<p>Circulating Tumor DNA Correlates with Outcome in Metastatic Melanoma Treated by BRAF and MEK Inhibitors – Results of a Prospective Biomarker Study</p>

We prospectively performed a longitudinal analysis of circulating tumor DNA (ctDNA) from 149 plasma samples and CT scans in Stage III and IV metastatic melanoma patients (n = 20) treated with targeted agents or immunotherapy using two custom next-generation sequencing (NGS) Ion AmpliSeq™ HD panels including 60 and 81 amplicons in 18 genes, respectively. Concordance of matching cancer-associated mutations in tissue and plasma was 73.3%. Mutant allele frequency (MAF) levels showed a range from 0.04% to 28.7%, well detectable with NGS technologies utilizing single molecule tagging like the AmpliSeq™ HD workflow. Median followup time of the tissue and/or plasma positive cohort (n = 15) was 24.6 months and median progression-free survival (PFS) was 7.8 months. Higher MAF ≥ 1% at baseline was not significantly associated with a risk of progression (Odds Ratio = 0.15; p = 0.155). Although a trend could be seen, MAF levels did not differ significantly over time between patients with and without a PFS event (p = 0.745). Depending on the cell-free DNA amount, NGS achieved a sensitivity down to 0.1% MAF and allowed for parallel analysis of multiple mutations and previously unknown mutations. Our study indicates that NGS gene panels could be useful for monitoring disease burden during therapy with ctDNA in melanoma patients.

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Association Between Circulating Tumor DNA and Pseudoprogression in Patients With Metastatic Melanoma Treated With Anti–Programmed Cell Death 1 Antibodies

JAMA Oncology ◽

10.1001/jamaoncol.2017.5332 ◽

2018 ◽

Vol 4 (5) ◽

pp. 717 ◽

Cited By ~ 84

Author(s):

Jenny H. Lee ◽

Georgina V. Long ◽

Alexander M. Menzies ◽

Serigne Lo ◽

Alexander Guminski ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Metastatic Melanoma ◽

Circulating Tumor Dna ◽

Programmed Cell Death 1 ◽

Tumor Dna

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Ultrasensitive detection of BRAF mutations in circulating tumor DNA of non-metastatic melanoma

ESMO Open ◽

10.1016/j.esmoop.2021.100357 ◽

2022 ◽

Vol 7 (1) ◽

pp. 100357

Author(s):

M.A. Gouda ◽

J. Polivka ◽

H.J. Huang ◽

I. Treskova ◽

K. Pivovarcikova ◽

...

Keyword(s):

Metastatic Melanoma ◽

Circulating Tumor Dna ◽

Ultrasensitive Detection ◽

Braf Mutations ◽

Tumor Dna

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Undetectable circulating tumor DNA (ctDNA) levels correlate with favorable outcome in metastatic melanoma patients treated with anti-PD1 therapy

Journal of Translational Medicine ◽

10.1186/s12967-019-2051-8 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 16

Author(s):

Teofila Seremet ◽

Yanina Jansen ◽

Simon Planken ◽

Hassan Njimi ◽

Mélanie Delaunoy ◽

...

Keyword(s):

Metastatic Melanoma ◽

Circulating Tumor Dna ◽

Favorable Outcome ◽

Melanoma Patients ◽

Tumor Dna

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Elevated Levels of BRAFV600 Mutant Circulating Tumor DNA and Circulating Hepatocyte Growth Factor Are Associated With Poor Prognosis in Patients With Metastatic Melanoma

JCO Precision Oncology ◽

10.1200/po.17.00168 ◽

2018 ◽

pp. 1-17 ◽

Cited By ~ 2

Author(s):

William Lu ◽

Luciana Burton ◽

James Larkin ◽

Paul B. Chapman ◽

Paolo A. Ascierto ◽

...

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Metastatic Melanoma ◽

Proportional Hazards ◽

Circulating Tumor Dna ◽

Phase Iii ◽

Disease Stage ◽

Enzyme Linked Immunosorbent Assay ◽

Hepatocyte Growth ◽

Tumor Dna

Purpose We performed a retrospective exploratory analysis to evaluate the prognostic and predictive effect of two circulating biomarkers, BRAFV600 mutant circulating tumor DNA (ctDNA) and circulating hepatocyte growth factor (cHGF), in metastatic melanoma. Materials and Methods This study evaluated patients from BRIM-3, a phase III trial comparing vemurafenib and dacarbazine in 675 patients with BRAFV600 mutated advanced melanoma. ctDNA was measured using droplet digital polymerase chain reaction, and cHGF was measured by enzyme-linked immunosorbent assay. Overall survival (OS) was estimated using the Kaplan-Meier method, and hazard ratios (HRs) were estimated using Cox proportional hazards modeling. Partitioning analysis was used to group patients into risk categories. Results Patients with elevated levels of baseline BRAFV600 ctDNA had significantly shorter median OS than those with undetectable levels of ctDNA (vemurafenib arm, 9.9 v 21.4 months, respectively, and dacarbazine arm: 6.1 v 21.0 months, respectively). Median OS was also shorter in patients with high levels of cHGF compared with those with low cHGF (vemurafenib arm, 11.9 v 17.3 months, respectively, and dacarbazine arm, 6.1 v 14.4 months, respectively). In a multivariable proportional hazards model with adjustment for lactate dehydrogenase, Eastern Cooperative Oncology Group status, disease stage, and treatment, ctDNA and cHGF were both independent prognostic factors for OS, (HR, 1.75; 95% CI, 1.35 to 2.28 for high v undetectable ctDNA; HR, 1.24; 95% CI, 1.00 to 1.53 for high v low cHGF). Using partitioning analysis, we found that patients with elevated ctDNA combined with elevated cHGF constituted the highest risk group with significantly shorter OS. Conclusion Here, we report that BRIM-3 patients with high levels of ctDNA and cHGF have worse OS regardless of treatment and that these factors are independent prognostic markers for metastatic melanoma.

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