Trending Topics in Gastroenterology | GastroAGI

Pancreatic Cancer Care Enters an Era of Biology-Guided Precision Management : Nat Rev Dis Primers | May 2026

Introduction Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies, characterized by aggressive tumor biology, late-stage diagnosis and limited long-term survival. Despite decades of therapeutic stagnation, recent advances in systemic therapy, molecular oncology, surgery and translational science are beginning to reshape the management landscape of pancreatic cancer. Problem Statement Traditional treatment paradigms for PDAC have been constrained by poor early detection, high metastatic potential, dense stromal desmoplasia and profound resistance to chemotherapy and immunotherapy. Although multimodal treatment approaches have improved outcomes incrementally, translating biologic discoveries into durable clinical benefit remains a major challenge. Summary This comprehensive primer outlines the ongoing transformation of pancreatic cancer management toward a multidisciplinary, biology-driven precision oncology model. Modern multiagent chemotherapy regimens have improved survival across resectable, locally advanced and metastatic disease settings, while advances in surgical strategy—including vessel-oriented and minimally invasive approaches—have expanded the pool of patients eligible for curative-intent resection. Importantly, resectability is increasingly being defined not only anatomically but also biologically, integrating treatment response, tumor behavior and systemic disease risk into therapeutic decision-making. The review highlights major advances in precision medicine, particularly the emergence of KRAS-directed therapies and individualized RNA vaccine strategies that may overcome longstanding therapeutic resistance in PDAC. The tumor microenvironment remains central to disease progression and treatment failure, with stromal and immune interactions representing both barriers and therapeutic opportunities for future combination approaches. The article also emphasizes rapid progress in early detection strategies, including surveillance of high-risk populations, artificial intelligence–assisted imaging and liquid biopsy technologies aimed at identifying PDAC at more treatable stages. Overall, this review portrays pancreatic cancer as a disease transitioning from purely anatomy-based management toward integrated biologic and molecular stratification, with precision therapeutics, immunologic innovation and advanced multimodal care collectively redefining future treatment paradigms.

COLOSOTO Trial Explores Chemotherapy-Sparing KRAS G12C Strategy in Frail Metastatic Colorectal Cancer : Digestive and Liver Disease | May 2026

Introduction KRAS G12C mutations represent a clinically important molecular subtype of metastatic colorectal cancer (mCRC), occurring in approximately 3–4% of cases and often associated with aggressive disease biology and limited responsiveness to conventional therapies. Recent advances in KRAS G12C inhibitors combined with EGFR blockade have demonstrated promising activity in refractory disease, opening new possibilities for biomarker-driven treatment strategies in colorectal cancer. Problem Statement Frail and elderly patients with unresectable mCRC frequently cannot tolerate standard doublet or triplet chemotherapy regimens because of age, comorbidities or impaired performance status. Current low-intensity fluoropyrimidine-based approaches offer only modest efficacy, and many vulnerable patients never reach later-line targeted therapies. Whether KRAS G12C-targeted combinations can be safely and effectively integrated earlier in treatment using chemotherapy-sparing strategies remains unknown. Summary The COLOSOTO trial is the first prospective study evaluating first-line treatment with 5-fluorouracil, panitumumab and sotorasib in frail or elderly patients with unresectable KRAS G12C-mutated metastatic colorectal cancer who are unfit for intensive chemotherapy. Building on encouraging activity observed with KRAS G12C inhibition plus EGFR blockade in refractory settings, this study investigates whether earlier deployment of this biologically driven combination can improve outcomes while maintaining tolerability in a clinically vulnerable population. The trial specifically targets patients traditionally underserved by standard treatment paradigms, including older adults and patients with impaired performance status. By combining limited-intensity chemotherapy with dual molecular targeting, the strategy aims to balance efficacy and toxicity while potentially avoiding the complications associated with aggressive cytotoxic regimens. The study also incorporates comprehensive geriatric assessment, quality-of-life evaluation and translational biomarker analyses including circulating tumor DNA monitoring, emphasizing a modern personalized oncology approach. Although limited by its single-arm design and relatively small sample size, the trial addresses a major unmet need in gastrointestinal oncology and may establish a new first-line therapeutic paradigm for frail patients with KRAS G12C-mutated colorectal cancer.

Molecular Tumor Boards Improve Survival in Refractory Solid Tumors : The Oncologist | May 2026

Introduction Precision oncology has transformed cancer care through the integration of genomic profiling and targeted therapies. However, translating complex next-generation sequencing data into clinically actionable treatment strategies remains difficult in patients with refractory solid tumors, particularly after multiple prior treatment failures. Molecular tumor boards (MTBs) have emerged as multidisciplinary platforms designed to bridge this gap by integrating genomic, clinical and therapeutic expertise. Problem Statement Although MTBs are increasingly implemented in oncology practice, real-world evidence demonstrating meaningful survival benefit remains limited, especially in heavily pretreated and biologically heterogeneous patient populations. A major unanswered question is whether adherence to MTB-recommended therapies truly improves clinical outcomes beyond the mere identification of actionable molecular alterations. Summary This large real-world study demonstrates that MTB-guided treatment strategies can significantly improve survival outcomes in patients with refractory solid tumors. Patients who received therapies matched to MTB recommendations experienced markedly prolonged overall survival and progression-free survival compared with patients who either did not receive recommended therapies or had no actionable molecular alterations. Importantly, the study suggests that the clinical benefit was not simply due to the presence of actionable genomic findings, but rather the successful translation of these findings into individualized treatment decisions through multidisciplinary interpretation. The MTB framework incorporated not only genomic alterations but also tumor biology, prior therapies, organ function, immunotherapy biomarkers and overall patient condition to guide precision treatment selection. The survival advantage remained consistent even among patients receiving immunotherapy-based regimens, highlighting the broader value of integrated molecular decision-making beyond targeted therapies alone. Notably, many patients had undergone multiple previous treatment lines, emphasizing the potential role of MTBs in highly refractory disease settings where standard therapeutic options are exhausted. The study also reinforces the growing relevance of tier 2 genomic alterations and combinatorial biomarker interpretation in modern oncology. Overall, these findings support the expanding role of multidisciplinary molecular oncology programs as a critical component of precision cancer care and demonstrate that structured MTB-guided treatment selection can meaningfully influence real-world oncologic outcomes.

Pan-RAS Inhibition with Daraxonrasib Shows Promising Activity in Advanced Pancreatic Cancer | New England Journal of Medicine

Introduction Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with limited survival gains despite advances in systemic therapy. More than 90% of PDAC tumors harbor activating RAS mutations, making RAS signaling a central therapeutic target. However, effective inhibition of the broader spectrum of RAS alterations in pancreatic cancer has remained a major challenge. Problem Statement Most currently available targeted therapies address only selected KRAS subtypes, while the majority of RAS-mutated PDAC lacks effective precision treatment options after progression on standard chemotherapy. A therapeutic strategy capable of targeting multiple active RAS variants simultaneously could potentially overcome this limitation and expand the applicability of RAS-directed therapy in pancreatic cancer. Summary This phase 1–2 study demonstrates encouraging clinical activity of daraxonrasib, a multiselective RAS(ON) inhibitor, in previously treated RAS-mutated PDAC. Daraxonrasib targets active guanosine triphosphate-bound mutant and wild-type RAS, enabling broader inhibition across multiple RAS mutation subtypes rather than focusing on a single KRAS alteration. In heavily pretreated patients, the drug produced meaningful objective response rates, particularly in tumors harboring RAS G12 mutations, with durable responses and progression-free survival outcomes that compare favorably with existing second-line therapies in PDAC. Importantly, responses were also observed across broader RAS mutation groups, suggesting potential applicability beyond highly selected molecular subsets. Toxicities were common but largely manageable, with gastrointestinal adverse effects, rash and mucosal toxicity representing the dominant treatment-related events. Approximately one-third of patients experienced grade 3 or higher adverse events, indicating that tolerability remains an important consideration in further development. Overall, this study represents one of the most promising advances in broad-spectrum RAS inhibition for pancreatic cancer and supports the emergence of pan-RAS targeting as a potentially transformative therapeutic strategy in RAS-driven solid tumors.

Pregnancy-Associated Cancer Is Linked to Treatment Delays and Adverse Birth Outcomes | Journal of Gastrointestinal Surgery

Introduction Pregnancy-associated cancers (PACs), defined as malignancies diagnosed during pregnancy or within the first postpartum year, represent a growing and highly complex clinical challenge. Management requires balancing timely maternal cancer treatment with fetal safety, often forcing difficult decisions regarding surgery, chemotherapy and radiation during pregnancy. Problem Statement Despite increasing recognition of PACs, limited large-scale data exist regarding how pregnancy affects timing of cancer treatment and the downstream impact on maternal and neonatal outcomes. Understanding these treatment patterns is essential because delays in oncologic care may compromise cancer control, while treatment modifications can influence obstetric and neonatal health. Summary This large multicenter analysis demonstrates that pregnancy-associated cancer significantly alters cancer treatment timelines and is associated with increased maternal and neonatal morbidity. Patients diagnosed with cancer during pregnancy experienced meaningful delays in locoregional therapies, including surgery and radiotherapy, likely reflecting concerns regarding fetal exposure and procedural risk. In contrast, chemotherapy initiation occurred earlier, suggesting greater clinical acceptance of selected systemic therapies during pregnancy when maternal disease control is prioritized. Importantly, gestational PAC was also associated with substantially higher risks of cesarean delivery, preterm birth, low birth weight and adverse neonatal condition at delivery, emphasizing the broader maternal-fetal consequences of cancer during pregnancy. Postpartum cancer diagnoses demonstrated shorter treatment initiation times, highlighting how pregnancy itself directly influences therapeutic decision making and care pathways. These findings underscore that PACs require highly coordinated multidisciplinary management involving oncology, maternal-fetal medicine, surgery and neonatology to balance oncologic urgency with fetal safety. The study also highlights the need for standardized care pathways and prospective research aimed at minimizing treatment delays while improving maternal and neonatal outcomes in this vulnerable population.

Questioning the Role of Para-Aortic Dissection in Advanced Gastric Cancer | Gastric Cancer

Introduction Gastric cancer with extensive lymph node metastasis carries a poor prognosis and presents major challenges in surgical management. In Japan, neoadjuvant chemotherapy followed by D2 gastrectomy with para-aortic lymph node dissection (PAND) has been explored as an aggressive multimodal strategy for patients with bulky nodal disease and/or para-aortic lymph node (PAN) involvement. However, the true therapeutic contribution of PAND remains uncertain. Problem Statement Although PAND has historically been incorporated into treatment strategies for advanced nodal gastric cancer, improvements in systemic chemotherapy may have altered the clinical relevance of extended lymphadenectomy. Determining whether PAND continues to provide meaningful survival benefit—particularly across biologically distinct nodal subgroups—is essential to avoid unnecessary surgical morbidity while preserving oncologic benefit. Summary This integrated analysis of three JCOG phase II trials evaluated the therapeutic value of PAND in gastric cancer with extensive lymph node metastasis after neoadjuvant chemotherapy. The findings suggest that the clinical utility of PAND differs substantially according to nodal disease pattern. In patients with bulky nodal disease without para-aortic involvement, PAND retained a modest therapeutic value, supporting the possibility that selected patients may still derive benefit from extended nodal dissection. In contrast, patients with clinically evident para-aortic metastasis demonstrated very limited benefit from PAND, particularly in the more recent chemotherapy trials where the therapeutic value index approached zero. Importantly, the incidence of para-aortic metastasis progressively decreased across successive studies, likely reflecting improvements in systemic therapy and better disease control before surgery. These observations suggest that advances in neoadjuvant chemotherapy may be reducing the incremental value of aggressive para-aortic surgery. The study supports a more individualized surgical strategy in advanced gastric cancer and emphasizes that decisions regarding omission or retention of PAND should be tailored separately for bulky nodal disease and para-aortic metastatic disease rather than treating these populations as a single entity.

LLMs Improve Accuracy and Completeness of Cancer Pathology Summaries | JCO Clinical Cancer Informatics

Introduction Modern oncology care depends on rapid interpretation of increasingly complex pathology reports that integrate histopathology, immunohistochemistry and molecular profiling. Synthesizing these data into concise, clinically usable summaries is time-intensive and cognitively demanding, creating workflow burden and increasing the risk of omission in busy oncology practice. Problem Statement Conventional physician-authored pathology summaries are often efficient but may incompletely capture key diagnostic and genomic information, particularly as molecular testing becomes more complex and voluminous. Large language models (LLMs) offer a potential solution, but their clinical reliability, completeness and safety in summarizing oncology pathology reports require careful evaluation before integration into routine practice. Summary This study demonstrates that open-source LLMs can generate clinically useful summaries of complex cancer pathology reports with greater completeness than physician-authored summaries while maintaining comparable correctness. Across 94 thoracic oncology cases, most LLMs outperformed physician summaries on objective measures of fidelity and consistently captured more complete clinicopathologic and genomic information, particularly molecular findings that were frequently omitted in routine documentation. Importantly, top-performing models maintained strong factual accuracy and low rates of clinically meaningful error, suggesting that LLM-assisted summarization can reduce documentation burden without compromising clinical usability. Performance, however, was model dependent: newer systems such as DeepSeek and Llama 3.1/3.2 performed reliably, whereas older or shorter-context models were more prone to omissions, unusable outputs and clinically relevant errors. The study highlights a key practical advantage of LLMs in oncology workflows—the ability to standardize and scale synthesis of increasingly complex pathology and genomic data—while also emphasizing the need for model selection, human oversight and task-specific validation. These findings support LLM-assisted pathology summarization as a promising workflow tool to improve documentation efficiency, reduce cognitive burden and enhance clinical information accessibility in cancer care.

Raltitrexed Shows Limited Clinical Activity in Advanced Colorectal Cancer | The Oncologist

Introduction Thymidylate synthase inhibition remains a central therapeutic strategy in colorectal cancer, most commonly achieved with fluoropyrimidines such as 5-fluorouracil (5-FU). Raltitrexed, a direct thymidylate synthase inhibitor, was developed to provide more selective pathway inhibition and potentially improve efficacy or tolerability compared with indirect fluoropyrimidine-based approaches. Problem Statement Whether direct thymidylate synthase inhibition can improve outcomes in advanced colorectal cancer, particularly after prior fluoropyrimidine exposure, has remained uncertain. Raltitrexed was hypothesized to offer clinical benefit through more specific target inhibition and to potentially overcome resistance to 5-FU-based therapy, but its true efficacy in advanced colorectal cancer required prospective evaluation. Summary This phase II ECOG-ACRIN study found that raltitrexed has minimal clinical activity in advanced colorectal cancer, both in treatment-naïve patients and in those previously exposed to 5-FU-based therapy. Across all treatment strata, objective response rates were very low and insufficient to justify further trial expansion, with only limited disease control and short progression-free survival observed. Survival outcomes were modest and did not suggest a meaningful advantage over existing fluoropyrimidine-based approaches. Toxicity was consistent with the known safety profile of raltitrexed, with no unexpected safety signals, but this did not offset its limited antitumor activity. Importantly, the study also failed to establish thymidylate synthase expression as a useful predictive biomarker, largely due to low response rates and limited discriminatory value. These findings suggest that direct thymidylate synthase inhibition alone is insufficient to meaningfully improve outcomes in advanced colorectal cancer and reinforce the limitations of relying on isolated antifolate pathway targeting in fluoropyrimidine-exposed disease. The study also underscores the broader need for more effective biomarker-driven and mechanistically distinct strategies in advanced colorectal cancer therapeutics.

Dual NAMPT–KRAS Targeting Emerges as a Promising Strategy in PDAC | CancerNetwork

Introduction KRAS remains the dominant oncogenic driver in pancreatic ductal adenocarcinoma (PDAC), yet therapeutic targeting of KRAS has produced only modest and often short-lived responses due to rapid adaptive resistance. As KRAS-directed therapies move into clinical development, understanding and overcoming metabolic escape mechanisms has become a major priority in pancreatic cancer research. Problem Statement Although pan-RAS inhibitors such as daraxonrasib have shown activity in KRAS-driven PDAC, tumor adaptation and acquired resistance remain major limitations. Emerging evidence suggests that KRAS inhibition induces metabolic rewiring, allowing tumor cells to shift survival dependence toward alternative pathways, thereby reducing the durability of RAS-directed therapy. Summary This AACR 2026 report highlights a promising metabolic co-targeting strategy in PDAC based on simultaneous inhibition of KRAS signalling and NAD salvage metabolism. Preclinical work presented by Azmi and colleagues showed that KRAS inhibition induces compensatory metabolic dependence on the NAMPT–NAD pathway, creating a therapeutically exploitable vulnerability. Dual targeting with the NAMPT inhibitor RPT-E-037 and the pan-RAS inhibitor daraxonrasib produced greater tumor regression, enhanced tumor cell death and longer survival in preclinical PDAC models compared with KRAS inhibition alone. Notably, RAS inhibitor–resistant PDAC models demonstrated increased sensitivity to NAMPT inhibition, supporting NAMPT as a biologically plausible resistance target and suggesting a strategy to extend the durability of KRAS-directed therapy. The combination also offers the potential to reduce required RAS inhibitor dosing, which may improve tolerability and enable longer treatment exposure. These findings position metabolic co-targeting as a compelling next step in KRAS-driven PDAC and support early clinical translation of combined NAMPT and pan-RAS inhibition, with phase 1 evaluation anticipated in 2027.

RFA Fails to Improve Outcomes in Locally Advanced Pancreatic Cancer | JAMA Network Open

Introduction Locally advanced pancreatic cancer (LAPC) remains a highly lethal disease with limited therapeutic options and poor long-term survival. For patients who remain unresectable after induction chemotherapy, local ablative strategies such as radiofrequency ablation (RFA) have been explored as a means to improve local control, prolong survival and potentially enhance quality of life. Problem Statement Although RFA has shown feasibility and encouraging outcomes in observational studies, high-quality randomized evidence supporting its use in LAPC has been lacking. Whether adding RFA to standard chemotherapy improves survival or symptom burden in patients with non progressive LAPC after induction chemotherapy has remained an important unanswered clinical question. Summary The PELICAN randomized clinical trial demonstrates that adding RFA to chemotherapy does not improve outcomes in patients with non progressive LAPC after induction chemotherapy. In this multicenter phase 3 trial, RFA combined with chemotherapy failed to improve overall survival or progression-free survival compared with chemotherapy alone. Importantly, the addition of RFA was associated with significantly more serious adverse events and consistently worse quality of life across multiple domains, including global health status, pain and digestive symptoms. These findings directly challenge prior observational data suggesting a benefit for local ablative therapy in LAPC and provide the strongest evidence to date against routine use of RFA in this setting. While RFA had been proposed as a strategy to improve local disease control or augment systemic therapy, this trial found no meaningful oncologic advantage and demonstrated clear treatment-related burden. The study strongly supports continued chemotherapy-based management as the preferred standard for unresectable LAPC after induction therapy and argues against the routine incorporation of RFA outside highly selected investigational settings.