Sisodia, Rajvardhan

Atezolizumab-bevacizumab and durvalumab-tremelimumab have established immunotherapy as a first-line standard of care in advanced hepatocellular carcinoma (HCC). Yet, objective response rates (ORRs) remain confined to approximately 15-20%, and no validated predictive biomarker exists for patient selection. Unlike melanoma and lung cancer, conventional markers, including programmed death-ligand 1, microsatellite instability-high status, and tumor mutational burden, have not demonstrated reliable predictive value in HCC. Prior narrative reviews comprehensively catalogued the biomarker landscape through 2022 but predate a wave of clinically significant publications. This narrative review synthesizes evidence published between 2020 and 2026, with particular emphasis on 2023–2026 data, within a unified clinical framework not provided by prior reviews. We critically evaluate tissue-based biomarkers, including the AI-derived Atezolizumab-Bevacizumab Response Signature-Pathology model, spatial multiplex immunohistochemistry, and β-catenin mutational profiling; blood-based biomarkers encompassing circulating tumor DNA for minimal residual disease detection and peripheral immune phenotyping; and serum indices including the CRAFITY score and neutrophil-to-lymphocyte ratio. Hepatitis B virus etiology and non-alcoholic steatohepatitis are discussed as biological modifiers of biomarker performance. We propose an original biomarker-guided clinical algorithm, a comparative clinical readiness table, and a disease-continuum biomarker timeline as practical tools for clinicians and trialists. Prospective biomarker-enrichment trials represent the most critical next step toward clinical translation.

Background Circulating tumor DNA (ctDNA) has rapidly evolved from a research tool to a clinically applicable biomarker in colorectal cancer (CRC), transforming the assessment of minimal residual disease (MRD) and recurrence risk. The growing availability of commercial assays has complicated test selection and interpretation, particularly for gastroenterologists who increasingly encounter ctDNA data in postoperative and surveillance settings. Methods We conducted a narrative review of the literature using PubMed, Embase, and Cochrane databases from January 2015 through March 2026, prioritizing randomized controlled trials, prospective cohort studies, and clinical practice guidelines relevant to ctDNA applications in CRC. The search employed predefined keyword combinations applied independently to each database. Two authors (A.S. and S.M.) independently screened titles and abstracts against the prespecified inclusion criteria, with disagreements resolved by discussion. Results Tumor-informed assays that analyze patient-specific mutations exhibit high specificity for MRD detection, with serial sampling sensitivity reaching 88% compared to 59% for tumor-agnostic approaches, based on a 2026 systematic review and diagnostic accuracy meta-analysis that pooled data across multiple platforms and settings; the authors note substantial study-level heterogeneity in platform design and patient populations, and results should be interpreted accordingly, but require tissue access and extended processing times. Tumor-agnostic tests are more rapid and accessible, incorporating genomic and epigenomic signals, though they exhibit site-specific sensitivity variations ranging from 100% for liver metastases to 40% for peritoneal recurrence and remain vulnerable to biological confounders such as clonal hematopoiesis (CH). Importantly, ctDNA interpretation is subject to additional biological limitations including tumor shedding variability by anatomical site and disease burden, the timing of sample collection relative to surgery or chemotherapy, platform-specific detection thresholds, and pre-analytical variables such as hemolysis and delayed plasma processing. Randomized evidence supports ctDNA-guided de-escalation of adjuvant therapy in stage II colon cancer, with 5-year follow-up from the DYNAMIC trial demonstrating comparable recurrence-free survival (88% vs. 87%) and overall survival (93.8% vs. 93.3%) despite reduced chemotherapy use. In stage III disease, ctDNA is strongly prognostic, but chemotherapy intensification based solely on molecular positivity has not improved outcomes. This review additionally addresses underexplored areas including ctDNA in rectal cancer and neoadjuvant therapy, the influence of microsatellite instability (MSI) status on assay performance, and disparities in ctDNA access across racial, socioeconomic, and geographic populations. Conclusions For gastroenterologists encountering ctDNA results in postoperative and surveillance settings, three principles should guide practice (i): match assay selection to clinical intent - tumor-informed platforms for MRD-directed adjuvant decisions, tumor-agnostic platforms when tissue is unavailable (ii); interpret results within biological and technical context, accounting for platform-specific sensitivity limitations, biological confounders, and quantitative VAF trajectory rather than binary thresholds; and (iii) integrate ctDNA findings into multidisciplinary pathways - de-escalation is supported by high-quality randomized evidence in stage II disease (Grade A; Level I), while chemotherapy escalation based solely on ctDNA positivity in stage III disease is not supported outside clinical trials (Grade C; Level I). Standardization of assay performance benchmarks and equitable access to testing remain critical unmet needs.

Antibody–drug conjugates (ADCs) are reshaping the therapeutic approach to advanced gastrointestinal cancers by integrating tumor-specific monoclonal antibodies with potent cytotoxic payloads to improve targeted tumor cell destruction while minimizing systemic exposure. Compared to traditional chemotherapy, trastuzumab deruxtecan has significantly improved objective response rates and overall survival in HER2-positive gastric and gastroesophageal junction tumors after trastuzumab-based therapy. This supports its role as an important second-line or later treatment option. The ongoing advancement of ADCs targeting CLDN18.2, TROP2, and CEACAM5 indicates that this therapeutic category will continue to expand across gastrointestinal neoplasms. Nonetheless, these advancements are accompanied by a specific and clinically significant toxicity profile. Hematologic suppression, gastrointestinal side effects, hepatotoxicity, and notably interstitial lung disease (ILD) are essential consequences that may need inpatient assessment and care. Interstitial lung disease (ILD), although uncommon, may be severe or lethal if not identified immediately and treated swiftly with medication cessation and corticosteroids. In hospitalized patients, distinguishing ADC-related toxicity from infection or disease progression is often difficult owing to overlapping clinical manifestations, requiring meticulous evaluation and interdisciplinary cooperation. As ADCs are integrated into earlier treatment lines and across a broader patient population, hospital systems must evolve to ensure prompt identification, consistent management protocols, and efficient collaboration between oncology and inpatient teams. This study analyzes the mechanisms, clinical effectiveness, and safety profile of ADCs in gastrointestinal oncology, pointing out the importance of institutional preparedness to safely incorporate these medicines into standard clinical practice. These features also align ADC therapy with personalized medicine by emphasizing biomarker-guided patient selection and individualized toxicity monitoring.