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    Prediction and monitoring of relapse in stage III melanoma using circulating tumor DNA

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    Authors
    Tan, L
    Sandhu, S
    Lee, Rebecca J
    Li, J
    Callahan, J
    Ftouni, S
    Dhomen, Nathalie
    Middlehurst, P
    Wallace, A
    Raleigh, J
    Hatzimihalis, A
    Henderson, M
    Shackleton, M
    Haydon, A
    Mar, V
    Gyorki, D
    Oudit, Deemesh
    Dawson, M
    Hicks, R
    Lorigan, Paul C
    McArthur, G
    Marais, Richard
    Wong, S
    Dawson, S
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    Affiliation
    Peter MacCallum Cancer Centre, Melbourne, Australia
    Issue Date
    2019
    
    Metadata
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    Abstract
    BACKGROUND: The advent of effective adjuvant therapies for patients with resected melanoma has highlighted the need to stratify patients based on risk of relapse given the cost and toxicities associated with treatment. Here we assessed circulating tumor DNA (ctDNA) to predict and monitor relapse in resected stage III melanoma. PATIENTS AND METHODS: Somatic mutations were identified in 99/133 (74%) patients through tumor tissue sequencing. Personalized droplet digital PCR (ddPCR) assays were used to detect known mutations in 315 prospectively collected plasma samples from mutation-positive patients. External validation was performed in a prospective independent cohort (n?=?29). RESULTS: ctDNA was detected in 37 of 99 (37%) individuals. In 81 patients who did not receive adjuvant therapy, 90% of patients with ctDNA detected at baseline and 100% of patients with ctDNA detected at the postoperative timepoint relapsed at a median follow up of 20?months. ctDNA detection predicted patients at high risk of relapse at baseline [relapse-free survival (RFS) hazard ratio (HR) 2.9; 95% confidence interval (CI) 1.5-5.6; P?=?0.002] and postoperatively (HR 10; 95% CI 4.3-24; P?<?0.001). ctDNA detection at baseline [HR 2.9; 95% CI 1.3-5.7; P?=?0.003 and postoperatively (HR 11; 95% CI 4.3-27; P?<?0.001] was also associated with inferior distant metastasis-free survival (DMFS). These findings were validated in the independent cohort. ctDNA detection remained an independent predictor of RFS and DMFS in multivariate analyses after adjustment for disease stage and BRAF mutation status. CONCLUSION: Baseline and postoperative ctDNA detection in two independent prospective cohorts identified stage III melanoma patients at highest risk of relapse and has potential to inform adjuvant therapy decisions.
    Citation
    Tan L, Sandhu S, Lee RJ, Li J, Callahan J, Ftouni S, et al. Prediction and monitoring of relapse in stage III melanoma using circulating tumor DNA. Ann Oncol. 2019.
    Journal
    Annals of Oncology
    URI
    http://hdl.handle.net/10541/621753
    DOI
    10.1093/annonc/mdz048
    PubMed ID
    30838379
    Additional Links
    https://dx.doi.org/10.1093/annonc/mdz048
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1093/annonc/mdz048
    Scopus Count
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