ABSTRACT
BACKGROUND: Detectable circulating tumor DNA (ctDNA) has been associated with worse prognosis in melanoma patients. MATERIAL AND METHODS: We studied plasma ctDNA as a prognostic biomarker in 19 patients with metastatic melanoma and a detectable tumor mutation (13 BRAF, 5 NRAS, and 1 KRAS). Patients had received chemotherapy, interferon-alpha, and vemurafenib in a prospective clinical trial. Mutant allele frequency (MAF %) was determined with droplet digital PCR from pretreatment and sequential plasma samples. RESULTS: Higher pretreatment plasma ctDNA levels (MAF ≥3%) and detectable plasma ctDNA levels (MAF >0%) at the time of radiologically confirmed best objective response were associated with poor prognosis even when accounting for other relevant prognostic factors including performance status, tumor mutation, metastasis stage, and lactate dehydrogenase levels in multivariable analysis. CONCLUSION: Higher pretreatment plasma ctDNA levels and sustained detectable plasma ctDNA levels during treatment indicated poor prognosis in metastatic melanoma patients.
Subject(s)
Circulating Tumor DNA , Melanoma , Neoplasms, Second Primary , Humans , Biomarkers , Biomarkers, Tumor/genetics , Circulating Tumor DNA/genetics , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Mutation , Prognosis , Prospective Studies , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/geneticsSubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Melanoma/drug therapy , Adult , Aged , Cohort Studies , Female , Follow-Up Studies , Humans , Interferon-alpha/administration & dosage , Lomustine/administration & dosage , Male , Melanoma/pathology , Middle Aged , Prognosis , Survival Rate , Temozolomide/administration & dosage , Vemurafenib/administration & dosage , Vincristine/administration & dosageABSTRACT
PURPOSE: Detection of bone metastases in breast and prostate cancer patients remains a major clinical challenge. The aim of the current trial was to compare the diagnostic accuracy of (99m)Tc-hydroxymethane diphosphonate ((99m)Tc-HDP) planar bone scintigraphy (BS), (99m)Tc-HDP SPECT, (99m)Tc-HDP SPECT/CT, (18)F-NaF PET/CT and whole body 1.5 Tesla magnetic resonance imaging (MRI), including diffusion weighted imaging, (wbMRI+DWI) for the detection of bone metastases in high risk breast and prostate cancer patients. MATERIAL AND METHODS: Twenty-six breast and 27 prostate cancer patients at high risk of bone metastases underwent (99m)Tc-HDP BS, (99m)Tc-HDP SPECT, (99m)Tc-HDP SPECT/CT, (18)F-NaF PET/CT and wbMRI+DWI. Five independent reviewers interpreted each individual modality without the knowledge of other imaging findings. The final metastatic status was based on the consensus reading, clinical and imaging follow-up (minimal and maximal follow-up time was 6, and 32 months, respectively). The bone findings were compared on patient-, region-, and lesion-level. RESULTS: (99m)Tc-HDP BS was false negative in four patients. In the region-based analysis, sensitivity values for (99m)Tc-HDP BS, (99m)Tc-HDP SPECT, (99m)Tc-HDP SPECT/CT, (18)F-NaF PET/CT, and wbMRI+DWI were 62%, 74%, 85%, 93%, and 91%, respectively. The number of equivocal findings for (99m)Tc-HDP BS, (99m)Tc-HDP SPECT, (99m)Tc-HDP SPECT/CT, (18)F-NaF PET/CT and wbMRI+DWI was 50, 44, 5, 6, and 4, respectively. CONCLUSION: wbMRI+DWI showed similar diagnostic accuracy to (18)F-NaF PET/CT and outperformed (99m)Tc-HDP SPECT/CT, and (99m)Tc-HDP BS.
Subject(s)
Bone Neoplasms/diagnostic imaging , Bone Neoplasms/secondary , Breast Neoplasms , Magnetic Resonance Imaging/methods , Multimodal Imaging/methods , Positron-Emission Tomography/methods , Prostatic Neoplasms , Bone and Bones/diagnostic imaging , Diphosphonates , Female , Fluorodeoxyglucose F18 , Humans , Male , Positron Emission Tomography Computed Tomography , Prospective Studies , Radionuclide Imaging , Sensitivity and Specificity , Technetium CompoundsABSTRACT
There are no identified biomarkers that could predict response to antiangiogenic or traditional chemoimmunotherapy in metastatic melanoma. We hypothesized that soluble angiogenic factor receptors might help us to identify patients responsive to treatment. A series of 48 patients with stage IV melanoma participating in two phase II clinical trials were included. The trials included treatment with carboplatin, vinorelbine, and subcutaneous interleukin-2 (n=22) or treatment with bevacizumab, dacarbazine, and low-dose interferon-α2a (n=26).Serum samples were prospectively collected and soluble vascular endothelial growth factor receptor 1 (s-VEGFR-1) and 2 (s-VEGFR-2) were measured before starting the trial treatment and during response evaluation.There was a trend toward longer overall survival among patients with higher-than-median serum VEGFR-1 levels (21.3 months) compared with 12.3 months in patients with low pretreatment s-VEGFR-1 levels (P=0.146). Pretreatment s-VEGFR-2 levels did not correlate to survival. Serum VEGFR-2 levels decreased during therapy in 44% of the patients and increased in 56% of the patients. VEGFR-2 increased in 78% (14 of 18) of the patients who progressed during therapy (P=0.017). VEGFR-2 decrease was associated with clinical benefit in 65% of the patients (11 of 17) and with progression in only four patients (P=0.016).High pretreatment levels of s-VEGFR-1 are associated with improved prognosis among patients with metastatic melanoma independently on therapy, whereas increased VEGFR-2 levels during therapy are associated with disease progression. These markers might be useful in selecting patients responsive to antiangiogenic therapy.
