<jats:title>Abstract</jats:title> <jats:p>Background: A recent phase II trial in recurrent small cell lung cancer (SCLC) demonstrated that patients with high SLFN11 expression in tissue biopsies had improved survival when treated with PARP inhibition (PARPi). EZH2 is also highly expressed in SCLC tissue and is associated with chemo-resistance through epigenetic silencing of SLFN11. Here we developed a liquid biopsy test to explore the clinical feasibility of utilizing SLFN11 and EZH2 expression on circulating tumor cells (CTCs) to aid in the prediction of drug response/resistance of DNA damaging chemotherapy or PARPi in SCLC.</jats:p> <jats:p>Material and methods: 26 blood samples (19 baseline and 7 on-therapy) from SCLC patients treated at MDACC were sent to Epic Sciences for CTC enumeration (intact DAPI, CK+, cancer cell morphology) and characterization with SLFN11 and EZH2 immunoassays. Nuclear localization and expression of SLFN11 and EZH2 were quantified.</jats:p> <jats:p>Results: 17/19 (89%) of baseline and 5/7 (71%) post-therapy samples had detectable CTCs. 19/26 (73%) samples had SLFN11+ CTCs and 8/26 (31%) samples had nuclear localized SLFN11. For samples with SLFN11+ CTCs detected, the percentage of SLFN11+ cells ranged from 2.4 to 100%. 10/26 (38%) samples had EZH2+ CTCs and 9/26 (35%) samples had nuclear localized EZH2. For samples with EZH2+ CTCs, the percentage of EZH2+ cells ranged from 19 to 83%. 6 samples had both nuclear localized SLFN11 and EZH2 CTCs detected.</jats:p> <jats:p>Conclusions: Inter- and intra-sample heterogenous SLFN11 and EZH2 protein expression was observed in SCLC patients. Use of these assays is underway in SCLC patient samples to assess correlation with PARPi and platinum agent response.</jats:p> <jats:p>Citation Format: Lauren Averett Byers, Allison Stewart, Carl Gay, John Heymach, Luisa Fernandez, David Lu, Robin Rich, Lincy Chu, Yipeng Wang, Ryan Dittamore. SLFN11 and EZH2 protein expression and localization in circulating tumor cells to predict response or resistance to DNA damaging therapies in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2215.</jats:p>