Circulating Tumor DNA Predicts Outcome from First-, but not Second-line Treatment and Identifies Melanoma Patients Who May Benefit from Combination Immunotherapy

Abstract BACKGROUND The current standard for determining eligibility of patients with metastatic melanoma for BRAF-targeted therapy is tissue-based testing of BRAF mutations. As patients are rarely rebiopsied, detection in blood might be advantageous by enabling a comprehensive assessment of tumor mutational status in real time and thereby representing a noninvasive biomarker for monitoring BRAF therapy. METHODS In all, 634 stage I to IV melanoma patients were enrolled at 2 centers, and 1406 plasma samples were prospectively collected. Patients were assigned to 3 separate study cohorts: study 1 for assessment of circulating tumor DNA (ctDNA) as part of companion diagnostics, study 2 for assessment of ctDNA for patients with low tumor burden and for follow-up, and study 3 for monitoring of resistance to BRAF inhibitor (BRAFi) or mitogen-activated protein kinase inhibitor therapy. RESULTS Overall, a high degree of concordance between plasma and tissue testing results was observed at 90.9% (study 1) and 90.1% (study 2), respectively. Interestingly, discrepant results were in some cases associated with nonresponse to BRAFi (n = 3) or a secondary BRAF-mutant malignancy (n = 5). Importantly, ctDNA results correlated with the clinical course of disease in 95.7% and with response to treatment. Significantly, the detection of BRAF mutant ctDNA preceded relapse assessed by Response Evaluation Criteria in Solid Tumors, and was more specific than serum S100 and lactate dehydrogenase. CONCLUSIONS Blood-based testing compares favorably with standard-of-care tissue-based BRAF mutation testing. Importantly, blood-based BRAF testing correlates with the clinical course, even for early-stage patients, and may be used to predict response to treatment, recurrence, and resistance before radioimaging under BRAFi therapy, thereby enabling considerable improvements in patient treatment.

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Monitoring BRAF and NRAS mutations with cell-free circulating tumor DNA from metastatic melanoma patients

Oncotarget ◽

10.18632/oncotarget.26343 ◽

2018 ◽

Vol 9 (90) ◽

pp. 36238-36249 ◽

Cited By ~ 10

Author(s):

Elodie Long-Mira ◽

Marius Ilie ◽

Emmanuel Chamorey ◽

Florence Leduff-Blanc ◽

Henri Montaudié ◽

...

Keyword(s):

Metastatic Melanoma ◽

Circulating Tumor Dna ◽

Melanoma Patients ◽

Tumor Dna

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Dynamics and characteristics of KRAS mutated circulating tumor DNA in patients with metastatic colorectal cancer during various treatments.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.665 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 665-665

Author(s):

Yuji Takayama ◽

Koichi Suzuki ◽

Kosuke Ichida ◽

Taro Fukui ◽

Nao Kakizawa ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Disease Progression ◽

Kras Mutation ◽

Circulating Tumor Dna ◽

Line Treatment ◽

Tumor Tissues ◽

Significant Difference ◽

Before And After ◽

Tumor Dna

665 Background: KRAS mutated circulating tumor DNA (MctDNA) can be detected in blood of patients with metastatic colorectal cancer (mCRC) but its dynamics and characteristics during anti-EGFR and other treatments are not well known. Methods: Four hundred and fifty-one plasma samples were collected prospectively from 85 patients who underwent chemotherapy due to mCRC in 2014 - 2017. KRAS mutation in codon12/13/61 was explored in tumor tissues and plasma. Results: KRAS assessment in tumor tissues showed 29 patients with KRAS mutation (MT), 56 patients without mutation (WT). Sensitivity and specificity of MctDNA was 86.4% and 100%, respectively. In 29 patients with MT, significant difference in PFS was observed between patients with MctDNA and without during 1st line treatment (3.0 months vs.15.0 months; p = 0.005). In 56 patients with WT, 27 patients showed MctDNA during various treatments. Different characteristics in appearance were recognized during several treatments including anti-VEGF, TAS-102 and regorafenib. KRAS mutation in codon12/13 was appeared before and after disease progression. KRAS mutation in codon 61 was, however, frequently detected before disease progression. A spike like appearance of KRAS mutation in codon12/13 was likely seen in response to induction of the sequential treatment. Significant difference in PFS was observed between patients with MctDNA and without during 1st line treatment (6.0 months vs. 13.0 months; p = 0.0017), as was observed in patients with MT. Conclusions: Dynamics and characteristics of KRAS status in blood may be involved in the treatment response and outcome in mCRC patients.

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Circulating tumor DNA for monitoring treatment response to anti-PD-1 immunotherapy in melanoma patients

10.26226/morressier.595a9c59d462b80296ca018f ◽

2017 ◽

Author(s):

Atsuko Ashida

Keyword(s):

Treatment Response ◽

Circulating Tumor Dna ◽

Melanoma Patients ◽

Monitoring Treatment ◽

Tumor Dna ◽

Monitoring Treatment Response

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Circulating tumor DNA (ctDNA) detection is associated with shorter progression-free survival in advanced melanoma patients

Scientific Reports ◽

10.1038/s41598-020-75792-1 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Gabriella Taques Marczynski ◽

Ana Carolina Laus ◽

Mariana Bisarro dos Reis ◽

Rui Manuel Reis ◽

Vinicius de Lima Vazquez

Keyword(s):

Somatic Mutations ◽

Limit Of Detection ◽

Progression Free Survival ◽

Circulating Tumor Dna ◽

Advanced Melanoma ◽

Plasma Samples ◽

Free Survival ◽

Melanoma Patients ◽

Digital Polymerase Chain Reaction ◽

Tumor Dna

Abstract BRAF, NRAS and TERT mutations occur in more than 2/3 of melanomas. Its detection in patient’s blood, as circulating tumor DNA (ctDNA), represents a possibility for identification and monitoring of metastatic disease. We proposed to standardize a liquid biopsy platform to identify hotspot mutations in BRAF, NRAS and TERT in plasma samples from advanced melanoma patients and investigate whether it was associated to clinical outcome. Firstly, we performed digital polymerase chain reaction using tumor cell lines for validation and determination of limit of detection (LOD) of each assay and screened plasma samples from healthy individuals to determine the limit of blank (LOB). Then, we selected 19 stage III and IV patients and determined the somatic mutations status in tumor tissue and track them in patients’ plasma. We established a specific and sensitive methodology with a LOD ranging from 0.13 to 0.37%, and LOB ranging from of 0 to 5.201 copies/reaction. Somatic mutations occurred in 17/19 (89%) patients, of whom seven (41%) had ctDNA detectable their paired plasma. ctDNA detection was associated with shorter progression free survival (p = 0.01). In conclusion, our data support the use of ctDNA as prognosis biomarker, suggesting that patients with detectable levels have an unfavorable outcome.

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