Gastric and upper gastrointestinal oncology: integrating breakthroughs from prevention to precision therapeutics

Abstract

Gastric and upper gastrointestinal (GI) oncology is at a point of transformation, with significant advances in each aspect of the disease continuum. Novel clinical tools and therapies, including randomized phase II and III trials, have provided new standards of care for patients, including preoperative chemoradiation for resectable gastric cancer and PD-L1 stratified immuno-chemotherapy in the metastatic setting. Also, many discoveries are co-evolving with newer methods, such as CAR-T therapy or reintroduced microbial undercover agents or burgeoning precision tools. However, obstacles remain, nursing the costs of CAR-T, the paradoxical survival benefit of PD-L1 P146R polymorphism, and other biological ineptitudes along with health system barriers. In this synthesis, we advocate for more closely integrated “bench-to-community” approaches to apply more effective combinations of health population prevention programs, biomarker-guided therapeutics, and omics profiling studies to accelerate and positively impact healthcare practices addressing biological or health system barriers.

Introduction

Gastric and upper gastrointestinal (GI) oncology is now entering a new era characterized by remarkable progress across the entire disease spectrum from prevention to end-stage treatment over the last two years. There have been several changing paradigms, including the re-establishment of preoperative chemoradiation as an option, immunochemotherapy as a new standard of care, and the innovation pathway of omics and chimeric antigen receptor T-cell (CAR-T) therapies. While we are experiencing unprecedented advancement in the science of gastric malignancies, we aim to specifically bring together the growing literature into clinical application while reflecting on how we implement and account for the fallibility of the time lag that exists across practices. The confluence of these advanced therapies creates opportunities and decisions of fascinating complexity for clinicians treating gastrointestinal malignancies. Advances in gastric and upper GI oncology that will change the way you get treatment, based on biomarkers and a new way of working. This editorial discusses these advances in gastric and upper GI oncology and will present an integrated model to connect translational innovations to clinical applications.

Therapeutic advances by disease stage

There have been considerable advances in treating GI cancers over the last few years. These advances have helped redefine how we treat GI cancers throughout the course of the disease from diagnosis to death. With these advances come a shift in the way we think about treating patients with GI cancers through the utilization of treatments that utilize precision medicine. This section provides insight into the ways in which these new strategies will continue to provide better care and demonstrate that there are still areas in which we can improve our knowledge and implementation of new strategies when caring for patients with GI cancers. As summarized in Table 1, these trials collectively support a paradigm shift toward biomarker-guided and stage-specific therapies. For example, the NEJM 2024 preoperative chemoradiation study for resectable disease demonstrated a staggering absolute improvement in pathologic complete response rates (17% vs. 8%), providing the standard, which is immensely important in high-risk patients who had difficult anatomy or nodal positive disease, while ensuring the preoperative chemotherapy remained for lower-risk patients [1]. This algorithmic shift, while astonishing, remains unanswered regarding its use in diffuse-type histology, and it highlights persisting inequalities in access to radiotherapy across healthcare systems. In the first line metastatic program, the GEMSTONE-303 trial (JAMA 2025) refined the selection of immunochemotherapy based on PD-L1 combined positive score (CPS) stratification data, adding evidence for a clear relationship of survival to therapeutic benefit (HR 0.66 for CPS ≥ 5)². The issues highlighted by the PRODIGE51 trial versus TFOX vs FOLFOX in terms of the length of progression-free survival (progression-free survival (PFS) 7.59 vs 5.98 months), that continue to cause distress in clinical practice is how chemotherapy intensity and tolerability defined in these trials [3]. In the second line, STRATEGY guided by the ARMANI trial provided all participants (51% of patients came from Canada, possibly Italy) data on improved overall survival with paclitaxel/ramucirumab switch maintenance (8.8 vs 6.1 months)(Fig. 1A), however, the more global beyond progression” conundrum of continue-switch mechanistic approach and impediments remains unanswered by this trial, though it remains at the core of current questions about addressing tumor evolution and identifying patterns of therapeutic resistance [4, 5]. Collectively, these scientific advances in therapeutic investigations profile the maturation of the field towards stage-related precision medicine, however, it still highlights the multifaceted clinical and biological complexities we must remain aware of to fully utilize the skills we have available.

Table 1.

The summary of clinical trials of disease stage

Trial Name	Line of Treatment	Sample Size	Intervention	Comparator	Endpoint	HR (95% CI)	Source
TOPGEAR	Preoperative (localized)	574	Chemoradiotherapy + perioperative chemo	Perioperative chemotherapy alone	pCR: 17% vs. 8%	–	NEJM 2024
GEMSTONE-303	1st-line metastatic	479	Sugemalimab + chemo	Chemotherapy alone	OS: HR 0.75 (CPS ≥ 5)	HR 0.66 (0.54–0.81)	JAMA 2025
PRODIGE 51	1st-line metastatic	507	TFOX	FOLFOX	PFS: 7.59 vs. 5.98 mo	HR 0.82 (0.68–0.99)	Lancet Oncology 2025
ARMANI	Maintenance (2nd-line)	280	Ramucirumab + Paclitaxel	Continue oxaliplatin-based chemo	OS: 8.8 vs. 6.1 mo	HR 0.75	Lancet Oncology 2024

Fig. 1.

Therapeutic Evolution and Precision Medicine Frameworks in Gastrointestinal Malignancies. A Therapeutic Advances by Disease Stage: Progressive improvements in treatment strategies across disease stages, including localized resectable disease, first-line metastatic settings, and second-line therapies. B Paradigm-Shifting Intervention Strategies: Emerging interventions that redefine therapeutic paradigms, such as cell-based therapy, and microbiota-targeted approaches, including Helicobacter pylori eradication and modulation of non-H. pylori microbial populations. C Emerging Architectures of Precision Medicine: Integration of spatial multi-omics, predictive algorithms, artificial intelligence, and exploration of biological paradoxes to construct next-generation precision medicine frameworks

Paradigm-shifting intervention strategies

In parallel, biologic and technological innovations are expanding the armamentarium of gastric oncology. While still in early-phase evaluation, these approaches foreshadow new treatment paradigms and conceptual shifts. The specialized area of gastrointestinal oncology has undergone revolutionary developments in cellular and microbiologic interventions that are changing the treatment landscape. For example, the Lancet 2025 satri-cel phase 2 trial showed a promising progression-free survival signal (3.25 vs. 1.77 months) in gastric cancers, suggesting potential benefit of CAR-T therapy, though further validation in larger phase III trials is warranted [6]. Simultaneously, microbial studies have consistently identified Helicobacter pylori as a likely etiologic factor in gastric carcinogenesis, supported by multiple epidemiologic and interventional studies. Eradication therapy demonstrated a stronger effect (HR 0.81) in the Linqu trial [7](Fig. 1B). While emerging data focused on non-H. pylori oncobiota, including S. anginosus, suggest a possible role in promoting gastric inflammation and carcinogenesis, although the causal mechanisms remain under investigation [8]. Both the advances in cellular therapies used as a targeted intervention, but also gastrointestinal tract microbiome interventions, are unwittingly aligned within a framework of convergence toward more targeted treatment options for gastrointestinal malignancies.

Emerging architectures of precision medicine

Translating molecular discoveries into equitable care delivery remains a challenge, shaped by healthcare infrastructure, reimbursement models, and technical reproducibility. Innovative advancements in tools for precision medicine have propelled gastrointestinal cancers in novel multi-dimensional approaches. Emerging spatial multi-omics technologies continue to uncover complex processes regarding resistance - and identified metabolic symbionts programmed to 12-fold an upregulated TGFB1-HSPB1 interactions present within tumor microenvironments - while more sophisticated predictive algorithms yield unprecedented predictive accuracy (area under the curve (AUC) 0.93) for treatment responses [9]. While predictive algorithms have emerged, artificial intelligence (AI) applications such as the GRAPE Initiative screening process demonstrate robust sensitivity (85.1%) and specificity (96.8%), such processes will lead to earlier detection opportunities [10](Fig. 1C). Despite the rapid evolution of precision oncology, unresolved challenges persist—such as the paradox of PD-L1^P146R polymorphism, which may influence response to anti-PD-1 therapy, though current evidence remains limited and requires further mechanistic clarification [11]. That said, it is of utmost importance to further develop curated predictive algorithms that integrate molecular, spatial, and clinical pathways of information, critical thinking to better address precision oncology.

Implementation challenges and future directions

The transition of these scientific advances into the clinic will require careful implementation of key enablers identified above, to maximize their potential. There are major issues of equity of access to healthcare with significant resource issues related to the cost-effectiveness of new therapies. CAR-T therapy was shown to be cost-effective with CAR T-cell drug cost accounting for 97.0%¹². Important questions will arise regarding the rationality of withholding potentially curative therapies based on cost. There are also gaps in the evidence when therapies are compared directly to alternative and more conservative approaches, particularly the comparison between chemoradiation and immune-based neoadjuvant approaches. The reproducibility of cutting-edge technologies and novel experimental therapies into clinical practice presents challenges [13]. In the future, we must develop adaptive response option clinical trial designs that build on an umbrella framework for patient selection and dynamic patient allocation to promote rapid optimization of therapies. Integration in public health should incorporate stepwise implementation of a prevention program of H. pylori screening, enhanced computed tomography (CT) with AI, and endoscopic surveillance based on risk. At the translational research level, investment in the development of theragnostic probes for fibrin deposits and for studies that utilize nanomedicine approaches to inhibit the Yes-associated protein (YAP) pathway, and the mechanism of postoperative recurrence will provide synergistic avenues to address current challenges in moving from discovery to clinical practice as well as overcoming economic and logistical barriers to implementation [14–16].

Conclusion

In summary, the way forward requires a composite approach that combines population-level intervention with molecular precision. At the preventive level this includes systematic microbial eradication schemes like H. pylori or other oncogenic microbial pathogens. At the treatment level, it is increasingly advisable to explore biomarker-driven, stage-specific treatment algorithms, informed by the evolving evidence base and individual tumor biology. In addition, it also involves building longitudinal surveillance systems for disease and other outcomes tracking, using spatial-omics and other profiling modalities. In the cases of gastrointestinal oncology, we need to break down barriers between discovery, delivery and population health. This necessitates unprecedented collaboration between basic science, clinicians, public health and policy stakeholders via a “bench to bedside to community” continuum.

Author contributions

JunLi Chen, LuLu Cai and Jian Li designed and wrote the manuscript. JiLong Wang and JunLi Chen did literature search and wrote the manuscript. LuLu Cai and Jian Li prepared the Figures. All authors listed have made a substantial contribution to the work. All authors have read and approved the article.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.