Abstract PD1-02: Circulating tumor DNA (ctDNA): A <i>real-time</i> application of precision medicine to the management of metastatic breast cancer (MBC)
Authors: G Rossi, LK Austin, RJ Nagy, AW Rademaker, WJ Gradishar, CA Santa-Maria, RL Curry-Edwards, S Jain, LE Flaum, R Lima Barros Costa, V Zagonel, LC Platanias, FJ Giles, A Talasaz, M Cristofanilli
Journal: Cancer Research (2017)

Abstract Background: Molecular diagnostic, in particular next-generation sequencing (NGS) technologies, improved the detection of actionable mutations (muts) in MBC at baseline and recurrence. We evaluated the ability of ctDNA to detect molecular abnormalities, monitor disease progression and predict outcome. Methods: We conducted a retrospective study of 91 patients (pts) with locally advanced and MBC, who had longitudinal assessment of their disease by ctDNA analysis. The plasma-based assay was performed utilizing Guardant360 (Guardant Health, CA), a digital NGS technology to sequence a panel of &amp;gt; 50 cancer genes. After tabulating number of muts and quantification of overall ctDNA detected for every patient at baseline, a receiver operating characteristic (ROC) analysis was performed to identify the best cut-offs that separated the pts who had a disease progression from those who hadn't, and the patients who died from those still alive. The overall survival (OS) analysis has been performed using Kaplan-Meier curves. Results: 84 pts (92%) had stage IV cancer. 63% cases were ER+, 27% HER2+, 29% TNBC. 277 blood samples were collected and 84% had muts. 65% of the pts had serial samples. The average number of alterations detected in each sample was 3 (0-27) and the average ctDNA fraction detected was 4.5% (0-88.2%). The most common alterations were: TP53 (52%), PIK3CA (40%), ERBB2 (20%), NOTCH1 (15.5%), APC (14%), MET (13%). 16 pts (19%) were initiated on a targeted therapy based on ctDNA test results. At the time of analysis 36 pts (39.6%) were dead, 55 (60.4%) were currently alive. PFS was 5.2 months (ms) and OS was 21.5 ms. A statistically significant difference in PFS and OS by log rank test was found between % ctDNA at baseline &amp;lt; 0.5 versus ≥ 0.5 (p = 0.003 and p = 0.012, respectively) and number of muts at baseline &amp;lt; 2 versus ≥ 2 (p = 0.059 borderline and p = 0.0015). Moreover, a statistically significant association by Fisher's exact test was found between the number of alterations and the % ctDNA detected in the baseline sample (% of pts with muts ≥ 2 was 19% when % ctDNA &amp;lt; 0.5%, versus 85% when % ctDNA ≥ 0.5%; p &amp;lt; 0.0001). PFS (ms) p = 0.059 (log rank test)Muts &amp;lt; 2 (n = 32)Muts ≥ 2 (n = 58)658%40%1230%13%1821%6%24--PFS(ms) p = 0.003 (log rank test)% ctDNA &amp;lt; 0.5(n = 27)% ctDNA ≥ 0.5(n = 60)665%39%1241%10%1823%6%24-- OS(ms) p = 0.002 (log rank test)Muts &amp;lt; 2(n = 32)Muts ≥ 2(n = 57)697%66%1288%51%1888%42%24-29%OS(ms) p = 0.012 (log rank test)% ctDNA &amp;lt; 0.5(n = 27)% ctDNA ≥ 0.5(n = 59)696%69%1290%55%1885%48%24-35% Conclusions: ctDNA liquid biopsy provides a real-time, quantitative NGS-based assessment of MBC which is useful for treatment planning, disease monitoring and prognostic evaluation. Future prospective studies should consider the use of ctDNA for molecular and prognostic stratification. Citation Format: Rossi G, Austin LK, Nagy RJ, Rademaker AW, Gradishar WJ, Santa-Maria CA, Curry-Edwards RL, Jain S, Flaum LE, Lima Barros Costa R, Zagonel V, Platanias LC, Giles FJ, Talasaz A, Cristofanilli M. Circulating tumor DNA (ctDNA): A real-time application of precision medicine to the management of metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD1-02.