Efficacy of nivolumab in advanced esophageal carcinoma: A systematic review of phase III clinical trials.

438 Background: Pembrolizumab, a monoclonal immunoglobulin G4 antibody is a programmed cell death protein 1 inhibitor, approved for treatment of advanced (metastatic or recurrent) esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). We performed a pooled analysis to assess the efficacy of pembrolizumab in esophageal carcinoma (EC) and to compare it with chemotherapy alone. Methods: We conducted a systemic literature search, using PubMed, EMBASE, and ClinicalTrials.gov, till July 30, 2024. Initial search yielded 412 articles. We excluded duplicates and irrelevant studies and included 4 clinical trials (CT) that reported pembrolizumab’s efficacy in EC. We estimated pooled objective response rate (ORR), partial response (PR), and hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS), along with 95% confidence interval (CI) and p-value in RevMan v.5.4. Subgroup analysis, based on combined positive score (CPS) for programmed cell death ligand-1 (PDL-1) expression and tumor histology type was also performed. Results: We included four CTs in our study; their characteristics are shown in the table. The estimated pooled ORR and PR of pembrolizumab in all patients was 21% (CI: 0.10-0.41) (p < 0.001) and 19% (CI: 0.08-0.37) (p < 0.001), respectively. Pooled median PFS was 3.05 mo (CI: 0.92-5.17) (p = 0.004), and pooled median OS was 8.05 mo (CI: 5.21-10.88) (p < 0.001). Pembrolizumab use in EC showed a reduced risk of disease progression vs chemotherapy alone [HR: 0.85 (CI: 0.75-0.96) (p < 0.05)] and a 21% reduction in mortality [HR: 0.79 (CI: 0.71-0.88) (p < 0.001)]. Safety analysis revealed less grade ≥3 adverse events [OR: 0.56 (CI: 0.35-0.90), p < 0.05)] with pembrolizumab compared with chemotherapy alone. On subgroup analysis between ESSC and EAC, pembrolizumab exhibited statistically nonsignificant responses with ORR (OR: 1.29, CI: 0.89-1.88, p = 0.18), OS (pooled HR: 0.94, CI: 0.76-1.15, p = 0.53). Pembrolizumab in patients with CPS ≥10 vs CPS <10 also showed statistically non-significant responses with ORR [OR: 1.70, CI: 0.99-2.91, p = 0.06), OS (pooled HR: 0.63 vs 1.00) (p = 0.05) and PFS (pooled HR: 0.62 vs 0.83, p = 0.08). Conclusions: Pembrolizumab alone or combined with chemotherapy compared with chemotherapy alone exhibited favorable responses in terms of ORR, OS and PFS with a manageable toxicity profile, setting a benchmark for future studies. Characteristics of included studies. Trial ID, phase Histology Line Number of patients Regimen Median follow-up (mo) ORR (%) Median PFS (mo) Median OS (mo) KEYNOTE-590, III ESCC, EAC 1 st 749 Pembro + chemo vs chemo 58.8 45 vs 29.3 6.3 vs 5.8 12.3 vs 9.8 KEYNOTE-181, III ESCC, EAC 2 nd 628 Pembro vs chemo 7.1 13.1 vs 6.7 2.1 vs 3.4 9.3 vs 6.9 KEYNOTE-180, II ESCC, EAC 3 rd or later 121 Pembro 5.8 9.9 2.0 5.8 KEYNOTE-028, 1b ESCC, EAC 3 rd or later 21 Pembro 7 30 1.8 7 Pembro: pembrolizumab, mo: month.

397 Background: Programmed death cell death protein-1 (PD-1) inhibitors combined with chemotherapy have demonstrated survival benefits in patients with advanced esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). Our pooled analysis aims to analyze the efficacy of PD-1 inhibitor plus chemotherapy in advanced esophageal carcinoma (EC) in phase III randomized clinical trials (RCTs). Methods: We collected data from eligible phase III RCTs searched through PubMed, EMBASE, ClinicalTrials.gov, and meeting abstracts till July 5, 2024. Initial screening revealed 792 articles. We excluded duplicates, review articles and irrelevant studies, and we included eight RCTs that reported objective response rate (ORR), treatment-related adverse events (TRAEs), overall survival (OS) and progression-free survival (PFS). Odds ratio (OR) for ORR and TRAEs, and hazard ratio (HR) for OS and PFS were computed along with a 95% confidence interval (CI) and p-value for pooled analysis, using a random effect model in RevMan v.5.4. We performed a subgroup analysis based on a combined positive score (CPS) for programmed cell death ligand-1 (PDL-1) expression and tumor histology. Results: We included eight phase III RCTs (Jupiter-06, Checkmate 648, Keynote 590, ESCORT-1st, Orient-15, Checkmate 649, ESCORT-NEO, and ASTRUM-007), including 4131 patients with 2137 in group A (PD-1 inhibitor + chemotherapy) and 1994 in group B (placebo + chemotherapy, or chemotherapy). PD-1 inhibitors against EC included nivolumab, pembrolizumab, camrelizumab, sintilimab, toripalimab, and serplulimab. A total of 9.9% of patients were diagnosed with EAC, and 90.1% were ESCC. A pooled analysis showed significant achievement in ORR in group A compared to group B with an OR of 2.19 (CI: 1.77-2.69, p < 0.05, I² = 60%). In terms of OS benefit, group A led to a 29% reduction in death risk compared to group B (HR: 0.71, CI: 0.66-0.76, p < 0.05, I² = 0). Group A also showed a significantly reduced risk of disease progression compared to group B (HR: 0.62, CI: 0.54-0.70, p < 0.05, I² = 60%). Safety analysis revealed more TRAEs (OR: 1.93, CI: 1.43-2.60, p < 0.01, I² = 11%) and grade ≥3 AEs (OR: 1.34, CI: 1.08-1.67, p < 0.05, I² = 54%) in group A compared with group B. Sub-group analysis based on CPS revealed that patients with CPS ≥10 showed more OS (pooled HR: 0.59 vs 0.75) (p = 0.04) and PFS (pooled HR: (0.59 vs 0.64) (p = 0.18) benefits as compared to patients with CPS <10. Survival analysis between ESCC and EAC also exhibited statistically non-significant OS benefits (p = 0.28). Conclusions: PD-1 inhibitor plus chemotherapy as a first-line therapy in advanced EC, mainly in patients with CPS ≥10, showed improved antitumor efficacy in terms of superior ORR, OS, and PFS, with a manageable toxicity profile providing a benchmark for future studies.

4035 Background: NIVO + chemo and NIVO + IPI demonstrated significant overall survival (OS) benefit vs chemo in previously untreated patients (pts) with advanced ESCC in the phase 3 CheckMate 648 study. We report expanded results from the primary analysis with 13-month (mo) minimum follow-up. Methods: Pts with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR) in pts with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%. Secondary endpoints planned for hierarchical testing included OS, PFS, and objective response rate (ORR) per BICR in all randomized pts. Duration of response (DOR) per BICR and PFS2 per investigator (time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death) were exploratory endpoints. Results: Among all pts randomized to NIVO + chemo (n = 321), NIVO + IPI (n = 325), or chemo (n = 324), PFS2 favored NIVO + chemo (HR 0.64, 95% CI 0.54–0.77) and NIVO + IPI (HR 0.74, 95% CI 0.62–0.88) vs chemo. ORR (95% CI) was 47% (42–53), 28% (23–33), and 27% (22–32), respectively. More responders with NIVO + chemo or NIVO + IPI vs chemo had prolonged DOR (≥12 mo; 39%, 48%, and 23%, respectively). Efficacy data by tumor cell PD-L1 and PD-L1 combined positive score will be presented. Grade 3/4 treatment-related adverse events with potential immunologic etiology (select TRAEs) occurred in ≤ 6% of pts with NIVO + chemo and NIVO + IPI, and non-endocrine select TRAEs resolved in 57%–95% of pts across organ categories (Table). Conclusions: NIVO + chemo and NIVO + IPI demonstrated favorable PFS2 and a higher proportion of pts with prolonged DOR vs chemo, as well as acceptable safety profiles. These results provide further support for each regimen as a new potential 1L standard of care in advanced ESCC. Clinical trial information: NCT03143153. [Table: see text]

Susceptibility to esophageal carcinoma (EC) is influenced by the interaction between genetic and environmental factors. To clarify the etiology of EC, several genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in PCLE1 and RFT2 genes as esophageal squamous cell carcinoma (ESCC) susceptibility loci in Asian populations. This study aimed to determine whether these SNPs also modify the risk of esophageal adenocarcinoma (EAC) and ESCC in western populations of Caucasian ethnicity. A European case-control study including 349 EC patients and 580 controls matched for age, sex, geographical location, and race was carried out. The SNPs rs2274223 in the PCLE1 gene at chromosome 10q23 and rs13042395 in the RFT2 gene at chromosome 20p13 were determined using PCR. Genotype distributions were compared between patients and controls, and odds ratios with 95% confidence intervals were calculated. The total EC group included 86 patients with ESCC and 258 patients with EAC. The distribution of PLCE1 and RFT2 genotypes did not differ between patients with EAC or ESSC, and the controls. In contrast to the modulation of the risk of ESCC in Asians, it is unlikely that the PLCE1 rs2274223 and RFT2 13042395 SNPs play a role in EAC or ESCC susceptibility in Dutch Caucasians.

Esophageal squamous cell carcinomas (ESCCs) and esophageal adenocarcinomas (EACs) account for >95% of esophageal malignancies and represent a major global health burden. ESCC is the dominant histology globally but represents a minority of U.S. cases, with EAC accounting for the majority of U.S. The patient outcomes for advanced ESCC and EAC are poor, and new therapeutic options are needed. Using a sensitive sequencing assay, we compared the genomic profiles of ESCC and EAC with attention to identification of therapeutically relevant genomic alterations. Next-generation sequencing-based comprehensive genomic profiling was performed on hybridization-captured, adaptor ligation-based libraries to a median coverage depth of >650× for all coding exons of 315 cancer-related genes plus selected introns from 28 genes frequently rearranged in cancer. Results from a single sample were evaluated for all classes of genomic alterations (GAs) including point mutations, short insertions and deletions, gene amplifications, homozygous deletions, and fusions/rearrangements. Clinically relevant genomic alterations (CRGAs) were defined as alterations linked to approved drugs and those under evaluation in mechanism-driven clinical trials. There were no significant differences by sex for either tumor type, and the median age for all patients was 63 years. All ESCCs and EACs were at an advanced stage at the time of sequencing. All 71 ESCCs and 231 EACs featured GAs on profiling, with 522 GAs in ESCC (7.4 per sample) and 1,303 GAs in EAC (5.6 per sample). The frequency of clinically relevant GAs in ESCC was 94% (2.6 per sample) and 93% in EAC (2.7 per sample). CRGAs occurring more frequently in EAC included KRAS (23% EAC vs. 6% ESCC) and ERBB2 (23% EAC vs. 3% ESCC). ESCC samples were enriched for CRGA in PIK3CA (24% ESCC vs. 10% EAC), PTEN (11% ESCC vs. 4% EAC), and NOTCH1 (17% ESCC vs. 3% EAC). Other GAs that differed significantly between histologic tumor types included SMAD4 (14% EAC vs. 1% ESCC), RB1 (14% ESCC vs. 2% EAC), SOX2 (18% ESCC vs. 1% EAC), and NFE2L2 (24% ESCC vs. 1% EAC). ESCC and EAC share similarly high frequencies of overall and clinically relevant genomic alterations; however, the profiles of genomic alterations in the two diseases differ widely, with KRAS and ERBB2 far more frequently altered in EAC compared with ESCC and with mammalian target of rapamycin (MTOR) pathway genes (PIK3CA and PTEN) and NOTCH1 more frequently altered in ESCC compared with EAC. Comprehensive genomic profiling highlights the promise of identifying clinically relevant genomic alterations in both ESCC and EAC and suggests new avenues for molecularly directed therapies in esophageal cancer.

e16044 Background: The prognosis of metastatic/locally advanced EC has significantly improved with the development of immune checkpoint inhibitors. Serplulimab has been approved in the treatment of various solid tumors (e.g. esophageal squamous cell carcinoma [ESCC], small cell lung cancer). Considering the lack of real-world evidence, this study aimed to explore the real-world effectiveness and safety of serplulimab as first-line therapy in patients with metastatic/locally advanced EC. Methods: Thismulticenterretrospective study included patients with metastatic/locally advanced EC who received first-line serplulimab-containing therapy from March 2022 to December 2023. The demographic and disease characteristics, chemotherapy regimens selected by physicians, treatment response and adverse events were collected from medical record. The outcomes included progression free survival (PFS), objective response rate (ORR), overall survival (OS), duration of response (DoR), time to treatment discontinuation (TTD) and safety. Results: A total of 57 patients were included, 45 (78.9%) were male with a mean age of 68 years. A majority of patients had ESCC (n=40, 70.2%) and metastatic disease (n=35, 61.4%). The most common chemotherapy regimens combined with serplulimab were paclitaxel plus cisplatin (n=27, 39.1%) and etoposide and platinum (n=13, 23.6%). With a median follow-up of 4.8 month (range: 0.7-19.7), the median PFS was 7.4 months (95% confidence interval [CI]: 3.7-11.1). The ORR and DCR were 22.8% and 96.5% in all patients, respectively. The median DoR and TTD were 4.7 months (95% CI: 4.3-not estimated [NE]) and 13.9 months (95% CI: 3.6-24.1), respectively, while the median OS was not reached (NR). The mPFS was 11.1 months (95% CI: 7.0-NE) in patients with ESCC, which was numerically longer than those with neuroendocrine carcinoma (6.5 months, 95% CI: 5.8-7.3, P=0.052). Other effectiveness outcomes in ESCC are presented in Table. Patients > 65 years had a significant improved mPFS compare to those ≤ 65 years (5.9 vs. 11.1 months, P=0.001). The rate of any grade adverse events (AEs) was 26.3% (n=15), while grade 3 or higher AEs was 10.5% (n=6), thrombocytopenia (7.0%, n=4), myelosuppression and pulmonary infection (both 5.3%, n=3) being the most common. Conclusions: First-line serplulimab combined with chemotherapy demonstrated promising effectiveness and favorable safety profile in patients with metastatic/locally advanced EC, especially in ESCC. The current real-world evidence indicates that serplulimab combined with chemotherapy could provide survival benefit for patients with advanced first-line EC. [Table: see text]

O-3 Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): Expanded efficacy and safety analyses from CheckMate 648

Esophageal carcinoma is a male-dominant malignancy worldwide, and esophageal adenocarcinoma (EAC) shows more significant sex bias than esophageal squamous cell carcinoma (ESCC) in morbidity and mortality. The G protein-coupled estrogen receptor 1 (GPER1) is involved in several sex-related cancers; however, its expression level in esophageal carcinoma has been poorly investigated and its role is not precisely defined, depending on histological types. In the present study, the mRNA levels of GPER1 in esophageal carcinoma were collected from GEPIA and Oncomine databases for meta-analyses. The protein expression levels of GPER1 were detected by immunohistochemistry in the tissue microarray of EAC and ESCC. The GPER1 selective agonist G1, antagonist G15, and siRNA were applied in vitro to investigate their impacts on esophageal cell lines. Analysis of the RNA levels from the databases showed a decreased expression of GPER1 in overall esophageal carcinoma, and low expression levels of GPER1 were found to be associated with low survival of tumor patients. However, in the subgroup of EAC and its precancerous lesion, Barrett's esophagus, overexpression of GPER1 RNA was increased when compared with the normal tissues. The average staining scores of GPER1 protein in the tissue microarray of EAC were significantly higher than normal esophageal samples, and the rate of positive staining increased with the grade of poor tumor differentiation. The scores of GPER1 protein in ESCC tissues were lower than those in the normal tissues. The results from cell line experiments in vitro showed that the GPER1 agonist G1 inhibited proliferation and promoted apoptosis of ESCC cells EC109 with positive expression of GPER1. G1 had no obvious effect on normal esophageal NE2 cells with weak expression of GPER1. In addition, GPER1 RNA knockdown and application of antagonist G15 reversed the effects of G1 on EC109. The results of this study indicate that the expression levels of GPER1 are higher in EAC than in ESCC, which might be correlated with the dimorphic estrogen signaling pathway in different types of esophageal carcinoma.

7 Background: ESCC and EAC are relatively rare malignancies in the US with EAC more common than ESCC. Using a sensitive CGP assay, we compared the genomic profiles of ESCC and EAC focused on the search for therapy targets. Methods: DNA was extracted from 40u of FFPE sections from 54 clinically advanced ESCC and 234 EAC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a median coverage depth of 652X for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The results were evaluated for all classes of genomic alterations (GA) including point mutations, short INDELs, copy number alterations and fusions/rearrangements. Clinically relevant genomic alterations (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: All ESCC and EAC were at an advanced stage (Stage III/IV) at the time of CGP and had similar gender and age (median 63 yrs) distribution. 54 (100%) of ESCC and 233 (99.6%) of EAC featured GA on profiling with 397 GA in ESCC (7.4/sample) and 1,317 GA (5.6/sample) in EAC. The frequency of clinically relevant GA in ESCC (2.7/sample; 93% of cases) and EAC (2.7/sample; 92% of cases) were identical. EAC featured a greater number of CRGA (72) than ESCC (46). CRGA more frequently altered in EAC than ESCC included KRAS (23% vs 7%) and ERBB2 (23% vs 4%). CRGA more frequently identified in ESCC than EAC included PIK3CA (28% vs 10%), PTEN (13% vs 4%) and NOTCH1 (22% vs 3%). Other GA that were significantly different in the 2 tumor types included SMAD4 (14% EAC vs 0% ESCC), RB1 (19% ESCC vs 2% EAC), SOX2 (17% ESCC vs 1% EAC) and NFE2L2(19% ESCC vs 0% EAC). HPV-16 was detected in 2 (4%) and HPV-18 in 1 (2%) of ESCC. HPV was not detected in EAC. Conclusions: ESCC and EAC share high frequencies of total GA and CRGA. However, KRAS and ERBB2 are far more frequently altered in EAC than ESCC and mTOR pathway genes (PIK3CA and PTEN) more frequently altered in ESCC than EAC. CGP shows significant promise to identify CRGA in both ESCC and EAC and drive the potential use of clinical outcome altering targeted therapies in both major types of esophageal cancer.

Background: NIVO plus IPI improved progression-free survival (PFS) and objective response rate (ORR) vs IPI alone in the phase II CheckMate 069 and phase III CheckMate 067 trials of treatment-naive patients (pts) with advanced melanoma (MEL). Here, we report the first OS results from CheckMate 067. Methods: Treatment-naïve patients (N=945) were randomized 1:1:1 to NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses followed by NIVO 3 mg/kg Q2W, NIVO 3 mg/kg Q2W + placebo, or IPI 3 mg/kg Q3W for 4 doses + placebo, until progression or unacceptable toxicity. Pts were stratified by PD-L1 status (<5% vs ≥5%), BRAF mutation status, and M-stage. Co-primary endpoints are PFS and OS in the NIVO-containing arms vs IPI. Results: At a minimum follow-up of 28 months, median OS has not been reached in the NIVO+IPI or NIVO groups, and was 20.0 months for IPI (hazard ratio [HR]: NIVO+IPI vs IPI, 0.55; P<0.0001; NIVO vs IPI, 0.63; P<0.0001). In descriptive analyses, the relative risk of death in the NIVO+IPI group was reduced by 12% compared with the NIVO group (HR=0.88); 2-year OS rates were 64%, 59% and 45% for NIVO+IPI, NIVO, and IPI, respectively. Consistent OS results favoring NIVO+IPI over NIVO were observed across subgroups (HR ~0.88, including M1c and LDH). In pts with tumor PD-L1 expression ≥5%, median OS appeared comparable between NIVO+IPI and NIVO. Median duration of response has not yet been reached with NIVO+IPI, and was 31.1 months for NIVO and 18.2 months for IPI. The safety profile remained similar to the initial report, with grade 3-4 treatment-related AEs in the NIVO+IPI, NIVO, and IPI groups of 58%, 21% and 28%, respectively.NR=not reached. Conclusions: Both NIVO+IPI and NIVO significantly improved OS vs IPI alone. In descriptive analyses, NIVO+IPI appeared to provide favorable survival outcomes over NIVO alone, including across clinically relevant subgroups. Median OS, mo (95% CI)NIVO+IPINIVOIPIITTNRNR (29.1-NR)20.0 (17.1-24.6)M1c30.5 (19.4-NR)23.4 (16.5-32.3)15.0 (11.5-17.7)LDH >ULN17.4 (10.7-NR)15.0 (11.7-23.4)10.9 (8.4-13.1)BRAF MutantNRNR (26.4-NR)24.6 (17.9-31.0)PD-L1 ≥5%NRNR28.9 (18.1-NR)PD-L1 <5%NR (31.8-NR)NR (23.1-NR)18.5 (13.7-22.5) Citation Format: James Larkin, Vanna Chiarion-Sileni, Rene Gonzalez, Piotr Rutkowski, Jean-Jacques Grob, C. Lance Cowey, Christopher D. Lao, Dirk Schadendorf, Pier Francesco Ferrucci, Michael Smylie, Reinhard Dummer, Andrew Hill, John Haanen, Michele Maio, Grant McArthur, Dana Walker, Linda Rollin, Christine Horak, F. Stephen Hodi, Jedd D. Wolchok. Overall survival (OS) results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naïve patients with advanced melanoma (CheckMate 067) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT075. doi:10.1158/1538-7445.AM2017-CT075

The role of the metabolic syndrome in the etiology of esophageal and gastric cancer is unclear. This was a large nationwide cohort study based on data from 11 prospective population-based cohorts in Norway with long-term follow-up, the Cohort of Norway (CONOR) and the third Nord-Trøndelag Health Study (HUNT3). The metabolic syndrome was assessed by objective anthropometric and metabolic biochemical measures and was defined by the presence of at least three of the following five factors: increased waist circumference, elevated triglycerides, low high-density lipoprotein cholesterol, hypertension and high glucose. Newly diagnosed cases of esophageal adenocarcinoma, esophageal squamous-cell carcinoma and gastric adenocarcinoma were identified from the Norwegian Cancer Registry. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models with adjustment for potential confounders. Among 192,903 participants followed up for an average of 10.6 years, 62 developed esophageal adenocarcinoma, 64 had esophageal squamous-cell carcinoma and 373 had gastric adenocarcinoma. The metabolic syndrome was significantly associated with an increased risk of gastric adenocarcinoma (HR 1.44, 95% CI 1.14-1.82), but not associated with esophageal adenocarcinoma (HR 1.32, 95% CI 0.77-2.26) or esophageal squamous-cell carcinoma (HR 1.08, 95% CI 0.64-1.83). Increased waist circumference was associated with an increased HR of esophageal adenocarcinoma (HR 2.48, 95% CI 1.27-4.85). No significant association was found between any single component of the metabolic syndrome and risk of esophageal squamous-cell carcinoma. High waist circumference (HR 1.71, 95% CI 1.05-2.80), hypertension (HR 2.41, 95% CI 1.44-4.03) and non-fasting glucose (HR 1.74, 95% CI 1.18-2.56) were also related to an increased risk of gastric adenocarcinoma in women, but not in men. Metabolic syndrome was associated with an increased risk of gastric adenocarcinoma in women. Of the individual components of the metabolic syndrome, high waist circumference was positively associated with risk of esophageal adenocarcinoma. Positive associations were also observed for women between high waist circumference, hypertension, high non-fasting glucose and risk of gastric adenocarcinoma. However, further evidence is warranted due to the limited number of cases and the inability to effectively identify gastric cardia adenocarcinoma.

Background: Esophageal carcinoma (EC) is one of the most common malignancies of the gastrointestinal tract worldwide and is unresponsive to therapy. Esophageal squamous cell carcinoma (ESCC) comprises the majority of EC in African Americans, Asians and other ethnic groups, while esophageal adenocarcinoma (EAC) predominates among Caucasians. Poor prognosis of EC in Caucasians and African Americans is reflected by five-year survival rates of 21% and 14 %, respectively. The aggressiveness and lower survival rate of African American ESCC patients than that from patients of other ethnic groups are evident even after adjusting for treatment modalities and socioeconomic factors. These characteristics suggest the existence of an ethnic- or race-dependent component of EC etiology. However, the genetic architecture of ESCC in AA is not well studied, and thus, mostly undefined. Our study aims to identify exonic mutations that may represent critical genetic changes in African American ESC carcinogenesis. Methods and Materials: Whole exome sequencing (WES) of matched tumor and normal tissue DNA from endoscopic biopsies from late-stage ESCC of nine African American Veteran male patients was conducted. This study was approved by the DC VAMC Institutional Review Board, and a written informed consent was obtained from each patient prior to biopsy. Biopsies were de-identified, freshly frozen and stored at -80 °C. To proceed to exon capture, we enriched our samples by using Agilent SureSelect XT Human All Exon V6+UTR. Paired-end sequencing at a read depth of 100X was performed on the exon libraries using the Illumina HiSeq 4000 sequencer. We applied Genome Analysis Toolkit's best practices WES pipeline to identify both germline and somatic variations in the dataset. The Seven Bridges Cancer Genomics Cloud platform was used for processing the data and annotating the variants. Variants were mapped to genomic regions and further aggregated at the gene level, pathways, and biological processes relevant to disease by using Reactome, Pathway Studio, and Ingenuity Variant Analysis. Results: In all samples, 27,586 variants consisted of 86% single nucleotide variation, 8.5% insertions and 5.5% deletions. Approximately half of the variants caused missense changes while 0.12% created nonsense mutations. High impact mutations occurred in genes that have a role in DNA damage repair, stress response, detoxification pathways, keratinization and immune surveillance. Conclusion: We found unique genomic variation in African American ESCC, that reveals a potential molecular signature for the aggressiveness and lethality of ESCC in this population. Future functional studies will be conducted to elucidate the role of these mutations in ESCC pathogenesis. Citation Format: Robert Wadleigh, Krithika Bhuvaneshwar, Gustavo Marino, Vincente Notario, Jack Lichy, Yuriy Gusev, Hayriye Verda Erkizan. Genetic architecture of esophageal squamous cell carcinoma in African American veterans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3426.

Phase II Study of Toripalimab in Combination with Induction Chemotherapy and Subsequent Chemo- Radiation in Patients with Advanced/Metastatic Esophageal Carcinoma (TR-EAT Trial)

Background: Esophageal cancer (EC) is one of the deadliest cancers in the world. However, the mechanism that drives the evolution of EC is still unclear. On this basis, we identified the key genes and molecular pathways that may be related to the progression of esophageal adenocarcinoma and squamous cell carcinoma to find potential markers or therapeutic targets.Methods: GSE26886 were obtained from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) among normal samples, EA, and squamous cell carcinoma were determined using R software. Then, potential functions of DEGs were determined using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The STRING software was used to identify the most important modules in the protein–protein interaction (PPI) network. The expression levels of hub genes were confirmed using UALCAN database. Kaplan–Meier plotters were used to confirm the correlation between hub genes and outcomes in EC.Results: In this study, we identified 1,098 genes induced in esophageal adenocarcinoma (EA) and esophageal squamous cell carcinoma (ESCC), and 669 genes were reduced in EA and ESCC, suggesting that these genes may play an important role in the occurrence and development of EC tumors. Bioinformatics analysis showed that these genes were involved in cell cycle regulation and p53 and phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. In addition, we identified 147 induced genes and 130 reduced genes differentially expressed in EA and ESCC. The expression of ESCC in the EA group was different from that in the control group. By PPI network analysis, we identified 10 hub genes, including GNAQ, RGS5, MAPK1, ATP1B1, HADHA, HSDL2, SLC25A20, ACOX1, SCP2, and NLN. TCGA validation showed that these genes were present in the dysfunctional samples between EC and normal samples and between EA and ESCC. Kaplan–Meier analysis showed that MAPK1, ACOX1, SCP2, and NLN were associated with overall survival in patients with ESCC and EA.Conclusions: In this study, we identified a series of DEGs between EC and normal samples and between EA and ESCC samples. We also identified 10 key genes involved in the EC process. We believe that this study may provide a new biomarker for the prognosis of EA and ESCC.

<div>Abstract<p><b>Purpose:</b> The current management of advanced esophageal squamous cell carcinoma (ESCC) remains unsatisfactory. We investigated the safety, efficacy, and biomarkers of SHR-1210, an anti-PD-1 antibody, in patients with recurrent or metastatic ESCC.</p><p><b>Experimental Design:</b> This study was part of a phase I trial in China. Patients with advanced ESCC who were refractory or intolerant to previous chemotherapy were enrolled. Eligible patients received intravenous SHR-1210 at a dose of 60 mg, with escalation to 200 and 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. The associations between candidate biomarkers (PD-L1 and somatic mutation load) and the efficacy of SHR-1210 were also explored.</p><p><b>Results:</b> Between May 11, 2016, and December 9, 2016, a total of 30 patients from one site in China were enrolled. Ten patients (33.3%) had an independently assessed objective response. Median progression-free survival was 3.6 months (95% CI, 0–7.2). Three (10.0%) treatment-related grade 3 adverse events were reported: two (6.7%) pneumonitis and one (3.3%) increased cardiac troponin I. No grade 4 or grade 5 treatment-related adverse events were reported. The exome sequencing and analysis showed that the mutational burden and the potential mutation-associated neoantigen count were associated with better responses. An objective response was more common in patients with PD-L1–positive tumors as defined by ≥5% staining (7 of 15 patients) than in those with PD-L1–negative tumors (1 of 9 patients).</p><p><b>Conclusions:</b> In this population of ESCC patients, SHR-1210 had a manageable safety profile and promising antitumor activity. <i>Clin Cancer Res; 24(6); 1296–304. ©2018 AACR</i>.</p></div>