with H1299 and HCC827, ctDNA PCR analysis with local irradiation in each region could specify mutation type matched to transplanted cell types, proposing an anatomically localized, target-enriched liquid biopsy. Furthermore, when we performed targeted deep sequencing of cfDNA to monitor ctDNA level in 11 patients with lung cancer who underwent radiotherapy, the average ctDNA level was increased within a week after the start of radiotherapy. ConclusionTLB using irradiation could temporarily amplify ctDNA release in xenograft mouse and lung cancer patients, which enables us to develop theragnostic method for cancer patients with accurate ctDNA detection.

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Transient appearance of circulating tumor DNA associated with de novo treatment

Cited by 12 publications

References 31 publications

Blood, Toil, and Taxoteres: Biological Determinants of Treatment-Induced ctDNA Dynamics for Interpreting Tumor Response

Blood, Toil, and Taxoteres: Biological Determinants of Treatment-Induced ctDNA Dynamics for Interpreting Tumor Response

Early circulating tumour DNA kinetics measured by ultra-deep next-generation sequencing during radical radiotherapy for non-small cell lung cancer: a feasibility study

Targeted Liquid Biopsy Using Irradiation to Facilitate the Release of Cell-Free DNA from a Spatially Aimed Tumor Tissue

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