Detection Of Dna Replication Blocker Slfn11 In Tumor Tissue And Circulating Tumor Cells To Predict Platinum Response In Small Cell Lung Cancer.

Abstract Small cell lung cancer (SCLC) is an aggressive form of neuroendocrine carcinoma, notable for early metastases and rapid relapse despite initial response to frontline platinum-based chemotherapy. To date, there are no validated predictive biomarkers in SCLC, hence all patients are treated the same way. Preclinical studies identified SLFN11, a putative DNA/RNA helicase that blocks replication at stressed replication fork, as a predictive biomarker to a wide range of agents targeting DNA damage such as platinum, topoisomerase I/II inhibitors and PARP inhibitors. Based on these observations, pre-specified biomarker analyses in a clinical trial demonstrated SLFN11 predicts better clinical outcomes in SCLC patients when treated with PARP inhibitor combinations such as temozolomide and veliparib. To better characterize the prevalence, heterogeneity and predictive value of SLFN11 in SCLC, we developed and validated a SLFN11 immunohistochemistry (IHC) assay meeting Clinical Laboratory Improvements Amendments (CLIA) standards, and a novel circulating tumor cell (CTC) assay (Epic Sciences®) to detect the expression level of SLFN11 in SCLC tumors or CTCs and correlated with clinical outcomes. We found that SLFN11 was expressed by IHC in roughly 50% of the SCLC clinical tumor samples, from three separate clinical trial cohorts (total of 207 extensive-stage SCLC patient samples). There was a wide range of H-scores by IHC which suggests heterogeneity in SLFN11 expression (H-score range 1.5-235). Similarly, analyses of patient CTCs from blood samples confirmed that SLFN11 is expressed in about 50% of treatment-naïve patients, however SLFN11 expression decreased significantly in patients on platinum treatment and at the time of relapse. Most patients had CTCs with pathologic features consistent with SCLC (i.e., were small, round, had high nuclear-to-cytoplasm ratios, and had salt-and-pepper like chromatin textures), although inter- and intra- patient heterogeneity was observed and SLFN11 expression was observed independent of morphologic subtype. Interestingly, SLFN11 expression was also found in white blood cells in the blood samples and was highest in platinum-naïve patients and lowest in patients while on platinum. Together, these data highlight the potential of SLFN11 as a predictive biomarker in SCLC. Based on our group and others' previous work, SLFN11 positivity by IHC is being used for selection of patients in an ongoing clinical trial (NCT04334941). In addition, given the substantial challenge of obtaining adequate tumor tissue in SCLC either at initial diagnosis or with re-biopsies, blood-based CTC analyses are an important tool to detect SLFN11 expression. Because of the dynamic nature of SLFN11 expression, CTC analyses can be especially valuable for longitudinal monitoring and may have real-time implications for treatment choice and response. Citation Format: Bingnan Zhang, C. Allison Stewart, Carl M. Gay, Qi Wang, Robert Cardnell, Junya Fujimoto, Luisa Fernandez, Adam Jendrisak, Cole Gilbertson, Joseph Schonhoft, Joshua Jones, Amanda K. Anderson, Ignacio I. Wistuba, Jing Wang, Rick Wenstrup, Lauren A. Byers. Detection of DNA replication blocker SLFN11 in tumor tissue and circulating tumor cells to predict platinum response in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 384.