Trending Topics in Gastroenterology | GastroAGI

KRAS ctDNA Predicts Outcomes After Neoadjuvant Therapy in PDAC: Annals of Surgery | July 2026

Introduction: Circulating tumor DNA (ctDNA) has emerged as a promising noninvasive biomarker for monitoring treatment response and residual disease in solid tumors. However, its prognostic value during neoadjuvant chemotherapy (NAC) for localized pancreatic ductal adenocarcinoma (PDAC) has not been well established. This study evaluated whether mutant KRAS ctDNA measured by digital droplet PCR (ddPCR) predicts survival in patients undergoing NAC and surgical resection. Why was this study needed? Reliable biomarkers are needed to assess response to neoadjuvant therapy in localized PDAC. Radiologic assessment alone often fails to accurately reflect tumor biology. The prognostic significance of serial KRAS ctDNA measurements during treatment remains unclear. ctDNA could help identify patients at high risk of recurrence after surgery. Results: Among 84 patients with localized PDAC receiving NAC, mutant KRAS ctDNA was detected in approximately half at diagnosis and in nearly 70% after NAC and after surgery. Around 18% of patients achieved complete ctDNA clearance during treatment, which was associated with significantly improved overall survival. In contrast, persistent detection of the KRAS G12V mutation after NAC and especially after surgical resection identified patients with substantially poorer survival outcomes. On multivariable analysis, postoperative detection of KRAS G12V was one of the strongest predictors of reduced overall survival, suggesting persistent molecular disease despite apparently curative treatment. Clinical Impact: Serial KRAS ctDNA monitoring may provide valuable prognostic information beyond conventional imaging and pathology. Clearance of ctDNA during neoadjuvant therapy identifies patients with favorable tumor biology, whereas persistent postoperative KRAS mutations may indicate minimal residual disease and identify candidates for intensified surveillance, additional systemic therapy, or enrollment in clinical trials. Bottom Line: Serial KRAS ctDNA monitoring during neoadjuvant treatment is a promising prognostic biomarker in localized PDAC, with postoperative persistence of KRAS G12V identifying patients at particularly high risk of poor survival.

Low-Dose Aspirin for Lynch Syndrome: Lancet | July 2026

Introduction: Aspirin is one of the few interventions proven to reduce colorectal and other Lynch syndrome–associated cancers. The earlier CaPP2 trial established 600 mg daily aspirin as an effective chemopreventive strategy, but concerns regarding long-term toxicity and bleeding have limited its widespread use. The CaPP3 trial evaluated whether lower aspirin doses could provide comparable cancer protection with improved safety. Why was this study needed?: . The optimal aspirin dose for cancer prevention in Lynch syndrome remains uncertain. . High-dose aspirin is associated with increased gastrointestinal toxicity and bleeding. . Lower doses may improve long-term adherence if efficacy is maintained. . Robust randomized evidence comparing different aspirin doses was lacking. Results: In this multicenter randomized trial involving nearly 1,900 individuals with Lynch syndrome, the 100 mg aspirin dose demonstrated cancer prevention outcomes broadly comparable to the 600 mg dose in the intention-to-treat analysis, although formal non-inferiority criteria were not fully met across all predefined analyses. The 300 mg dose did not demonstrate non-inferiority. Importantly, adverse events increased with higher aspirin doses, and serious bleeding events were least frequent with the 100 mg regimen. Overall, the lower-dose strategy appeared to retain much of the chemopreventive benefit while offering a more favorable safety profile. Clinical Impact: These findings support a shift toward lower-dose aspirin for cancer prevention in individuals with Lynch syndrome. Although the statistical threshold for non-inferiority was not formally achieved, the similar cancer outcomes and substantially lower bleeding risk with 100 mg daily make it an attractive option for long-term chemoprevention. Ongoing follow-up will clarify whether these findings remain consistent over a longer duration. Bottom Line: Low-dose (100 mg) aspirin demonstrated cancer prevention outcomes comparable to high-dose aspirin with fewer bleeding complications, supporting its consideration as the preferred long-term chemopreventive strategy for patients with Lynch syndrome while awaiting longer-term follow-up.

4-Year Benefit of Durvalumab in BTC: JAMA Oncol | July 2026

Introduction: The TOPAZ-1 trial established durvalumab combined with gemcitabine and cisplatin (GemCis) as the first immunotherapy-based first-line standard of care for advanced biliary tract cancer (BTC). However, long-term survival outcomes and durability of benefit beyond the initial analysis remained uncertain. This post hoc analysis reports efficacy and safety after more than four years of follow-up. Why was this study needed?: . Long-term survival data for immunotherapy in advanced BTC were lacking. . The durability of benefit with durvalumab beyond the primary analysis required confirmation. . Long-term safety with prolonged immunotherapy exposure remained uncertain. . Extended follow-up was needed to validate durvalumab plus GemCis as the standard first-line regimen. Results: After more than four years of follow-up, durvalumab plus GemCis continued to demonstrate a sustained overall survival advantage over chemotherapy alone. Long-term survival rates remained consistently higher with the addition of durvalumab, confirming durable clinical benefit in a subset of patients. Importantly, the safety profile remained stable over time, with no increase in treatment-related serious adverse events or treatment discontinuations compared with chemotherapy alone. These findings reinforce the long-term efficacy and tolerability of the regimen. Clinical Impact: This extended analysis provides compelling evidence that adding durvalumab to GemCis delivers durable survival benefits without compromising long-term safety. The persistence of a meaningful survival advantage beyond four years strengthens confidence in immunotherapy as the foundation of first-line treatment for advanced biliary tract cancer and provides reassurance regarding prolonged treatment outcomes. Bottom Line: More than four years of follow-up confirms that durvalumab plus gemcitabine–cisplatin provides durable survival benefit with a manageable long-term safety profile, reinforcing its role as the standard first-line treatment for advanced biliary tract cancer.

The First Standardized PET Response Framework for Neuroendocrine Tumors: The Lancet Oncology | July 2026

Introduction: Somatostatin receptor (SSTR) PET/CT has become indispensable for diagnosing, staging, and monitoring neuroendocrine tumors (NETs). However, until now, there has been no standardized method for assessing treatment response using SSTR PET imaging. This international consensus introduces the SSTR-PeRForm (Somatostatin Receptor PET Response Framework) to harmonize response assessment. Why was this guideline needed? • No standardized PET-based response criteria currently exist for NETs. • Existing RECIST criteria may not adequately reflect functional changes seen on SSTR PET. • Variability in PET interpretation limits consistency across clinical practice and research. • Uniform response criteria are needed for clinical trials and routine patient care. • Standardized reporting may improve treatment decisions and future research. Key Recommendations: • Response assessment should primarily rely on changes in tumor volume of SSTR-expressing lesions rather than SUV-based measurements. • Partial Response (PR): ≥40% reduction in target lesion volume with no new lesions. • Progressive Disease (PD): ≥40% increase in target lesion volume or appearance of new lesions. • Complete Response (CR): Complete disappearance of pathological somatostatin receptor uptake. • Unconfirmed Progressive Disease (uPD): A new category for equivocal findings requiring repeat imaging before confirming progression. • SUV measurements alone should not be used to define treatment response. • Volumetric assessment and identification of new lesions are considered the most clinically relevant imaging parameters. • The framework is intended for both clinical trials and routine practice, pending prospective validation against survival outcomes. Clinical Impact: SSTR-PeRForm is the first internationally endorsed framework for SSTR PET response assessment in NETs. It provides a standardized, practical approach that is expected to improve reporting consistency, treatment monitoring, and the design of future clinical trials. Bottom Line: SSTR-PeRForm establishes the first consensus-based PET response criteria for neuroendocrine tumors. By emphasizing volumetric tumor changes and new lesion detection, it lays the foundation for standardized response assessment and future outcome-based validation.

Staging Laparoscopy in Gastric Cancer: Annals of Surgical Oncology | July 2026

Introduction: Staging laparoscopy (SL) is recommended for patients with locally advanced gastric cancer to detect occult peritoneal metastases before curative treatment. However, its real-world utilization across Europe remains uncertain. This large GASTRODATA study evaluated the impact of staging laparoscopy on treatment pathways and clinical outcomes. Why was this study needed? • Staging laparoscopy is recommended by current guidelines but remains underutilized. • Occult peritoneal metastases may be missed on conventional imaging. • The impact of SL on multimodality treatment and surgical outcomes is unclear. • Real-world European data on SL practice have been limited. • Better staging may improve patient selection for curative treatment. Results: • Only one-third of patients underwent staging laparoscopy, highlighting substantial underutilization across European centers. • Patients who did not undergo staging laparoscopy experienced higher postoperative complications, higher 90-day mortality, and were less likely to receive neoadjuvant or adjuvant chemotherapy. • Absence of staging laparoscopy was associated with greater staging inaccuracy, more advanced pathological disease, and reduced use of multimodal treatment. Clinical Impact: This study reinforces the importance of routine staging laparoscopy in patients with locally advanced gastric cancer. Accurate staging facilitates appropriate multimodal treatment, avoids non-therapeutic surgery in patients with occult metastatic disease, and may improve short-term outcomes through better patient selection. Bottom Line: Staging laparoscopy remains underused despite guideline recommendations. Wider implementation may improve staging accuracy, optimize multimodality treatment, and potentially improve outcomes for patients with locally advanced gastric cancer.

Celecoxib Boosts Neoadjuvant Immunotherapy in dMMR/MSI-H CRC : Lancet Oncol | Jul 2026

Introduction: Neoadjuvant immune checkpoint inhibitors have transformed the management of mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) locally advanced colorectal cancer, achieving unprecedented pathological response rates. Experimental evidence suggests that cyclooxygenase-2 (COX-2) inhibition may enhance antitumor immunity by modifying the inflammatory tumor microenvironment, providing a rationale for combining celecoxib with PD-1 blockade. Problem Statement: Although neoadjuvant PD-1 inhibitor monotherapy produces excellent outcomes in dMMR/MSI-H colorectal cancer, a substantial proportion of patients still have residual viable tumor after treatment. Whether adding celecoxib can further improve pathological complete response without compromising safety has remained uncertain. Summary: The multicenter phase 2 PICC-2 trial evaluated neoadjuvant toripalimab plus celecoxib versus toripalimab alone in patients with locally advanced dMMR/MSI-H colorectal cancer. The combination significantly increased the proportion of patients achieving pathological complete response compared with PD-1 inhibitor monotherapy, while maintaining a comparable safety profile. Nearly all patients successfully completed neoadjuvant treatment and proceeded to surgery, demonstrating the feasibility of this strategy in routine clinical practice. Importantly, the addition of celecoxib did not increase severe treatment-related toxicity, and no new safety concerns emerged. These findings support the concept that targeting COX-2–mediated inflammation can enhance the effectiveness of immune checkpoint blockade in this highly immunogenic tumor subtype. If confirmed in larger phase 3 studies, combining celecoxib with neoadjuvant PD-1 inhibition may become an inexpensive, readily accessible approach to maximize pathological response and further improve organ preservation and long-term oncologic outcomes in patients with dMMR/MSI-H locally advanced colorectal cancer.

Cancer Cachexia: Science | July 2026

Introduction: Cancer-associated cachexia is a devastating syndrome characterized by loss of appetite, weight loss, and muscle wasting, affecting up to half of patients with lung cancer. This landmark study uncovers a previously unrecognized mechanism linking dietary fat, tumor-derived prostaglandin E2 (PGE2), and sensory nerve signaling to the development of cachexia. Why was this study needed? • The mechanisms driving cancer cachexia remain poorly understood. • Current therapies have limited efficacy in preventing appetite loss and muscle wasting. • Cachexia has traditionally been attributed to circulating inflammatory factors. • The influence of dietary fat on cachexia progression has been unclear. • New therapeutic targets are urgently needed to improve outcomes in cancer patients. Results: • A high-fat diet paradoxically worsened cachexia, increasing appetite loss and weight loss in mice with Lkb1-mutant lung cancer. • Tumor-derived prostaglandin E2 (PGE2) activated local lung sensory nerves, driving cachexia through neural signaling rather than circulating inflammatory mediators. • Blocking PGE2 production or silencing sensory neurons markedly reduced cachexia, identifying a novel therapeutic pathway. Clinical Impact: This study fundamentally changes our understanding of cancer cachexia by demonstrating that local tumor–nerve communication, rather than systemic inflammation alone, can drive appetite loss and wasting. It also raises important questions about the routine use of high-fat nutritional supplementation in selected patients with cancer cachexia. Bottom Line: Cancer cachexia is not solely a systemic inflammatory disorder. Tumor-derived PGE2 activates sensory nerves to promote cachexia, and targeting the PGE2–sensory neuron axis may represent a promising new therapeutic strategy for preventing cancer-associated weight loss.

Liquid Biopsy-Guided Cetuximab Rechallenge in mCRC: ESMO GI Cancers Congress | July 2026

Introduction: Resistance to anti-EGFR therapy has traditionally been considered irreversible in metastatic colorectal cancer (mCRC). However, emerging evidence suggests that resistance is dynamic and can be monitored using circulating tumor DNA (ctDNA). The CAPRI-2 trial evaluated whether liquid biopsy could identify patients who remain sensitive to cetuximab beyond disease progression. Why was this study needed? • Most patients eventually develop resistance to anti-EGFR therapy. • RAS/BRAF wild-type status alone may not identify patients suitable for cetuximab rechallenge. • Liquid biopsy offers a non-invasive method to detect acquired resistance mutations. • Better patient selection could maximize benefit while avoiding ineffective therapy. • Precision-guided rechallenge strategies require prospective validation. Results: • Patients with no ctDNA-detected anti-EGFR resistance mutations ("negative hyperselected") consistently achieved higher response rates, longer progression-free survival, and superior overall survival with continued cetuximab-based therapy. • Cetuximab retained meaningful activity beyond disease progression in carefully selected patients, suggesting that EGFR dependence can persist despite radiological progression. • These findings support liquid biopsy-guided treatment selection, although randomized studies are still needed before routine clinical adoption. Clinical Impact: This study strengthens the role of ctDNA as a real-time biomarker for guiding anti-EGFR rechallenge in metastatic colorectal cancer. Rather than discontinuing cetuximab solely because of disease progression, clinicians may be able to personalize therapy based on molecular evolution detected by liquid biopsy. Bottom Line: Liquid biopsy is redefining anti-EGFR rechallenge in metastatic colorectal cancer. Patients without ctDNA evidence of resistance mutations appear to derive continued benefit from cetuximab, moving treatment selection from radiological progression to molecular progression.

PD-(L)1 Inhibitors Plus Chemotherapy in Advanced Gastric Cancer: CGH | July 2026

Introduction: Immune checkpoint inhibitors combined with chemotherapy have become the standard first-line treatment for advanced HER2-negative gastric and gastroesophageal junction cancers. This meta-analysis evaluated whether treatment benefits differ between Asian and non-Asian populations. Why was this study needed? Gastric cancer differs across geographic regions in terms of incidence, biology, and clinical practice. Whether these differences influence the efficacy and safety of first-line PD-(L)1 inhibitor-based therapy has remained uncertain. What did the study show? • Seven phase III randomized trials involving more than 6,700 patients were included. • PD-(L)1 inhibitors plus chemotherapy significantly improved overall survival compared with chemotherapy alone. • Progression-free survival was also significantly prolonged with chemoimmunotherapy. • Survival benefits were consistent in both Asian and non-Asian patients, with comparable treatment effects across regions. • Treatment-related adverse events were similar between chemoimmunotherapy and chemotherapy alone. • The findings support the generalizability of first-line PD-(L)1 inhibitor therapy regardless of geographic region. Clinical Impact: This analysis confirms that the survival benefit of adding PD-(L)1 inhibitors to chemotherapy is not restricted to a particular ethnic or regional population. These data reinforce current global recommendations supporting chemoimmunotherapy as first-line treatment for eligible patients with advanced HER2-negative gastric and gastroesophageal junction cancer. Take-Home Message: First-line PD-(L)1 inhibitor plus chemotherapy provides a consistent survival benefit for advanced gastric and gastroesophageal junction cancer in both Asian and non-Asian populations, supporting its worldwide use as a standard-of-care treatment.

CLDN18.2 and Gastric Cancer: Cancer Letters | July 2026

Introduction: The treatment of advanced gastric cancer is rapidly evolving from conventional chemotherapy to biomarker-driven precision medicine. Claudin 18.2 (CLDN18.2), a tight junction protein selectively expressed in gastric epithelial cells and many gastric cancers, has emerged as one of the most promising therapeutic targets. Why was this review needed? Following the approval of zolbetuximab for HER2-negative, CLDN18.2-positive advanced gastric cancer, numerous CLDN18.2-targeted therapies are under development. This review summarizes the current evidence and future directions of this rapidly expanding therapeutic field. What did the review show? • CLDN18.2 is an established biomarker and therapeutic target in advanced gastric cancer. • Zolbetuximab combined with chemotherapy is now the first approved CLDN18.2-targeted therapy for HER2-negative, CLDN18.2-positive gastric adenocarcinoma. • Next-generation monoclonal antibodies are being developed to improve efficacy and durability of response. • Antibody-drug conjugates (ADCs) enable selective delivery of cytotoxic agents to CLDN18.2-expressing tumor cells. • Bispecific antibodies simultaneously target CLDN18.2 and immune pathways, enhancing antitumor activity. • CLDN18.2-directed CAR-T cell therapy has shown encouraging early clinical activity in heavily pretreated patients. • Combination strategies with chemotherapy, immunotherapy, and other targeted agents may further improve clinical outcomes. • Resistance mechanisms, patient selection, biomarker standardization, and treatment-related toxicities remain important challenges. Clinical Impact: Routine assessment of CLDN18.2 expression is becoming increasingly important in advanced gastric cancer. Expanding CLDN18.2-directed therapies are expected to broaden personalized treatment options and improve outcomes for appropriately selected patients. Take-Home Message: CLDN18.2 has emerged as a major therapeutic target in gastric cancer, marking a shift toward biomarker-guided treatment. As monoclonal antibodies, ADCs, bispecific antibodies, and CAR-T therapies continue to evolve, precision targeting of CLDN18.2 is poised to become a cornerstone of future gastric cancer management.