Esophageal Adenocarcinoma

This comprehensive immune phenotype study of a large series of untreated GEACs, identified that tumors with an esophageal tumor location have more immune suppressive features compared to tumors in the gastro-esophageal junction or stomach which might explain the location-specific responses to checkpoint inhibitors in this disease. These findings provide an important rationale for stratification according to tumor location in clinical studies and the development of location-dependent immunomodulatory treatment approaches.

P2, N=25, Recruiting, University of Southampton | Not yet recruiting --> Recruiting | Trial primary completion date: Nov 2025 --> Mar 2026

P2, N=168, Recruiting, Canadian Cancer Trials Group | Not yet recruiting --> Recruiting

Our findings underscore the possibility of distinct molecular mutation patterns in EAC among different races. Further studies are needed to validate our findings, which could contribute to precision medicine in EAC.

However, unlike breast cancer, the efficacy of other anti-HER2 drugs, such as lapatinib, pertuzumab, and T-DM1, has failed to improve outcomes in advanced and locally advanced resectable GEA. Recently, the combination of trastuzumab with pembrolizumab, along with chemotherapy, and the development of trastuzumab deruxtecan, with its specific bystander activity, demonstrated improved outcomes, renewing attention in the treatment of this disease. This review will summarise historical and emerging therapies for the treatment of HER2-positive GEA, with a section dedicated to the HER2 molecular pathway and the use of novel blood biomarkers, such as circulating tumour DNA and circulating tumour cells, which may be helpful in the future to guide treatment decisions.

P3, N=700, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

P1/2, N=263, Recruiting, Salubris Biotherapeutics Inc | N=149 --> 263

P1, N=17, Completed, Turning Point Therapeutics, Inc. | Active, not recruiting --> Completed | N=42 --> 17

P=N/A, N=70, Completed, Cancer Institute and Hospital, Chinese Academy of Medical Sciences | Recruiting --> Completed | Trial completion date: May 2025 --> Dec 2023 | Trial primary completion date: May 2025 --> Dec 2023

Functional enrichment analysis showed that the signature was mainly clustered in cell proliferation related biological processes or pathways. The four-gene signature identified in the current study may be a potential prognostic factor for predicting OS of EAC patients.

High LINC00626 expression promotes esophageal-gastric junction adenocarcinoma metastasis by activating the JAK1/STAT3/KHSRP signal axis.

These results serve as the first comprehensive examination of the relationship between SMARCA4ms and clinical outcomes in GEA.

P2/3, N=224, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Mar 2024 --> Jun 2024

By quantitative proteomic analysis we have identified GPA33 as an EAC-selective biomarker. Integrated analysis of proteome, transcriptome, and genome in EAC has revealed several genes with tumor-selective, post-transcriptional regulation of protein expression which may be an exploitable vulnerability.

P3, N=450, Not yet recruiting, Merck Sharp & Dohme LLC

SMAD3 inhibition diminished ATM phosphorylation by enhancing the binding of PP2A to ATM, causing excessive levels of DNA damage. Our results identify SMAD3 as a promising therapeutic target for future combination strategies for the treatment of patients with EAC.

P1, N=10, Terminated, NeoImmuneTech | Phase classification: P2 --> P1

P1, N=10, Recruiting, University of Manitoba | Not yet recruiting --> Recruiting

Single-cell RNA-sequencing revealed that, in addition to inducing apoptosis, cisplatin treatment triggered ferroptosis in a NER-deficient gastric cancer, validated by intracellular GSH assay. Overall, our study provides preclinical evidence that a subset of GEAs harbor genomic features of HR and NER deficiency and may therefore benefit from platinum chemotherapy and PARP inhibitors.

P1, N=105, Recruiting, ImmunoGenesis | Phase classification: P1a/1b --> P1

P=N/A, N=22, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

Expression of COMP in gastric and esophageal adenocarcinoma was correlated with shorter OS and RFS. A reduced number of immune cells infiltrated the tumor microenvironment when COMP expression was detected. This phenomenon could be attributed to the denser collagen deposits, a hallmark of tumor fibrosis observed in COMP-expressing tumors.

P=N/A, N=155, Completed, Columbia University | Active, not recruiting --> Completed

P1, N=824, Recruiting, Seagen Inc. | Trial completion date: Oct 2024 --> Oct 2028 | Trial primary completion date: Jul 2024 --> Nov 2026

P2, N=94, Active, not recruiting, National Cancer Institute (NCI)

gAD-induced upregulation of miR-378a-3p significantly inhibited the proliferation of EAC by targeting UHRF1. Therefore, gAD may serve as an alternative therapy for chemotherapy- and radiation-refractory EAC or other cancers with the same mechanism of pyroptosis action.

P2, N=27, Not yet recruiting, Weill Medical College of Cornell University

However, 14 days of intraperitoneal administration of 20-mg/kg 5-fluorouracil (5-FU), but not 20-mg/kg ferrichrome, induced weight loss and myelosuppression in both young and aged mice. Our findings indicate that ferrichrome induces DNA damage-inducible transcript-3, thereby producing anti-tumor effects, including cell cycle arrest and apoptosis, with minimal adverse effects in esophageal cancer cells. This illustrates the high potential of ferrichrome as an anti-tumor drug against esophageal carcinoma.

P2, N=360, Recruiting, Arcus Biosciences, Inc. | N=200 --> 360 | Trial completion date: Nov 2025 --> Jun 2027 | Trial primary completion date: Sep 2025 --> Sep 2026

P2, N=51, Suspended, Gustave Roussy, Cancer Campus, Grand Paris | N=112 --> 51 | Trial completion date: Mar 2027 --> Dec 2027 | Recruiting --> Suspended | Trial primary completion date: Mar 2024 --> Dec 2024

This finding suggests that E/GE-ADC can sporadically stain positive for NKX3.1, introducing potential challenges in definitively determining the primary site of origin in certain clinical scenarios. Along with a literature review of NKX3.1 expression in other tumor types, our study provides additional important information about the extent to which this immunostain can be seen in E/GE-ADCs, which, to our knowledge, has not been reported.

Patients treated with frontline programmed death 1 inhibitors who had 18F-BMS-986229 accumulation in any lesions on PET imaging had longer progression-free survival than patients without tracer accumulation in any lesions (median progression-free survival, 28.4 vs. 9.9 mo), though the small sample size prevents any definitive conclusions. PD-L1 PET imaging was safe, feasible, and concordant with pathologic evaluation and offers a potential noninvasive tool to assess PD-L1 expression.

P1/2, N=240, Not yet recruiting, Boehringer Ingelheim

The activity of perioperative chemotherapy-free immune checkpoint regimens in patients with nonmetastatic dMMR/MSI-H cancer is highly promising and underscores the need to identify this unique subgroup. We recommend MMR/MSI testing for all patients with GEA at diagnosis, and review the key rationale and clinical management implications for patient with dMMR/MSI-H tumors across disease stages.

Currently, there are no standard guidelines for treatment of these tumors; however, palliative radiotherapy and systemic chemotherapy may provide benefit. More recently, immunotherapy and novel therapeutic targets have shown some promise for these patients.

We achieve 91.4% and 87.3% AUROCs on discovery and external test datasets for the H&E model, comparable to the TFF3 model. Our proposed semi-automated clinical workflow can reduce pathologists' workload to 48% without sacrificing diagnostic performance, enabling pathologists to prioritize high risk cases.

P2, N=85, Completed, Jules Bordet Institute | Active, not recruiting --> Completed

P=N/A, N=120, Recruiting, University Health Network, Toronto | Trial completion date: Nov 2021 --> Nov 2025 | Trial primary completion date: Nov 2021 --> Nov 2025

P=N/A, N=84, Completed, University Health Network, Toronto | Active, not recruiting --> Completed | N=200 --> 84

The results demonstrate that detection of ecDNA using clinical-grade NGS assays is feasible and that key oncogene FH-amp on ecDNA (e.g., EGFR, FGFR2) are common in select tumor types. ECHO may be developed as a clinical trial device to prospectively identify patients with oncogene ecDNA+ FH-amp for clinical testing of ecDNA-directed therapies.

In addition, knowing the unusual patterns of HER2 expression is also important to avoid inaccurate evaluation. In this review, we discuss the key considerations when evaluating HER2 status in solid tumours for clinical decision making, including tissue handling and preparation for HER2 biomarker testing, as well as pathologist's readout of HER2 testing results in breast carcinomas, gastroesophageal adenocarcinomas, colorectal adenocarcinomas, gynaecologic carcinomas, and non-small cell lung carcinomas.

P2, N=74, Active, not recruiting, Jazz Pharmaceuticals | Recruiting --> Active, not recruiting | N=362 --> 74