Abstract 5534: Analysis of <i>TERT</i> <i>mutant</i> circulating tumor DNA as a potential biomarker of disease activity in patients with unresectable stage III/IV melanoma receiving immuno-oncology therapies
Authors: Mahrukh M. Syeda, Broderick Corless, Melissa Wilson, Yesung Lee, Jeremy Tchack, Todd Wechter, Una Moran, George Karlin-Neumann, Anna C. Pavlick, Iman Osman, Yongzhao Shao, David Polsky
Journal: Cancer Research (2018)

Abstract Purpose: Our goal is to develop response predictive biomarkers for melanoma patients that are more sensitive than standard measures of disease activity. TERT promoter mutations occur frequently in many cancers, especially melanoma. We developed droplet digital PCR assays that detect the 2 most frequently occurring TERT promoter mutations, C228T and C250T. We previously demonstrated that these assays could detect TERTmutant cell-free, circulating tumor DNA (ctDNA) in the plasma of metastatic melanoma patients. In the current study we sought to compare the clinical sensitivity and specificity of these blood-based assays to the current blood biomarker, lactate dehydrogenase (LDH), in detecting the presence of metastatic melanoma and disease progression among patients with unresectable Stage III/IV disease. Methods: We analyzed 71 patients' tumors with unresectable stage III/IV metastatic melanoma undergoing treatment with immuno-oncology therapies, prospectively acquired by the NYU Interdisciplinary Melanoma Cooperative Group. TERT mutations were identified in tumors using droplet digital PCR (ddPCR) or SNaPShot assays (prior to the development of the ddPCR assays). Patients with TERT mutant tumors were selected for further study based on the availability of serial blood collections and radiographic scan data. ddPCR assays used to analyze ctDNA from these patients were chosen based on the tumor mutation detected. Plasmas used for ctDNA analysis ranged from 1-5 mL (73% having at least 4 mL). The ctDNA results were compared with LDH levels and disease status based on radiographic scans and clinical notes. Results: We identified TERT mutations in 31/71 (44%) tumors (18/31 C228T and 13/31 C250T). Our final data set consisted of 26 patients with 85 plasmas. Among patients with available pretreatment samples, ctDNA and LDH were elevated in 14/24 (58%) and 5/24 (21%) patients, respectively (p-value=0.012, McNemar exact test). Among patients whose disease progressed, ctDNA and LDH were elevated at the time of progression in 11/16 (69%) and 4/16 (25%) patients, respectively (p=0.039). Among the patients who had either a complete response (n=2), partial response (n=3), or stable disease (n=3), 1/8 had a slightly elevated ctDNA (3.8 copies/mL with normal level &amp;lt;3 copies/mL). None of the patients had an elevated LDH. One patient had a mixed response associated with an elevated ctDNA (13.2 copies/mL) and RECIST score equal to 3.4 cm, and then the ctDNA dropped below baseline when the RECIST measurement fell to 2.8 cm on a follow-up scan. Conclusion: These data demonstrate that ddPCR assays detecting TERT C228T or C250T mutations in ctDNA of metastatic melanoma patients have a greater sensitivity to detect the presence of metastatic disease and disease progression than the currently used standard, LDH. Citation Format: Mahrukh M. Syeda, Broderick Corless, Melissa Wilson, Yesung Lee, Jeremy Tchack, Todd Wechter, Una Moran, George Karlin-Neumann, Anna C. Pavlick, Iman Osman, Yongzhao Shao, David Polsky. Analysis of TERTmutant circulating tumor DNA as a potential biomarker of disease activity in patients with unresectable stage III/IV melanoma receiving immuno-oncology therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5534.