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e21504 Background: The immune checkpoint inhibitors (ICIs), have improved survival with durable response for advanced malignant melanomas, but, only a minority of patients has achieved. To stay sway failure of triage patients, considerable side effects and costs of ICB therapies, the development of robust signatures predictive of response to ICB therapies is warranted. Methods: Clinical data were collected at Seoul St. Mary’s Hospitals. Among them, we examined RNA expression profile by QuantSeq 3’ mRNA-Sequencing and the composition, and spatial distance of immune cells by multiplex immunofluorescent staining. Results: The gene sets with relatively higher RNA expression in the good response group, were as follows; hematopoietic cell dedifferentiation gene, T-cell related adaptive immunity gene, IFN-related cytokine gene, and macrophage (TAM), NK cell, innate immunity gene set. Meanwhile, in the poor response group, inflammatory response, fibrosis response genes was increased.The cell densities of T cells, cytotoxic T cells, Treg cells, CD8+Treg cells, and exhausted T cells in the good response group tended to be higher, which was clearer in the peritumoral (PT) area than the intratumoral (IT) area. For the good response group, M1/M2 ratio in the IT area was significantly higher compared to that of poor response group (p = 0.045). According to the nearest neighbor analysis for % of melanoma cells within 15um distance present a close distance from M1, M2, and NK cells tended to be higher in the IT area than PT area. For the cases with higher spatial distribution from M1 in the IT area, PFS and OS was significantly extended (PFS, p = 0.0021; OS, p = 0.036). The gene sets with relatively higher mRNA expression in high neighborhood macrophage group, were cell death, apoptosis process gene set. In low neighboring M1 macrophage group, relatively higher mRNA expressions of extracellular component inflammation and fibrosis gene, cell migration, and cell de-differentiation gene set were observed. Conclusions: Taken together, our results suggest 4 key points. First, good and poor responder groups for ICB show marked differences from mRNA profiling to protein expression according to central dogma. Second, immune cells can be distributed sporadically in many places, but the actionable ground of the adaptive immune cells of the T cell family is the PT, and the playground of innate immune cells such as TAM and NK cells is the IT. In particular, the anti-tumor response of M1 macrophage and M2 macrophage was oppositely in IT. Third, high TAMs in IT are interpreted to have a tumoricidal effect because they show a stationery state while coding the killing effect gene set. In addition, topologically, spatial analysis as well as bulk genomics are important for predicting tumor response for ICIs.

e16172 Background: Despite recent advancements in the understanding of the molecular biology of biliary tract cancer (BTC), target therapy and immunotherapy have demonstrated only limited efficacy, with cytotoxic systemic therapy still being the most effective treatment in BTC, except for surgery. Thus, this study aimed to analyze the role of DKK1 or β-catenin as a prognostic factor in BTC and determine the clinical association of ß-catenin and DKK1 with CD8+ tumor-infiltrating lymphocyte (TIL). Methods: We used data in The Cancer Genome Atlas (TCGA) Research Network and the clinicopathological data of 145 patients with BTC who had undergone primary radical resection between 2006 and 2016. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue sections, and whole tissue sections of representative tumor samples were used for antigen retrieval. Results: CD8+TIL expression was a significant predictor of favorable overall survival (OS) and recurrence-free survival (RFS) (median OS, 34.9months in TIL-high, 16.7months in TIL-low, P < 0.0001 respectively; median RFS, 27.1months in TIL-high, 10months in TIL-low, P < 0.0001 respectively). Positive ß-catenin expression and high DKK1 expression was also associated with a shorter OS (median OS, 23.95months in positive ß-catenin, 26.1months in negative ß-catenin, P = 0.1009 respectively; median OS, 19.4months in high DKK1, 31.65months in Low DKK1, P = 0.0093 respectively), but not RFS (p = 0.1466, at ß-catenin respectively; p = 0.2924, in DKK1 respectively). In the CD8+TIL-high BTC group, the tumor expression of β-catenin and DKK1 had a significant negative impact on either OS or RFS (p = 0.0146 and p = 0.0112, at ß-catenin respectively; p = 0.0950 and p = 0.3904, in DKK1 respectively). However, in the TIL-low BTC group, there were no differences in OS or RFS according to ß-catenin and DKK1 expression (p = 0.5108 and p = 0.8431, at ß-catenin respectively; p = 0.1127 and p = 0.1095, in DKK1 respectively). Cox regression multivariate analysis demonstrated that CD8+ TIL (hazard ratio [HR], 0.490; 95% confidence interval (CI), 0.303-0.791; p = 0.004) and β-catenin (HR, 1.652; 95% CI, 1.035-2.639; p = 0.036) retained significant association with OS after adjustment for all variables. Conclusions: Among patients with resected BTC, β-catenin and DKK1 protein levels are associated with poor clinical outcomes, whereas high CD8+ TIL levels are associated with good clinical outcomes. This confirms the differential clinical role of Wnt/β-catenin and DKK1 proteins according to TIL expression in BTC.

e21096 Background: Small cell lung cancer (SCLC) is a highly proliferative and rapidly growing tumor with poor prognosis, even in limited disease (LD), and a timely and accurately high intensity therapy is necessary. During the concurrent chemoradiotherapy (CCRT), etoposide with platinum (EP) regimen is recommended, however, irinotecan with cisplatin (IP) regimen is also effective. Therefore, we performed a large-scale, retrospective and nationwide cohort study to analyze the efficacy of CCRT in patients with LD-SCLC Methods: The population data were extracted from the Health Insurance Review and Assessment Service of Korea database from January 1, 2008, to November 30, 2016. Among 14,490 patients with SCLC patients who received chemotherapy, a total of 4,496 patients with LD-SCLC were analyzed. The primary objectives were to evaluate the survival outcomes of CCRT for LD-SCLC. Results: Patients who received EP-CCRT (n = 4,187) had better PFS of 11.233 months (95% confidence interval (CI) 10.900 – 11.667, P = 0.0477) and prolonged OS of 22.233 months (95% CI 21.233 – 23.333, P < 0.0001) than those who received IP-CCRT (n = 259; PFS = 9.567 months, 95% CI = 8.500 – 10.667; OS = 16.433 months, 95% CI = 14.467 – 18.333; P = 0.0477). After the failure of CCRT, we observed that dual chemotherapy (n = 925; OS = 9.133 months, 95% CI = 8.400 - 10.100) has better survival benefit (P < 0.0001) than single agent chemotherapy (n = 815; OS = 7.500 months, 95% CI, 6.933 – 8.133). IP chemotherapy demonstrated a better OS (9.567 months, 95% CI, 8.667 – 10.333 vs. 7.100 months, 95% CI, 5.100 – 10.400, P = 0.0170, respectively) than EP regimen in the platinum-resistant group; patients with PFS within 6 months after CCRT. However, in platinum sensitive group; patients who recurred after 6 months, the clinical benefit of EP regimen was superior to IP regimen (OS = 17.183 months, 95% CI, 13.033 – 25.633 vs. 6.617 months, 95% CI, 5.433 – 7.767; P < 0.0001). Cox proportional hazards regression analysis demonstrated that age, EP-CCRT, and dyslipidemia retained significant associations with OS after adjusting for all variables. Conclusions: In Korean population, concurrent thoracic radiotherapy with EP regimen had significantly favorable effects on OS and PFS. In addition, after the failure of CCRT, combination chemotherapy had clinical benefits over single agents. Among combination chemotherapy, IP combination regimen showed significantly favorable effects on OS and PFS, especially in the platinum-resistant group.

e20633 Background: Although immune checkpoint blockades (ICBs) therapy can lead to favorable and durable results by reinvigorating the anti-tumor immune response in some patients, many other patients experience poor prognosis and even tumor overgrowth can be seen in real practice. We aimed to assess these hyperprogressive disease (HPD) in patients who underwent ICB therapy. Methods: We retrospectively reviewed medical records of non-small cell lung cancer patients (n = 243) treated with anti-PD-1 or anti-PD-L1 monotherapy. HPD was defined as a tumor growth kinetics ratio > 2 during anti-PD-1/PD-L1 therapy and a time-to-failure of less than 2 months. We analyzed the association of Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and CRP-albumin ratio (CAR) with HPD and the difference of immune composition in TME by multiplex IHC. Results: Overall, 231 patients were included. The median age was 64.2 years; most patients were male (74.9%) and smokers (70.1%, n = 162). 25 patients (10.8%) met the criteria for HPD. Oncogenic drive mutant status was significantly associated with HPD (18.6% vs 9.04%; P = 0.001). Kaplan Meier overall survival estimates showed a clear trend toward worse outcomes for patients with HPD (median, 5.6 months; P < 0.001) than for those without (median, 7.4 months). We also analyzed the association of NLR, PLR and CAR with HPD. Serologic markers at the time of first response evaluation (post 6 weeks, i.e.,) showed a prognostic value for HPD after ICB use ( P < 0.001, 0.008, 0.017). In multiplex IHC, there was no difference in T cell related immune marker of CD 3/4/8/45RO and FOXP3, dendritic cell, NK cell and other co-inhibitory signal markers between two groups. However, the key point was the M2 polarized tendency in the HPD group when the macrophage M1 / 2 markers of CD68, CD163, CD206 and CCR7 were observed. This suggests that changes in the AXL pathway and EMT features associated with reinvigorating anti-tumor immunity in M2 polarized cells may lead to changes in poor prognosis to HPD. Conclusions: Despite improved recognition of HPD, its etiology and predisposing factors remain unclear, but it is clear that the prognosis becomes poor when it occurs. We observed that some serologic biomarkers (NLR, PLR and CAR. i.e.,) can be used to predict HPD. Multiplex IHC can be used not only to predict HPD, but also to validate its mechanism. Furthermore, we undergo whole exon sequencing and multiplex IHC to understand mechanism of Hyperprogression.