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PURPOSE Pembrolizumab or nivolumab plus chemotherapy was approved as a first-line treatment for high programmed cell death ligand 1 (PD-L1)–expressing esophageal squamous cell carcinoma (ESCC) by the European Medicines Agency, whereas the US Food and Drug Administration approved this regimen regardless of PD-L1 expression. The superiority of programmed death-1 (PD-1) antibody plus chemotherapy over chemotherapy alone in patients with low PD-L1–expressing ESCC remains debatable. METHODS Post hoc analysis of the Chinese JUPITER-06 study focusing on efficacy stratified by PD-L1 tumor proportion score (TPS; using JS311 antibody) was conducted. Electronic databases were searched to identify eligible randomized controlled trials for meta-analysis. Study-level pooled analyses of hazard ratios (HRs) for overall survival and progression-free survival and odds ratios for objective response rate according to PD-L1 expression were performed. RESULTS The post hoc analysis of JUPITER-06 showed more prominent clinical benefit with PD-1 antibody plus chemotherapy than with chemotherapy alone in both the high and low PD-L1–expressing subgroups. Five randomized controlled trials were included in the meta-analysis, and two PD-L1 expression scoring criteria, TPS (≥ 1%/< 1%) and combined positive score (CPS, ≥ 10/< 10), were analyzed. Significant overall survival benefit by adding PD-1 antibody to chemotherapy was observed in both the TPS < 1% (HR, 0.74; 95% CI, 0.56 to 0.97) and CPS < 10 (HR, 0.77; 95% CI, 0.66 to 0.89) subgroups. Similarly, significantly prolonged progression-free survival was observed in both the TPS < 1% (HR, 0.66; 95% CI, 0.50 to 0.86) and CPS < 10 (HR, 0.63; 95% CI, 0.47 to 0.84) subgroups. In addition, the objective response rate of the TPS < 1% subgroup was significantly improved (odds ratio, 1.71; 95% CI, 1.27 to 2.29). In all high PD-L1–expressing subgroups, the pooled benefit of PD-1 antibody plus chemotherapy was significantly better than that of chemotherapy. CONCLUSION This study provided novel evidence supporting the superiority of PD-1 antibody plus chemotherapy to chemotherapy alone in patients with advanced ESCC with low PD-L1 expression. Further studies of predictive biomarkers are warranted.

ObjectiveCirculating tumour DNA (ctDNA) sequencing is increasingly used in the clinical management of patients with colorectal cancer. However, the genomic heterogeneity in ctDNA during treatments and its impact on clinical outcomes remain largely unknown.DesignWe conducted a prospective cohort study (NCT04228614) of 171 patients with unresectable metastatic colorectal cancer (mCRC) who underwent first-line treatment and prospectively collected blood samples with or without tumour samples from patients at baseline and sequentially until disease progression or last follow-up.ResultsThe RAS/BRAF alterations in paired baseline tissue and plasma samples from 63 patients displayed a favourable concordance (81.0%, 51/63). After a period of first-line treatment (median time between baseline and last liquid biopsy, 4.67 months), 42.6% (26/61) of RAS-mutant patients showed RAS clearance and 50.0% (5/10) of BRAF-mutant patients showed BRAF clearance, while 3.6% (3/84) and 0.7% (1/135) of patients showed new RAS or BRAF mutations in ctDNA. Patients with plasma RAS/BRAF clearance showed similar progression-free survival (PFS) and overall survival (OS) with patients who remained RAS/BRAF wild-type, while much better outcomes than those who remained RAS/BRAF mutant. Patients who gained new RAS/BRAF mutations showed similar prognosis as those who maintained RAS/BRAF mutations, and shorter PFS and OS than those who remained RAS/BRAF wild-type.ConclusionThis prospective, serial and large-scale ctDNA profiling study reveals the temporal heterogeneity of mCRC-related somatic variants, which should be given special attention in clinical practice, as evidenced by the finding that the shift in plasma RAS/BRAF mutational status can yield a drastic change in survival outcomes.

Metabolic inhibition via PFKFB3 inhibition has demonstrated considerable tumor inhibitory effects in various studies; however, PFKFB3 inhibition did not show satisfactory tumor inhibition when used in clinical trials. PFKFB3 is a crucial metabolic enzyme that is highly upregulated in cancer cells and directly affects tumor glycolysis. Here, we showed that PFKFB3 inhibition suppresses tumors in vitro and in vivo in immune-deficient xenografts. However, this inhibition induces the upregulation of PD-L1 levels, which inactivated cocultured T-cells in vitro, compromises anti-tumor immunity in vivo, and reduced anti-tumor efficacy in an immune-competent mouse model. Functionally, PD-1 mAb treatment enhances the efficacy of PFKFB3 inhibition in immunocompetent and hu-PBMC NOG mouse models. Mechanistically, PFKFB3 inhibition increases phosphorylation of PFKFB3 at residue Ser461, which increases interaction with HIF-1α, and their colocalization into the nucleus, where HIF-1α transcriptionally upregulate PD-L1 expression and causes subsequent tumor immune evasion. Higher phos-PFKFB3 correlated with higher PD-L1 expression, lower CD8 and GRZMB levels, and shorter survival time in ESCC patients.

Background Numerous reports on microRNAs have illustrated their role in tumor growth and metastasis. Recently, a new prognostic factor, miR‐125b‐2‐3p, has been identified for predicting chemotherapeutic sensitivity in advanced colorectal cancer (CRC). However, the specific mechanisms and biological functions of miR‐125b‐2‐3p in advanced CRC under chemotherapy have yet to be elucidated. Methods MiR‐125b‐2‐3p expression was detected by real‐time PCR (RT‐PCR) in CRC tissues. The effects of miR‐125b‐2‐3p on the growth, metastasis, and drug sensitivity of CRC cells were tested in vitro and in vivo. Based on multiple databases, the upstream competitive endogenous RNAs (ceRNAs) and the downstream genes for miR‐125b‐2‐3p were predicted by bioinformatic analysis, followed by the experiments including luciferase reporter assays, western blot assays, and so on. Results MiR‐125b‐2‐3p was significantly lowly expressed in the tissues and cell lines of CRC. Higher expression of miR‐125b‐2‐3p was associated with relatively lower proliferation rates and fewer metastases. Moreover, overexpressed miR‐125b‐2‐3p remarkably improved chemotherapeutic sensitivity of CRC in vivo and in vitro. Mechanistically, miR‐125b‐2‐3p was absorbed by long noncoding RNA (lncRNA) XIST regulating WEE1 G2 checkpoint kinase (WEE1) expression. The upregulation of miR‐125b‐2‐3p inhibited the proliferation and epithelial‐mesenchymal transition (EMT) of CRC induced by lncRNA XIST. Conclusions Lower miR‐125b‐2‐3p expression resulted in lower sensitivity of CRC to chemotherapy and was correlated with poorer survival of CRC patients. LncRNA XIST promoted CRC metastasis acting as a ceRNA for miR‐125b‐2‐3p to mediate WEE1 expression. LncRNA XIST‐miR‐125b‐2‐3p‐WEE1 axis not only regulated CRC growth and metastasis but also contributed to chemotherapeutic resistance to CRC., Low expression of miR‐125b‐2‐3p in CRC was linked to lower chemotherapeutic sensitivity and poor survival. The lncRNA XIST promoted CRC invasion and migration by functioning as a ceRNA for miR‐125b‐2‐3p to mediate WEE1 expression. Our findings suggest that the lncRNA XIST‐miR‐125b‐2‐3p‐WEE1 axis not only regulated CRC growth and metastasis but also contributed to chemotherapeutic resistance to CRC, which may shed light on their targeted applications.

Gastrointestinal cancer causes countless deaths every year due to therapeutic resistance. However, whether metabolic alterations contribute to chemoresistance is not well understood. In this study, we report that fatty acid (FA) catabolism was activated in gastrointestinal cancer cells treated with oxaliplatin, which exhibited higher expression of the rate-limiting enzymes carnitine palmitoyltransferase 1B (CPT1B) and CPT2. The clinical analysis also showed that high expression of these enzymes was associated with poor oxaliplatin-based chemotherapy outcomes in patients. Furthermore, genetic or pharmacological inhibition of CPT2 with perhexiline disturbed NADPH and redox homeostasis and increased reactive oxygen species (ROS) generation and cell apoptosis in gastrointestinal cancer cells following oxaliplatin treatment. Specifically, the combination of oxaliplatin and perhexiline significantly suppressed the progression of gastrointestinal cancer in cell-based xenograft and patient-derived xenograft (PDX) models. Mechanistically, CPT2 was transcriptionally upregulated by nuclear factor of activated T cells 3 (NFATc3), which translocated to the nucleus in response to oxaliplatin treatment. In summary, our study suggests that the inhibition of CPT-mediated FA catabolism combined with conventional chemotherapy is a promising therapeutic strategy for patients with gastrointestinal cancers.

BackgroundLong noncoding RNAs (lncRNAs) play nonnegligible roles in the epigenetic regulation of cancer cells. This study aimed to identify a specific lncRNA that promotes the colorectal cancer (CRC) progression and could be a potential therapeutic target.MethodsWe screened highly expressed lncRNAs in human CRC samples compared with their matched adjacent normal tissues. The proteins that interact withLINRIS(Long Intergenic Noncoding RNA for IGF2BP2 Stability) were confirmed by RNA pull-down and RNA immunoprecipitation (RIP) assays. The proliferation and metabolic alteration of CRC cells withLINRISinhibited were tested in vitro and in vivo.ResultsLINRISwas upregulated in CRC tissues from patients with poor overall survival (OS), andLINRISinhibition led to the impaired CRC cell line growth. Moreover, knockdown ofLINRISresulted in a decreased level of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), a newly found N6-methyladenosine (m6A) ‘reader’.LINRISblocked K139 ubiquitination of IGF2BP2, maintaining its stability. This process prevented the degradation of IGF2BP2 through the autophagy-lysosome pathway (ALP). Therefore, knockdown ofLINRISattenuated the downstream effects of IGF2BP2, especially MYC-mediated glycolysis in CRC cells. In addition, the transcription ofLINRIScould be inhibited by GATA3 in CRC cells. In vivo experiments showed that the inhibition ofLINRISsuppressed the proliferation of tumors in orthotopic models and in patient-derived xenograft (PDX) models.ConclusionLINRISis an independent prognostic biomarker for CRC. TheLINRIS-IGF2BP2-MYC axis promotes the progression of CRC and is a promising therapeutic target.

4054 Background: Circulating tumor DNA (ctDNA) is a promising biomarker for detecting molecular residual disease (MRD) and relapse after definitive treatment in multiple solid cancers. However, the significance of ctDNA is rarely clarified in locoregional gastric cancer (GC). Here, we conducted a prospective and observational study to evaluate the utility of ctDNA in predicting the recurrence risk of GC. Methods: From October 2016 to June 2019, 100 patients with stage II/III resectable GC were recruited in this study (NCT02887612). Primary tumors and plasma samples were collected perioperatively and after adjuvant chemotherapy (ACT). Somatic variants were captured via a targeted sequencing panel of 425 cancer-related genes. The plasma of patients was defined as ctDNA positive only if one or more variants detected in the plasma presented in at least 2% of the primary tumors. All the patients received curative-intent standard-of-care therapy. Results: Preoperative ctDNA was detectable in 38 (38.0%) patients but showed limited value for predicting recurrence. After surgery (median days, 4), the plasma of 25 (25.0%) patients were still ctDNA positive and they had higher recurrence risk than the non-positive patients (hazard ratio [HR], 2.74 (95% CI: 1.37–5.48); P = 0.003). Forty-one patients had evaluable plasma after ACT and 10 (24.4%) of them who were ctDNA positive had remarkably higher recurrence and death risk compared with ctDNA-negative patients (recurrence-free survival [RFS] HR = 14.99 (95% CI: 3.08–72.96); P < 0.001; overall survival HR, 11.88 (95% CI: 2.38–59.24); P < 0.001). In particular, post-ACT ctDNA achieved better predictive performance (sensitivity, 77.8%; specificity, 90.6%) than both postoperative ctDNA and post-treatment tumor biomarkers (i.e., CEA, CA199, and CA72-4). In all multivariate analyses, ctDNA positivity was an independent factor of RFS. Patients with ERBB4 mutation in their primary tumors had poorer RFS compared to those were ERBB4 wildtype (HR = 3.46 (95% CI: 1.32–9.03); P = 0.007). A comprehensive model incorporating ctDNA status for recurrence risk prediction showed a higher concordance index (0.78; 95%CI, 0.71–0.84) than the model without ctDNA status (0.71; 95%CI, 0.64–0.79; P = 0.009). Conclusions: Postoperative and post-ACT ctDNA was associated with MRD and high risk of relapse in patients with stage II/III GC and can be utilized to guide GC management in post-surgical settings.

Background Immune checkpoint inhibitors (ICIs) have achieved impressive success in different cancer types, yet responses vary and predictive biomarkers are urgently needed. Growing evidence points to a link between DNA methylation and anti-tumor immunity, while clinical data on the association of genomic alterations in DNA methylation-related genes and ICI response are lacking. Methods Clinical cohorts with annotated response and survival data and matched mutational data from published studies were collected and consolidated. The predictive function of specific mutated genes was first tested in the discovery cohort and later validated in the validation cohort. The association between specific mutated genes and tumor immunogenicity and anti-tumor immunity was further investigated in the Cancer Genome Altas (TCGA) dataset. Results Among twenty-one key genes involving in the regulation of DNA methylation, TET1-mutant (TET1-MUT) was enriched in patients responding to ICI treatment in the discovery cohort (P 0.05 in both two non-ICI-treated cohorts). In TCGA dataset, TET1-MUT was strongly associated with higher tumor mutational burden and neoantigen load, and inflamed pattern of tumor-infiltrating T lymphocytes, immune signatures and immune-related gene expressions. Conclusions TET1-MUT was strongly associated with higher ORR, better DCB, longer PFS, and improved OS in patients receiving ICI treatment, suggesting that TET1-MUT is a novel predictive biomarker for immune checkpoint blockade across multiple cancer types.

Background/Aims: Small cell carcinoma of the esophagus (SCCE) is a rare and highly deadly malignancy with rapid disease progress and extensive metastasis, whereas present therapy for the cancer is limited, making the identification of a new treatment strategy an area of intense research. We previous reported the genomic characteristics and alterations of the SCCE, but the transcriptome abnormality of the cancer has not been investigated yet. Method: we performed an RNA Sequencing on nine paired samples from patients with SCCE and conducted a series of comprehensive analysis on the data. DESeq2 and GSEA were applied on transcriptome of SCCE tumor tissue and their para-normal to identify differential expressive genes and associated pathways. Besides, with MCP-counter and a list of immunity related genes, we also compared immune signal of the expression data in pair. By applying a rigorous batch removing strategy, including preprocessing raw data in identical method and RUVSeq, transcriptome data of healthy esophageal mucosa from GTEx was involved as control samples in comparison. In addition, we applied CIBERSORT to calculate the fraction of different tumor infiltrated leukocytes (TILs) of SCCE and compare the number with those of other cancers that have been proven to be potentially responsive to immunotherapy. Results: We identified 1486 and 1782 genes were significantly up-regulated and down-regulated in SCCE tumor tissue against their para-normal, respectively. Pathway analysis revealed the E2F Target and G2M checkpoint are significantly enriched in tumor tissue. Immune signal analysis across the samples in pair showed that in 3 out of 9 paired sample, immunity reaction upregulates in tumor tissue. T-SNE cluster across transcriptome data of SCCE tumor tissue, their para-normal and healthy esophageal mucosa showed the para-normal tissue, namely the normal tissue adjacent to tumor, is more similar to tumor tissue than the healthy. CIBERSORT analysis showed the difference in TILs fraction between SCCE and the compared cancers. For example, the relative fraction of plasma cell of SCCE is higher than those of ESCC(P=0.040), CIN type of STAD(P=0.040), while lower than those of SCLC(P=0.020). M2 macrophages is higher in SCCE than ESCC(P=0.002), EAC(P Conclusion: In summary, our analysis provides transcriptome evidence that immunotherapy might be an efficient treatment strategy for small cell esophagus cancer. Citation Format: Qi Zhao, Yan-xing Chen, Ying-nan Wang, Qi-nian Wu, Hui Sheng, JIa-jia Hu, Yun-xin Lu, Ze-xian Liu, Zhi-xiang Zuo, Feng Wang, Rui-hua Xu. Systematic transcriptome analysis of small cell carcinoma of esophagus suggests a possibility for immunotherapy [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 4242.