Trending Topics in Gastroenterology | GastroAGI

ENCODER: Liquid Biopsy for Young-Onset Colorectal Cancer- Gastroenterology Feb.26

Introduction Early-onset colorectal cancer (EOCRC), defined as CRC diagnosed before the age of 50, is rising globally and has become a leading cause of cancer-related death in young adults, particularly men. Despite this, screening uptake in younger populations remains poor, largely because current strategies rely on age thresholds and invasive tests. This study asks a critical question: Can a simple blood-based test help identify EOCRC early—before symptoms or advanced disease develop? The clinical problem Most EOCRC cases are diagnosed outside traditional screening programs, often at more advanced stages. Colonoscopy is effective but impractical as a population-wide tool in young adults. Stool-based tests may help, but still suffer from limited acceptance. A highly accurate, noninvasive blood test could dramatically change early detection and screening strategies for this growing at-risk population. What the ENCODER study did: Large international, multicenter study across the US, Europe, and Japan. Identified a panel of 6 circulating biomarkers, including exosome-derived small RNAs, using advanced sequencing techniques. Built a machine-learning model to distinguish EOCRC from non-cancer controls. Tested the model in an independent external cohort, ensuring real-world robustness. Evaluated biomarker changes before and after surgical resection to assess biological relevance. Key findings clinicians should understand 1) High accuracy for EOCRC detection The liquid biopsy reliably distinguished EOCRC patients from healthy controls across multiple cohorts and countries, demonstrating strong generalizability. 2) Works even in very young adults Remarkably, the test performed well even in individuals aged 20–35 years, a group in whom CRC is often least suspected. 3) Strong performance in early, screen-relevant stages The assay was particularly effective for stage I–III EOCRC, the window where early detection has the greatest impact on survival. 4) Detects advanced precancerous lesions The test showed moderate ability to detect high-grade dysplasia, suggesting potential utility not only for cancer detection but also for interception. 5) Biomarkers track with tumour removal Liquid biopsy signals dropped rapidly after surgery, supporting a direct biological link to tumour burden and raising the possibility of future use in surveillance or minimal residual disease monitoring. How this could fit into practice This study does not suggest replacing colonoscopy. Instead, it points toward a complementary screening strategy, particularly for: Young adults below the standard screening age, individuals reluctant to undergo invasive testing, and populations with rising EOCRC incidence but low screening participation. A blood-based test could serve as a first-line risk stratification tool, identifying individuals who should proceed to diagnostic colonoscopy. Key limitations to keep in mind This was a case–control design, not a population screening trial. Performance in real-world, low-prevalence screening settings remains to be tested. Cost-effectiveness, implementation logistics, and comparison with stool-based tests are still unknown. Bottom-line takeaway: The ENCODER study provides compelling proof-of-concept that an exosome-based liquid biopsy can accurately detect early-onset colorectal cancer—even in very young adults—and may become a valuable adjunct to future screening strategies. One-line GastroAGI takeaway A simple blood test could help close the screening gap for early-onset colorectal cancer.

Metastasis Directed Therapy- JAMA Oncol 2026

**Metastasis-Directed Therapy (MDT) Overview:** MDT refers to localised treatments aimed specifically at metastatic lesions in patients with cancer. These therapies include techniques such as stereotactic body radiotherapy (SBRT), surgical resection, and thermal ablations (e.g., radiofrequency or cryoablation). MDT is particularly valuable for patients with oligometastatic disease, where the number of metastases is limited and potentially treatable. **Utility in Metastatic Disease:** MDTs have redefined the therapeutic approach to metastatic cancer by offering the possibility of long-term disease control or even cure in select patients. Rather than focusing solely on systemic therapies, MDT targets visible metastatic lesions, suppressing prometastatic signalling and disrupting interlesional communication. Clinical evidence suggests that MDT can delay systemic therapy initiation, extend progression-free survival, and improve overall outcomes when applied iteratively or comprehensively. Emerging research highlights the importance of treating all visible disease to prevent reseeding and progression. MDT's effectiveness is influenced by factors such as tumour biology, immune phenotype, and metastatic kinetics, underscoring the need for personalised strategies. MDT represents a shift toward transforming metastatic cancer into a manageable or potentially curable condition.

ACS 2026 Statastical Report

The ACS  publishes an annual "Cancer Facts & Figures" report, which provides comprehensive statistics on cancer incidence, survival rates, mortality, and trends in the United States. The report typically highlights progress in early detection, advancements in treatment, and disparities in cancer outcomes. For example, recent statistics have shown that the 5-year cancer survival rate has reached 70%, a significant milestone reflecting decades of improvement in cancer research, early screening, and innovative therapies such as immunotherapy and targeted treatments. However, underlying challenges persist, including disparities in access to care, variations in survival rates by cancer type, and missed opportunities for early detection. The ACS continues to emphasize the need for equitable and personalized approaches to cancer prevention, treatment, and survivorship care.

GEP-NET- Gastroenterology Jan.26

### Overview of GEP-NETs Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a subtype of neuroendocrine neoplasms (NENs) that arise from neuroendocrine cells within the gastrointestinal (GI) tract and pancreas. These tumors are relatively rare but are increasingly recognized due to advancements in diagnostic techniques, particularly in gastroenterology. #### Common Sites of GEP-NETs - **Stomach (gastric NETs, gNETs)** - **Pancreas (pancreatic NETs, pNETs)** - **Small intestine (small intestinal NETs, siNETs)** - **Rectum (rectal NETs, rNETs)** - **Appendix** --- ### Epidemiology - **Increasing Incidence:** The incidence of GEP-NETs has risen significantly over the past few decades. For example, in the United States, the incidence of NETs increased more than sixfold between 1973 and 2012. - **Geographic and Racial Variations:** The prevalence of specific GEP-NET subtypes varies by region. For instance, rectal NETs are more common in North America, while pancreatic NETs are frequently seen in Europe and Asia. Black individuals in the U.S. have a higher incidence of GEP-NETs compared to other racial groups. - **Prevalence:** The overall prevalence of NETs is about 0.05% (1 in 2,000), with rectal and small intestinal NETs being the most common subtypes. --- ### Classification and Pathology The **2022 World Health Organization (WHO) classification** divides GEP-NETs based on: 1. **Differentiation**: Well-differentiated neuroendocrine tumors (NETs) versus poorly differentiated neuroendocrine carcinomas (NECs). 2. **Grade**: Tumor grade is determined by the **Ki-67 index** or **mitotic count**, which reflect the tumor's aggressiveness. - **Grade 1 (low-grade):** Indolent behavior. - **Grade 2 (intermediate-grade):** Moderate aggressiveness. - **Grade 3 (high-grade):** More aggressive, but distinct from poorly differentiated NECs. Immunohistochemical markers like **chromogranin-A (CgA)**, **synaptophysin**, and **INSM1** support the diagnosis of GEP-NETs. --- ### Clinical Features GEP-NETs can be classified as **functional** or **nonfunctional**: - **Functional tumors** secrete bioactive hormones, leading to specific syndromes. For example: - **Carcinoid Syndrome (CS):** Caused by serotonin secretion, leading to flushing, diarrhea, and valvular heart disease. - **Insulinomas:** Hypoglycemia due to insulin overproduction. - **Gastrinomas (Zollinger-Ellison Syndrome):** Hypersecretion of gastrin causing peptic ulcers and diarrhea. - **Nonfunctional tumors** do not secrete hormones and may present with nonspecific symptoms like abdominal pain or mass effects. --- ### Diagnostic Strategies #### 1. **Laboratory Tests** - **24-hour urinary 5-HIAA (5-hydroxyindoleacetic acid):** - Preferred for diagnosing Carcinoid Syndrome (sensitivity >90% for small intestinal NETs). - **Serum markers:** - Chromogranin-A (CgA): Limited utility due to false positives (e.g., with proton pump inhibitors or chronic atrophic gastritis). - Hormone levels: Useful for functional NETs (e.g., insulin, gastrin, glucagon). #### 2. **Imaging** - **Anatomic Imaging:** - **CT Scan (Triple-Phase):** Best for detecting hypervascular liver metastases and staging. - **MRI:** Ideal for pancreatic NETs and hepatic metastases. - **Functional Imaging:** - **Somatostatin Receptor PET (SSTR PET):** - Uses tracers like 68-Gallium or 64-Copper DOTA-TATE. - Superior sensitivity compared to traditional octreotide scans. - Recommended for staging, identifying occult primary tumors, and determining eligibility for radioligand therapy (RLT). --- ### Management of GEP-NETs #### 1. **Endoscopic Management** - Endoscopic techniques play a significant role in diagnosis and treatment of smaller, localized GEP-NETs. - **Endoscopic Mucosal Resection (EMR):** For small, low-grade tumors. - **Endoscopic Submucosal Dissection (ESD):** Allows deeper resection for larger lesions. - **Endoscopic Ultrasound (EUS):** Critical for biopsy and staging. #### 2. **Surgical Resection** - Surgical removal remains the cornerstone for localized or resectable metastatic disease, especially in higher-grade tumors. #### 3. **Medical and Systemic Therapies** - **Somatostatin Analogs (SSA):** First-line treatment for hormone control and tumor growth inhibition. - **Radioligand Therapy (RLT):** Targets tumors expressing somatostatin receptors. - **Targeted Therapies:** - **mTOR inhibitors (e.g., everolimus):** For advanced disease. - **Antiangiogenic agents (e.g., sunitinib):** For pancreatic NETs. - **Chemotherapy:** Reserved for high-grade or poorly differentiated NECs. --- ### Future Directions and Research 1. **Molecular Markers:** Identifying biomarkers to improve diagnostic accuracy and personalize treatment. 2. **Endoscopic Techniques:** Refining criteria for endoscopic therapy and understanding long-term outcomes after resection. 3. **Immunotherapy:** Investigating its role in treating high-grade GEP-NETs. 4. **Disparities in Care:** Addressing racial and socio-economic disparities in survival outcomes. --- ### Conclusion GEP-NETs are increasingly encountered in gastroenterology practice due to advancements in diagnostic modalities like endoscopy and imaging. Early detection and a multidisciplinary approach, including endoscopic, surgical, and systemic therapies, are critical for improving outcomes. Continued research into molecular markers and treatment strategies will further refine management and enhance survival for patients with GEP-NETs.

T1 CRC and ESD(GIE, Jan-2026)

### T1 Colorectal Cancer (CRC) - **T1 CRC** refers to early-stage colorectal cancer where the tumor has invaded the submucosa but has not yet spread further. - It is subdivided into **superficial submucosal invasive cancer (s-SMIC)** and **deep submucosal invasive cancer (d-SMIC)** based on the depth of invasion. - **s-SMIC**: Less invasive; better prognosis. - **d-SMIC**: More invasive; higher risk of lymphovascular invasion and metastasis. ### Endoscopic Submucosal Dissection (ESD) - **ESD** is a minimally invasive endoscopic technique used to remove early-stage gastrointestinal tumors, including T1 CRC, en bloc (in one piece) to achieve clear margins. - It is increasingly being used as an alternative to primary surgery for patients with suspected T1 CRC, especially for those with s-SMIC. ### Key Findings from the Study (2011–2022) 1. **Effectiveness of ESD**: - ESD was more effective in achieving a free vertical margin (VM-R0) in suspected s-SMIC cases compared to d-SMIC cases. - The VM-R0 rate for suspected s-SMIC was 90.6%, while it was significantly lower for suspected d-SMIC at 55.4%. - The en bloc resection rate was also higher in s-SMIC (90.5%) compared to d-SMIC (61.9%). 2. **Challenges in d-SMIC**: - For suspected d-SMIC cases, the VM-R0 rate particularly decreased for pT1Sm2-3 lesions (55.7%). - None of the investigated clinical or polyp-related features (age, sex, polyp location, size, morphology, and Hiroshima classification) could predict VM-R1 resections in d-SMIC cases. 3. **Adverse Events**: - The adverse event rate was slightly higher in d-SMIC cases (5.8%) compared to s-SMIC cases (3.6%). 4. **Implications for Treatment**: - The lower success rate of ESD (in terms of VM-R0) for d-SMIC highlights the need for careful patient selection. - For suspected d-SMIC cases, alternative treatment strategies, including surgery, may be more appropriate to ensure complete resection and reduce the risk of recurrence. ### Clinical Significance - For **s-SMIC**, ESD is a highly effective and safe option, offering high rates of curative resection with minimal complications. - For **d-SMIC**, the lower VM-R0 rates suggest that ESD alone may not always be sufficient, and primary surgery may be considered for better oncological outcomes. ### Future Perspectives (2026 and Beyond) - As ESD techniques continue to evolve, future studies may focus on improving the success rates for d-SMIC cases. - The development of advanced imaging techniques and predictive tools could help in better identifying patients who are suitable for ESD versus surgery. - Long-term follow-up data from ongoing or future studies (such as the one in 2026) will be crucial in determining the role of ESD in managing T1 CRC, particularly for d-SMIC cases.

Novel Therapeutic approach for pancreatic cancer(GIE,Jan-2026)

The novel therapeutic approach for pancreatic cancer, as detailed in the study published in *Gastrointestinal Endoscopy (GIE), January 2026*, involves the combination of intratumoral phosphorus-32 (32P) implantation with systemic chemotherapy. This innovative strategy is aimed at addressing the unmet need for improved treatment outcomes in patients with locally advanced pancreatic cancer (LAPC), a condition that traditionally has poor prognosis and limited treatment options beyond chemotherapy. ### Key Highlights of the Approach: 1. **Combination Therapy:** - The study evaluates the efficacy of combining phosphorus-32 implantation with chemotherapy compared to chemotherapy alone, marking the first comparative analysis of its kind. - Phosphorus-32 is a radioactive isotope that delivers targeted intratumoral radiation, minimizing exposure to surrounding healthy tissues. 2. **Improved Outcomes:** - **Overall Survival:** Patients receiving the combination therapy demonstrated significantly longer overall survival compared to those on chemotherapy alone. - **Local Disease Control:** The addition of phosphorus-32 improved local progression-free survival, highlighting its ability to control tumor growth at the primary site. - **Tumor Response and Downstaging:** Combination therapy resulted in greater tumor size reduction over time and higher rates of downstaging, increasing the likelihood of converting unresectable tumors to borderline resectable disease. - **Surgical Resection:** Patients treated with phosphorus-32 had a higher chance of undergoing surgical resection, offering a potential for curative intervention. 3. **Mechanistic and Practical Advantages:** - **Targeted Radiation:** Phosphorus-32 provides localized radiation that synergizes with chemotherapy, potentially enhancing its effectiveness within the tumor microenvironment. - **Outpatient Feasibility:** The implantation procedure is minimally invasive and performed as a single outpatient endoscopic procedure, adding convenience for patients. - **Safety Profile:** The study reported no major short-term complications related to the phosphorus-32 implantation, underscoring its favorable safety profile. - **Chemotherapy Continuity:** Unlike external-beam radiation, phosphorus-32 does not interrupt systemic chemotherapy, allowing uninterrupted systemic treatment. 4. **Real-World Evidence:** - The study utilized retrospective data from two tertiary centers, reflecting real-world clinical practice. - Advanced statistical methods, including propensity score–weighted and landmark analyses, were employed to mitigate bias and ensure robust findings. 5. **Limitations and Future Directions:** - As a nonrandomized, retrospective study, the findings are subject to residual confounding and cannot definitively establish causality. - The results strongly support the need for prospective randomized controlled trials to confirm the efficacy and safety of this novel combination approach. ### Conclusion: The combination of intratumoral phosphorus-32 implantation with chemotherapy represents a promising therapeutic strategy for locally advanced pancreatic cancer. It offers improved local tumor control, prolonged survival, enhanced tumor downstaging, and increased opportunities for surgical resection, all with a favorable safety profile and practical feasibility. The study paves the way for future randomized trials to validate these findings and potentially establish this approach as a new standard of care for LAPC.

Screening for Esophageal Cancer

Screening for esophageal cancer is a critical strategy to improve early detection and survival rates, given the disease's poor prognosis due to late-stage diagnosis. However, effective screening approaches differ based on the subtype of esophageal cancer (Esophageal Squamous Cell Carcinoma [ESCC] vs. Esophageal Adenocarcinoma [EAC]), regional disease patterns, and individual risk factors. ### **Key Considerations for Esophageal Cancer Screening:** #### **1. Subtypes of Esophageal Cancer:** - **Esophageal Squamous Cell Carcinoma (ESCC):** - Dominates globally, especially in high-incidence regions such as East Asia, Africa, and parts of South America. - Strongly linked to environmental risk factors like tobacco, alcohol, dietary carcinogens, air pollution, and socioeconomic factors. - Often associated with "field cancerization," where synchronous or metachronous cancers occur in the head, neck, and esophagus. - **Esophageal Adenocarcinoma (EAC):** - Increasing in Western countries, driven by obesity, gastroesophageal reflux disease (GERD), and Barrett’s esophagus (a precursor lesion). - Screening focuses on identifying individuals with Barrett’s esophagus and other high-risk features. #### **2. Screening Strategies by Subtype:** - **ESCC Screening:** - **Population-Based Screening:** Recommended in high-incidence regions (e.g., East Asia) using endoscopic methods to detect early-stage disease. - **Endoscopy:** High-definition white-light endoscopy is the cornerstone, often enhanced by advanced imaging techniques like narrow band imaging and virtual chromoendoscopy for better detection of early neoplastic lesions. - **Nonendoscopic Tools:** Emerging technologies like Cytosponge, salivary markers, breath tests, and buccal DNA analysis show promise as scalable, noninvasive screening options. - **Lugol-Voiding Lesions:** Multiple Lugol-voiding lesions are biomarkers of field cancerization and future cancer risk, aiding in identifying high-risk individuals. - **Artificial Intelligence (AI):** AI-assisted endoscopy improves real-time lesion recognition and matches or exceeds expert diagnostic performance. - **EAC Screening:** - **Targeted Screening:** Routine population screening is not justified; instead, high-risk individuals (e.g., those with Barrett’s esophagus, GERD, obesity) are prioritized. - **Endoscopy:** Structured examination from the hypopharynx to the esophagogastric junction is essential for reducing missed lesions. - **Nonendoscopic Tools:** Swallowable devices combined with biomarker assays provide scalable alternatives to endoscopy for triaging EAC risk. - **Barrett’s Esophagus Role:** Screening strategies often center on detecting and monitoring Barrett’s esophagus, as it is the precursor lesion for EAC. #### **3. Regional Screening Importance:** Screening strategies must be tailored to regional disease patterns to maximize cost-effectiveness and outcomes. For example: - **High ESCC Regions:** Population-level endoscopic screening is critical for early detection. - **Western Countries:** Focus is on targeted screening for EAC based on individual risk factors like GERD and obesity. #### **4. Role of Risk Factor Stratification:** Accurate identification of high-risk populations is essential for optimizing screening yield and efficiency. Risk factors include: - **ESCC:** Tobacco, alcohol, poor diet, air pollution, and socioeconomic conditions. - **EAC:** GERD, Barrett’s esophagus, obesity, and Western lifestyle habits. #### **5. Emerging Technologies and Future Directions:** - **Nonendoscopic Screening:** Tools like Cytosponge and swallowable devices offer less invasive, scalable options for early detection. - **Artificial Intelligence:** AI integration into endoscopy enhances lesion recognition and reduces diagnostic errors. - **Biomarkers:** Salivary markers, breath tests, and buccal DNA analysis are under investigation for noninvasive screening, although liquid biopsy methods currently have limited sensitivity for early-stage esophageal cancer. - **Integrated Strategies:** Combining endoscopy, noninvasive tools, biomarkers, and AI allows for personalized, risk-based screening pathways. ### **6. Limitations:** - **Liquid Biopsy Challenges:** Current blood-based multicancer detection assays lack adequate sensitivity for early-stage esophageal cancer. - **Cost Considerations:** Endoscopic screening can be expensive and resource-intensive, making regional tailoring essential. ### **Conclusion:** Screening for esophageal cancer requires a nuanced approach based on subtype, regional incidence, and individual risk factors. While endoscopy remains the cornerstone for early detection, advances in noninvasive tools, biomarkers, and AI offer promising avenues for scalable and personalized screening strategies. In high-incidence regions, population-based ESCC screening is effective, whereas targeted screening for EAC is preferred in Western populations.

Glecirasib with or without Cetuximab in previously treated CRC with KRAS mutation - Lancet Gastroenterol Hepatol

The study published in *Lancet Gastroenterology & Hepatology* investigates the efficacy and safety of glecirasib (JAB-21822), a novel covalent small molecule KRASG12C inhibitor, as monotherapy or in combination with the anti-EGFR antibody cetuximab in patients with previously treated colorectal cancer (CRC) harboring KRASG12C mutations. Below is a detailed summary: ### Background: KRASG12C mutations are present in approximately 4% of patients with colorectal cancer and are associated with poor prognosis, reduced treatment response rates, and lower overall survival. Resistance to KRASG12C inhibitors has been linked to EGFR signaling, making combination therapies targeting KRASG12C and EGFR an area of interest for improving outcomes in these patients. ### Study Design: Two open-label, non-randomized trials were conducted: 1. **JAB-21822-1002**: Evaluating glecirasib monotherapy (phase 1 dose escalation and phase 2a expansion). 2. **JAB-21822-1007**: Evaluating glecirasib in combination with cetuximab (phase 1b dose escalation and phase 2 expansion). Participants were adults (≥18 years) with histologically or cytologically confirmed advanced or metastatic CRC harboring KRASG12C mutations. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and at least one measurable lesion per RECIST criteria. For phase 1, participants were required to have failed, been unsuitable for, or refused standard of care treatment. For phase 2, patients must have received at least first-line standard of care and experienced disease progression or intolerance. - **Monotherapy Trial**: Participants received oral glecirasib at 800 mg once daily in 21-day treatment cycles until disease progression, intolerable toxicity, or withdrawal. - **Combination Trial**: In addition to glecirasib (800 mg once daily), cetuximab was administered intravenously (initial loading dose of 400 mg/m² followed by either 250 mg/m² weekly or 500 mg/m² biweekly). ### Primary Endpoints: - **Monotherapy Trial**: - Phase 1: Safety (treatment-emergent adverse events, serious adverse events, dose-limiting toxicities, etc.). - Phase 2a: Objective response rate (ORR, defined as complete or partial response). - **Combination Trial**: - Phase 1b: Dose-limiting toxicities, maximum tolerated dose, and recommended phase 2 dose. - Phase 2: Objective response rate. ### Findings: #### Monotherapy Trial: - **Safety**: - Among 44 patients, treatment-emergent adverse events (TEAEs) occurred in 100% of patients, with 53% experiencing grade ≥3 TEAEs. - Treatment-related adverse events (TRAEs) were reported in 87% of patients, with 27% experiencing grade ≥3 TRAEs. - Serious TEAEs were observed in 33% of patients, but none were treatment-related. - No dose-limiting toxicities or clinically significant unexpected laboratory values of grade ≥3 were observed. - **Efficacy**: - Objective response rate was 23% (95% CI 11–38), with ten partial responses out of 44 patients. #### Combination Trial: - **Safety**: - Among 47 patients, TEAEs occurred in 100% of patients, with 19% experiencing grade 3 or 4 TRAEs. - The most common TRAEs included rash (83%), increased blood bilirubin (62%), increased conjugated bilirubin (36%), elevated alanine aminotransferase (34%), and anemia (32%). - Serious TRAEs occurred in 9% of patients and included interstitial lung disease, pleural effusion, pericardial effusion, pyrexia, and rash. No treatment-related deaths were reported. - **Efficacy**: - Objective response rate was 50% (95% CI 35–65), with 23 partial responses out of 46 patients. ### Interpretation: The study demonstrated that glecirasib monotherapy and its combination with cetuximab are promising treatment options for patients with advanced, refractory colorectal cancer harboring KRASG12C mutations. The combination therapy showed higher efficacy (50% ORR) compared to monotherapy (23% ORR), suggesting that simultaneous inhibition of KRASG12C and EGFR signaling pathways may overcome resistance mechanisms and enhance clinical outcomes. ### Safety Profile: Both monotherapy and combination therapy were generally well tolerated, with manageable adverse events. The incidence of grade 3 or 4 TRAEs was similar between the two trials (20% for monotherapy and 19% for combination therapy). Serious TRAEs were rare, and no treatment-related deaths were observed. ### Conclusion: Glecirasib, either as monotherapy or in combination with cetuximab, represents a promising therapeutic strategy for KRASG12C-mutated CRC. The results support further exploration of glecirasib-based combinations in earlier lines of treatment or in broader patient populations. The combination approach, in particular, warrants further investigation as it demonstrated enhanced efficacy compared to monotherapy. ### Future Directions: Further studies are needed to: 1. Optimize glecirasib-based combination regimens. 2. Evaluate treatment in earlier disease stages or lines of therapy. 3. Investigate mechanisms of resistance to KRASG12C inhibitors. 4. Explore biomarkers for predicting response to therapy. These trials are registered with ClinicalTrials.gov (NCT05009329 and NCT05194995) and remain active but are no longer recruiting participants.

New Drugs for hepatobiliary Cancers - J of Hepatology - Jan.26

The treatment of hepatobiliary cancers, including hepatocellular carcinoma (HCC) and biliary tract cancer (BTC), is undergoing significant advancements with the development of novel drugs and therapeutic strategies. These developments are primarily categorized into two key strategies: 1. **Immune System Targeting Beyond Conventional Checkpoints**: - Novel therapies are being developed to target immune checkpoints beyond the well-established ones like PD-1 and CTLA-4. This includes new antibodies aimed at alternative immune checkpoints and cytokines that regulate tumor immune responses. - Combinations of these antibodies with already approved immunotherapy regimens are being investigated in Phase II and III clinical trials. - Cellular therapies, such as chimeric antigen receptor (CAR)-T cells and tumor-infiltrating lymphocytes (TILs), are in early clinical testing for both HCC and BTC. - Advances in antibody engineering have enabled the development of bispecific T-cell engagers, which are designed to enhance immune responses against tumors. 2. **Targeting Traditionally Undruggable or Novel Pathways**: - New drugs are being developed to target pathways and molecules previously considered undruggable, such as PPAR-α, KRAS, histone deacetylase, and β-catenin. - Antibody-drug conjugates (ADCs) targeting HER2 or nectin-4, which have shown success in other cancers, are being explored for BTC. Additionally, these advances are influencing the treatment of less common liver cancer subtypes, such as sarcomatoid HCC and combined HCC-cholangiocarcinoma. Emerging genomic data and clinical experiences suggest that these rare cancers may be responsive to immune checkpoint inhibitors. Including these subtypes in clinical trials could accelerate the development of effective therapies. In conclusion, the ongoing innovations in immunotherapy, cellular therapies, and targeted drug development are reshaping the treatment landscape for hepatobiliary cancers, offering new hope for improved outcomes in these challenging malignancies.

Tumour Microenvironment in ICC

The tumor microenvironment (TME) in intrahepatic cholangiocarcinoma (iCCA) plays a pivotal role in tumor progression, immune evasion, and therapeutic resistance. iCCA is characterized by a highly complex and heterogeneous TME, comprising cancer cells, immune cells, stromal cells, extracellular matrix components, and signaling molecules. This intricate environment influences tumor growth, metastasis, and response to treatments. Key players in the TME include tumor-associated macrophages, particularly CD163hi M2-like macrophages, which promote immune suppression and tumor progression by impairing CD8+ T cell-mediated antitumor responses. Cancer-associated fibroblasts (CAFs) contribute to the formation of a fibrotic barrier, preventing immune cell infiltration and creating an immunosuppressive milieu. Granulocytes and other myeloid cells further exacerbate immune suppression. The TME in iCCA can be classified into distinct spatial subtypes, such as "immune hot," "immune suppressive," and "immune desert," which correlate with prognosis and treatment response. For example, immune hot TMEs, enriched in antitumor immune cells, are more responsive to immunotherapy, while immune desert TMEs, lacking immune cells, are associated with poor outcomes. By influencing immune evasion mechanisms and modulating therapy resistance, the TME is a critical determinant of iCCA progression. Targeting the TME through combination therapies, such as immunotherapy and antifibrotic agents, holds promise for improving patient outcomes.