Background: Clinical benefit in response to chemotherapeutic agents that induce replication stress such as PARP inhibitors and cisplatin has been associated with mutations in DNA damage repair (DDR) genes. However, prediction of benefit is not solely explained by DDR mutations; therefore, additional biomarkers for prediction of clinical benefit of these agents are needed. SLFN11 is recruited to stalled replication forks where it sensitizes cells to DNA damage induced replication stress . Presence of SLFN11 protein expression in tumor cells is related to pre-clinical and clinical benefit of PARPi in small cell lung cancer. Previously, we reported high cellular heterogeneity in progressive mCRPC, and as such, we sought to examine whether SLFN11 protein expression was expressed in patients offered platinum chemotherapy to understand the subclonal heterogeneity of CTCs with and without SLFN11 protein expression.

Material and methods: 30 blood samples from mCRPC patients prior to treatment with a platinum chemotherapy from MSKCC were sent to Epic Sciences for CTC enumeration and SLFN11 protein expression characterization. Nuclear localization of SLFN11 was reviewed by a trained technician. 70 CTCs from patients with and without SLFN11 CTCs were single cell sequenced and analyzed for copy number alterations (CNA) and clonality.

Results: 83% (25/30) of patient samples had detectable CTCs, and 53% (16/30) samples had at least one SLFN11+ CTC. For patients with SLFN11(+) CTCs, 81% (13/16) had only nuclear localized SLFN11 expression; 6% (1/16) had a mix of CTCs with nuclear and non-nuclear localized SLFN11 expression; 13% (2/16) had no nuclear localized SLFN11 expression. In 13 patients with exclusively nuclear localized SLFN11 expression, the % of SLFN11(+) CTCs ranged from 2-100% with median of 11%. Single CTC NGS analysis of patients demonstrated genomic heterogeneity between CTCs. In patients with both SLFN11+ and SLFN11- CTCs, no discernable clonal or CNA difference was observed between SLFN11+ and SLFN11- CTCs.

Conclusions: SLFN11 protein expression was observed subclonally in a majority fraction of patients with progressive mCRPC prior to platinum chemotherapy. SLFN11 expression heterogeneity was not consistent with a genetic mechanism. Studies examining whether SLFN11+ CTCs as a sensitivity marker to PARPi & cisplatin, but not ARSi or taxanes in mCRPC are ongoing.

Citation Format: Luisa Fernandez, John Poirier, Angel Rodriguez, Melanie Hulling, Robin Richardson, Ramsay Sutton, Rhett Jiles, Joseph Schonhoft, Jerry Lee, Nadia Ebrahim, Emily Carbone, Ethan Barnett, Mark Landers, Yipeng Wang, Ryan Dittamore, Charles Rudin, Howard Scher. Characterization of SLFN11 protein expression in circulating tumor cells (CTCs) of patients with metastatic castration resistant prostate cancer (mCRPC) prior to platinum based chemotherapy [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 1348.