Abstract 5687: Detection and monitoring of IDH mutations in unamplified plasma cell-free DNA in patients with advanced cancers treated with IDH inhibitors

Abstract

Abstract Background: Cell-free (cf) DNA from plasma of patients with advanced cancers offers an easily obtainable material for detection of IDH mutations, which can be used for diagnostics and monitoring purposes. Methods: Plasma was serially collected from patients with advanced cancers with IDH1 R132 or IDH2 R172 mutations, who were enrolled to clinical trials with IDH1, IDH2 or pan-IDH inhibitors. cfDNA was purified and up to 16 ng of each DNA was tested for mutations in the R132 hotspot of IDH1 and R172 hotspot of IDH2 using the QX200 Droplet Digital PCR™ platform (Bio-Rad). Results (mutation allele frequency [MAF] in the wild-type background or the number of IDH-mutant copies/mL of plasma) were compared both to treatment outcomes and to the results of mutation analysis of either archival primary or metastatic tumor tissue obtained at different points of clinical care from a CLIA-certified laboratory. Results: Of the 28 patients (cholangiocarcinoma, 24; other cancers, 4) with IDH1 R132 mutations (N=25) or IDH2 R172 mutations (N=3) in the tumor tissue, IDH mutations were detected in 26 (93%) of plasma cfDNA samples even though median time from tissue to plasma sampling was 16.5 months (3.5-71.1 months). Quantity (< median vs. > median MAF or copies/mL) of IDH-mutant cfDNA was not associated with survival (median not reached vs. 11.1 months, P=0.26). The best radiological response to treatment with IDH inhibitors was stable disease for > 4 months (5/28, 18%) and the median progression-free survival was 1.8 months (95% CI 1.4-2.2). The median quantity of IDH-mutant cfDNA (MAF and copies/mL) at baseline, on therapy and at disease progression did not differ (P=0.16). Changes in quantity (MAF and copies/mL) of IDH-mutant cfDNA within first 3 weeks of therapy were not associated with response on radiographic imaging (P>0.65) or progression-free survival (P>0.12). Conclusions: Detection of IDH mutations in a small amount of unamplified plasma cfDNA using ddPCR has excellent sensitivity compared to conventional clinical IDH mutation testing of archival specimens. Quantity and change in IDH-mutant cfDNA did not correspond with treatment outcomes. Citation Format: Filip Janku, Helen J. Huang, Rachna T. Shroff, Milind Javle, Anthony P. Conley, Anjali Raina, Veronica R. Holley, Aung Naing, Daniel D. Karp, David Fogelman, Ahmed O. Kaseb, Rajyalakshmi Luthra, George A. Karlin-Neumann, Funda Meric-Bernstam. Detection and monitoring of IDH mutations in unamplified plasma cell-free DNA in patients with advanced cancers treated with IDH inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5687. doi:10.1158/1538-7445.AM2017-5687