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Background Long non-coding RNAs (lncRNAs) are involved in innate and adaptive immunities in cancers by mediating the functional states of immunologic cells, pathways, and genes. However, whether lncRNAs could serve as effective biomarkers for molecular classification and prediction of cancer immunotherapy efficacy are largely unknown. Methods This study analyzed lncRNA and genomic data of 348 atezolizumab-treated bladder cancer patients from phase II IMvigor 210 trial and 3,021 patients in lung cancer, breast cancer, bladder cancer, and melanoma cohorts from The Cancer Genome Atlas. We investigated lncRNA-based immune subtypes associated with cancer immunotherapy efficacy. We built a novel lncRNA score using computational algorithms and integrated it with programmed-death ligand 1 (PD-L1) expression and tumor mutation burden (TMB) to achieve accurate immunotherapeutic prediction. Results The results from IMvigor 210 trial showed that four distinct microenvironment-based subtypes characterized by lncRNA expression and tumor specific cytotoxic T lymphocytes (CTLs) infiltration had significant difference in overall survival (OS) (hazard ratio [HR] 0.77, 95%CI 0.67–0.88; P = 0.0002), with the greatest benefits in Immune-Active Class, followed by Immune-Exclusion Class, Immune-Dysfunctional Class, and Immune-Desert Class. High NKILA lncRNA expression was identified as a negative predictor of immunotherapeutic OS benefits and a critical regulator of dysfunctional immune response. Patients with low- versus high- lncRNA scores were associated with significantly longer OS in IMvigor 210 trial (HR 0.32, 95% CI 0.24–0.42; P Conclusion We suggested immunotherapy for patients in Immune-Functional Class, especially for those in high CTL Immune-Active Class. Multiomics comprising lncRNA score, PD-L1 expression and TMB could accurately predict immunotherapy efficacy. Legal entity responsible for the study Herui Yao. Funding Grants from the National Natural Science Foundation of China (81372819, 81572596, U1601223), the Natural Science Foundation of Guangdong Province (2017A030313828), the Guangzhou Science and Technology Program (201704020131), the Sun Yat-Sen University Clinical Research 5010 Program (2018007). Disclosure All authors have declared no conflicts of interest.

Background Immune checkpoint inhibitors (ICIs) therapy has been a pivotal treatment for NSCLC. However, additional biomarkers should be found out to cover more patients who may derive the greatest benefit from ICIs. Frameshift mutation by insertion or deletion (fsindel) has come to prominence due to its higher immunogenicity. Previous study has identified a positive correlation between fsindel and favorable clinical benefit in NSCLC. But it still requires validation. Therefore, we conducted a study to further assess the predictive role of fsindel. Methods A publicly available cohort of 385 ICIs-treated NSCLC patients from MSKCC were analyzed. We categorized patients into two groups; 0 fsindel (FS-) and more than 1 fsindel (FS+). The OS, PFS and response to ICIs therapy (ORR, DCR and DCB) were evaluated. We also developed a combined model of TMB and fsindel to further clarify the role of fsindel. Results 214 patients (55.58%) were found to be fsindel present (FS+). 189 patients (88.32%) were treated with PD-1/PD-L1 inhibitor monotherapy. Among the 356 patients with OS data, the OS of the FS+ patients was similar with that of FS- patients (median OS: 11 months vs. 12 months, P = 0.615). 240 patients (131 FS+, 109 FS-) were able to be evaluated for response to ICIs therapy. The median PFS was similar between FS+ and FS- group (median PFS, 3.43 months vs. 3.17 months, P = 0.114). The presence of fsindel was correlated with higher ORR (24.43% vs 15.60%, P = 0.091), DCR (56.49% vs 53.21%, P = 0.611) and DCB (35.77% vs. 24.04%, P = 0.055). TMB-H patients show significant difference in OS (median OS: 15 months vs. 10 months, P = 0.017) and marginally-significant difference in PFS (median PFS, 4.73 months vs. 2.60 months, P = 0.051). Moreover, TMB-H and FS+ patients had significantly better PFS and OS compared to patients who had either TMB-H or FS+ or neither (TMB-L and FS-) (median PFS = 6.17 months, P pfs = 0.004; median OS = 19 months, P os = 0.013). Conclusions Our study supported that fsindel might serve as a synergistic biomarker which could predict the efficacy of ICIs therapy for NSCLC patients. It might help us to precisely identify patients who could derive more benefit from ICIs therapy, especially in the fsindel present patients with higher TMB. Legal entity responsible for the study The authors. Funding National Key R&D Program of China (Grant No.2016YFC0905500, 2016YFC0905503). Disclosure All authors have declared no conflicts of interest.

Background Observational studies show that Alzheimer’s disease (AD) and lung cancer is negatively associated in both directions. However, whether there is a causal relationship between AD and lung cancer remains uncertain. Mendelian Randomization (MR) is a novel approach for the assessment of causality, using genome-wide significant single-nucleotide polymorphisms (SNP) as instrument variables (IV) to eliminate the bias caused by confounders. In this study, we utilized a bi-directional two-sample MR analysis to estimate the potential causality between AD and lung cancer. Methods The genome-wide association study (GWAS) summary data of AD and lung cancer were derived from the International Genomics of Alzheimer’s Project (IGAP,17,008 AD cases and 37,154 controls) and the International Lung Cancer Consortium (ILCCO, 11,348 lung cancer cases and 15,861 controls), respectively. We performed a bi-directional two-sample MR analysis to determine the causal relationship between AD and lung cancer. To be specific, Inverse-Variance Weighted (IVW), MR-Egger and Weighted Median methods were utilized for deriving causal estimates. Single SNP analysis and leave-one-out analysis were also conducted to identify if a single SNP is driving the association. We also performed the MR-Egger regression and MR-PRESSO analysis for the evaluation of horizontal pleiotropy. Results There was no causal relationship between AD and lung cancer in bi-directional MR. The results of Single SNP analysis and leave-one-out analysis indicated that no single SNP was driving the association. No directional horizontal pleiotropy was detected in the MR-Egger regression analysis. The MR-PRESSO analysis did not detect horizontal pleiotropy. There was no evidence for violations of MR assumptions in the sensitivity analysis. Table . 1847P Mendelian randomization estimates of the causality Exposure Outcome Inverse Variance Weighted MR Egger Weighted Median OR (95%CI) P-value OR (95%CI) P-value OR (95%CI) P-value Alzheimer’s Disease Lung Cancer 1.040 (0.965-1.121) 0.299 1.033 (0.890-1.199) 0.676 0.999 (0.902-1.106) 0.980 Lung Cancer Alzheimer’s Disease 0.919 (0.794-1.062) 0.253 1.223 (0.597-2.504) 0.637 0.920 (0.836-1.013) 0.091 Conclusions We found no causality between AD and lung cancer through the two-sample MR analysis. However, further study is warranted. Legal entity responsible for the study The authors. Funding National Key R&D Program of China (Grant No. 2016YFC0905500, 2016YFC0905503). Disclosure All authors have declared no conflicts of interest.

Background Meta-analyses and cohort studies have shown blood trace mineral concentration may be associated with incidence risk of lung cancer. However, there is no comprehensive study to investigate causal relationship between blood trace mineral and lung cancer. The purpose of this study is to inspect the causal effect of blood trace mineral concentration on lung cancer with Mendelian randomization (MR) method. Methods With a two‐sample MR approach, we analyzed the summary data of zinc, selenium, copper from the Queensland Institute of Medical Research(QIMR, 2603 individuals) and The Avon Longitudinal Study of Parents and Children (ALSPAC, 10115 individuals), data of calcium from discovery cohorts(39400 individuals) and replication cohorts(21875 individuals), data of iron from Genetics of Iron Status Consortium(23986 individuals), data of lung cancer patients from Consortium and International Lung Cancer Consortium (ILCCO, 11 348 lung cancer cases and 15 861 controls) to assess the possible causal relationship of blood trace mineral concentration on the risk of lung cancer. Results Our results indicated that genetically predicted higher blood copper level has a positive association with lung cancer, each per-unit increase in copper is associated with a 14% increase in the risk of lung cancer (odds ratio [OR]: 1.14, 95% CI = 1.01‐1.29; P = 0.04). Additionally, blood calcium, zinc, selenium, iron were not causal factors for lung cancer. Conclusions Genetically higher blood copper is positively associated with risk of lung cancer, and more work is needed to examine the potential mechanism. Legal entity responsible for the study The authors. Funding National Key RD Science and Technology Program of Guangdong (Grant No. 2017B020227001, 2016A020215084); Science and Technology Program of Guangzhou (Grant No. 201607020031, 201400000001-2); Chinese National Natural Science Foundation project (Grant No. 81772476, 81572659,81602011); Pearl River Nova Program of Guangzhou (Grant No. 201610010048); National Natural Science Funds for Young Scholars of China (Grant No. 81502355). Disclosure All authors have declared no conflicts of interest.

Background Immune checkpoint blockade (ICB) therapy has been a pivotal treatment for lung cancer, yet predictive biomarkers are still lacking. PBRM1 mutation is associated with greater sensitivity to immunotherapy for clear cell renal cell carcinoma. To our knowledge, the frequency and clinical relevance of PBRM1 mutation in lung cancer remain unknown. Therefore, we conducted a retrospective study to evaluate the prevalence of PBRM1 mutation and its preliminary response to ICB therapy in NSCLC. Methods We analyzed the combined NSCLC cohort of 2767 patients, from 3 sources: (1) The Cancer Genome Atlas (TCGA) (N = 1144), (2) Memorial Sloan Kettering Cancer Center (MSKCC) (N = 1567), and (3) Dana Farber Cancer Institute (DFCI) (N = 56). We first estimated the prevalence of PBRM1 mutation in the whole NSCLC cohort. A subset of ICB-treated patients (N = 441) with annotated clinical records were further analyzed for association between PBRM1 mutation and response to ICB therapy. We also calculated the overall survival (OS) of 454 non-ICB treated patients. Institutional review board approval and informed consent were waived because all data were de-identified and publicly available. Results Of 2767 patients included in our study, PBRM1 mutation was identified in 75 NSCLC patients (2.70%). Among 39 PBRM1-mutant patients with annotated clinical records, 25 patients (64.1%) were treated with PD-1/PD-L1 inhibitor monotherapy. In the cohort of ICB-treated patients (N = 441, PBRM1 MT=25), the OS of the PBRM1-mutant patients was worse than that of those without mutation (P = 0.03, median OS 6 vs. 13 months). In total, 14 patients, all with PBRM1 mutation, were able to be evaluated for response to ICB therapy. The median PFS was 2.1 months. The ORR was 28.6%, the DCR was 50%, and the DCB was 14.29%. In the cohort of non-ICB-treated patients (N = 454, PBRM1 MT=14), there seems to be no difference between the OS of the PBRM1 mutation subgroup and PBRM1 wild type subgroup (P = 0.097). Conclusions Our findings suggested that PBRM1-mutant NSCLC patients might get less survival benefit from ICB therapy, unlike previously reported data in clear cell renal cell carcinoma. Further prospective research is warranted to confirm the negative predictive role of PBRM1 in NSCLC ICB therapy. Legal entity responsible for the study The authors. Funding This work was supported by: National Key R&D Program of China (Grant No. 2016YFC0905500, 2016YFC0905503), Chinese National Natural Science Foundation project (Grant No. 81872499, 81772476), Science and Technology Program of Guangdong (Grant No. 2017B020227001), and Science and Technology Program of Guangzhou (Grant No. 201607020031, 201704020072). Disclosure All authors have declared no conflicts of interest.

Background PD-L1 expression was approved by U.S. FDA as companion or complementary diagnostic for most anti-PD-1/ PD-L1 inhibitors, which is well accepted as one of the important biomarkers in the selection of patients who would have high potential to respond. By far, the PD-L1 prevalence in Chinese solid tumor patients is poorly reported. In lung cancer, the correlation between PD-L1 expression and another important biomarker tumor mutation burden (TMB) has been demonstrated to be weak, however, the results in other types of solid tumor are still limited, which needs further explorations. Methods A total of 6,571 Chinese solid tumor patients, including 1,534 lung cancer patients and 5,037 other solid tumor patients, from 70 sites were studied. The tissue samples, either surgical resection specimens or biopsy samples, were both stained by clinical validated PD-L1 IHC assay and performed the next generation sequencing (NGS) using a validated commercial 381-cancer-gene panel, with panel size over 0.5 MB. TMB was calculated according to NGS results. Results 835 of 1534 (54.4%) lung cancer patients had PD-L1 expression >1% on tumor cells. The PD-L1 prevalence in NSCLC, small cell lung cancer, squamous cell carcinoma, adenocarcinoma and adenosine squamous cell carcinoma were 55.4%, 16.1%, 64.2%, 52.7% and 66.7%, respectively. Among 5,037 non-lung solid tumor patients, the proportion of PD-L1 expression >1% is 28.4%, 23.5%, 38.9%, 29.5%, 60% and 37.1% in gastric cancer, colorectal cancer, hepatobiliary cancer, urologic cancer, head and neck cancer and gynecological cancer. The average TMB of PD-L1 expression >1% solid tumor patients (excluding lung cancer) was 10.87/ MB, which is statistically significant higher than PD-L1 expression Conclusions The PD-L1 prevalence varied in different tumor type subgroups. And TMB was significant different between PD-L1 expression >1% and Legal entity responsible for the study 3D Medicine, Shanghai. Funding 3D Medicine, Shanghai. Disclosure All authors have declared no conflicts of interest.

Background Rhabdomyosarcoma (RMS) represents a malignant tumor of skeletal muscle origin, accounting for 5-10% of childhood cancers and more than 50% of pediatric soft tissue sarcoma. The head and neck occupied about 35% of the main sites of RMSs and most of these tumors are located in orbit, which contributes to 10% of all sites of RMSs. Due to the rarity of orbital RMS, the published studies of the clinical and pathological factors of orbital RMS could only provide limited information due to the small numbers of cohort or single institution. The aim of the current study was to evaluate the cumulative incidence of cancer-specific and competing risk death for patients with orbital RMS after surgery and build nomograms to predict survival based on a large population-based cohort. Methods Patients pathologically diagnosed with orbital RMS between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively collected. Nomograms for estimating overall survival (OS) and cancer-specific survival (CSS) were established based on Cox regression model and Fine and Grey’s model. The precision of the nomograms was evaluated and compared using concordance index (C-index) and the area under receiver operating characteristic (ROC) curve (AUC). Results A total of identified 217 patients with orbital RMS were retrospectively collected. The 10-, 20- and 40-year OS rates and cancer-specific mortality were 82.5%, 72.2% and 48.9%, respectively and 14.8%, 21.7% and 21.7%, respectively. The established nomograms were well calibrated and validated, with C-index of 0.901 and 0.944 for OS prediction, 0.923 and 0.904, for CSS prediction in the training and validation cohort, respectively. The values of AUC for 10-, 20-, and 40-year OS and CSS prediction were 0.908, 0.826 and 0.847, and 0.924, 0.863 and 0.863, respectively. Conclusions The survival rates were evaluated for patients with orbital RMS and the specialized nomograms were established for OS and CSS prediction for the first time, which showed relatively good performances and could be convenient individualized predictive tools for prognosis. Legal entity responsible for the study The authors. Funding This study was supported by the funding of Sun Yat-sen University Grant for Medical Humanities Practice and Teaching (No. 23000-18008023). Disclosure All authors have declared no conflicts of interest.

Aim: Non-small-cell lung cancer (NSCLC) patients harboring KRAS mutations were associated with worse prognosis and lower response to epidermal growth factor receptor (EGFR) targeted therapy including EGFR tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR monoclonal antibodies than those with wild-type tumors. However, whether the underlying biological differences are associated with the efficacy of cytotoxic chemotherapy in advanced NSCLC patients remains controversial. Thus, we sought to perform a meta-analysis incorporating all available evidences to evaluate the clinical outcome according to the KRAS mutation status in patients with advanced NSCLC treated with front-line conventional chemotherapy. Methods: We searched electronic databases for eligible literature. The primary outcomes were objective response rate (ORR), six-month and one-year progression-free survival (PFS) rate. The pooled odds ratio (OR) was calculated using random-effects model. Subgroup analyses stratified by literature type, mutation analysis method, therapeutic regimen, patient origin, EGFR mutation status in KRAS wild-type patients were proposed. All calculations were performed using REVIEW MANAGER version 5.0. Heterogeneity and publication bias were quantitatively evaluated. Results: A total of 10 studies involving 1677 advanced NSCLC patients with known KRAS mutation status who had received first-line chemotherapy were included. KRAS mutants had lower ORR than wild-type patients (25.1% vs. 34.4%) significantly (OR 0.67, 95% CI 0.50-0.88, P = 0.004). Additionally, patients with KRAS mutation had numerically lower six-month (51.0% vs. 56.8%) and one-year (10.3% vs. 13.3%) PFS rate than wild-type patients, but there was no significant difference between the two groups (Six-month PFS: OR 0.75, 95% CI 0.54-1.04, P = 0.08; One-year PFS: OR 0.75, 95% CI 0.47-1.21, P = 0.25). Results of the subgroup analyses were almost concordant with the overall ones. Conclusions: This comprehensive analysis revealed that advanced NSCLC patients with KRAS mutations had significantly lower ORR and potentially lower six-month/one-year PFS rates compared with wild-type patients after first-line chemotherapy. KRAS mutation status should be considered as an essential factor in studies regarding chemotherapy regimens or other non-targeted agents. Disclosure: All authors have declared no conflicts of interest.

Aim: With targeted therapy improving the survival of advanced stage epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients, resistannce remains a major issue in the application of EGFR tyrosine kinase inhibitors (TKIs). Bim, a Bcl-2 family pro-apoptotic protein, has been intensively studied for its role in various targeted therapies. Hence we investigated the epigenetic regulation of Bim in NSCLC cell lines and patients in the hope of identifying its relationship with EGFR TKI resistance. Methods: Methylation specific PCR, pyrosequencing and nested quantitative MSP (nested q-MSP) were applied to study the methylation status of BIM in NSCLC cell lines and the BIM methylation profile in NSCLC patients was assessed by nested q-MSP. PC9 and its gefitinib-resistant cell lines were treated with methylation inhibitor 5-aza-2′-deoxycytidine (AZA) and histone deacetylation inhibitor trichostatin A (TSA) before gefitinib treatment. Bim RNA level, cell survival and resistance to gefitinib were examined. The distribution of various levels of methylated BIM and their relationship with EGFR TKI efficacy was statistically analyzed. Results: 8 NSCLC cell lines all carried hypo-methylated BIM. AZA did not increase the expression of Bim in PC9 and its gefitinib-resistant cell lines, nor did it reverse their resistance to gefitinib. Instead, cells experienced less apoptosis from gefitinib when pre-treated with AZA. TSA on the other hand, not only increased the expression of Bim RNA significantly in the three cell lines, but also reversed their resistance to gefitinib. 25 (78.1%) patients with hypo-methylated BIM and 7 (21.9%) with partial or hyper-methylated BIM were identified. Hypo-methylated BIM distributed randomly in different clinicalpathological charcteristics. In both the entire study group and EGFR mutant group, hypo-methylated BIM carriers experienced no significant PFS difference compared with patients with partial or hyper-methylated BIM. Conclusions: All cell lines in the study and the majority of patients were with hypo-methylated BIM. AZA didn't reverse the resistance to EGFR TKI in acquired resistant cell lines PC9/R and PC9/G2, while HDACi TSA did. Thus histone deacetylation, rather than promoter methylation, may play a major role in the epigenetic silencing of BIM and leads to EGFR TKI resistance in NSCLC. Disclosure: All authors have declared no conflicts of interest.