What are some novel treatment options in molecular biology for hepatobiliary surgery, particularly for advanced liver cancer?

Novel Molecular Biology Research Topics in Hepatobiliary Surgery for Advanced Liver Cancer

The most promising research frontier in molecular biology for hepatobiliary surgery centers on combination immunotherapy with anti-angiogenic agents, conversion surgery following molecular therapy, and identification of predictive biomarkers for treatment selection in hepatocellular carcinoma.

High-Priority Research Areas

Combination Immunotherapy and Anti-Angiogenic Therapy

Atezolizumab plus bevacizumab represents the current standard for first-line advanced HCC, demonstrating superior overall survival (67.2% at 12 months) compared to sorafenib (54.6%) 1. Research should focus on:

• Mechanisms of synergy between checkpoint inhibitors and VEGF inhibition, as the interplay between anti-angiogenic drugs and immunotherapy has shown encouraging preliminary results in phase I studies 2
• Lenvatinib plus pembrolizumab combinations, which achieved 46% objective response rates using mRECIST criteria in phase Ib studies, with median overall survival of 22 months 1
• Durvalumab plus tremelimumab combinations as emerging alternatives requiring mechanistic investigation 1

Conversion Surgery Following Molecular Therapy

Conversion surgery after molecular therapy represents a paradigm shift, with lenvatinib achieving 8.4% conversion rates and >80% disease-specific survival at three years 3. Critical research questions include:

• Optimal timing for conversion surgery following tumor downstaging with molecular agents 3
• Pathological response assessment, as complete radiological response does not guarantee complete pathological response 3
• Patient selection criteria for conversion candidates, particularly those with intermediate or advanced HCC initially deemed unresectable 1
• Combination strategies with hepatic arterial infusion chemotherapy (HAIC) or radiation therapy to maximize conversion rates 1

Biomarker Development for Treatment Selection

Currently, only alpha-fetoprotein (AFP ≥400 ng/mL) serves as a validated biomarker for ramucirumab selection, representing a critical unmet need 1. Research priorities include:

• Predictive biomarkers for immunotherapy response, including CRAFITY score validation and prognostic nutritional index assessment 1
• Molecular subclassification based on TERT, CTNNB1, and TP53 mutations, though these remain non-actionable targets 1
• Wnt/β-catenin pathway activation as a marker of immunotherapy resistance 1
• Gut microbiota profiling to predict checkpoint inhibitor efficacy 1
• PD-L1 expression (CPS ≥1 or ≥10) for patient stratification in various combination regimens 1, 4

Novel Molecular Targets Beyond Current Therapies

Emerging targets beyond RAF/VEGF/PDGFR pathways require investigation 5. Promising areas include:

• Transforming growth factor-beta (TGF-β) inhibition, currently in phase II evaluation 2
• MET (hepatocyte growth factor receptor) targeting for patients with specific molecular profiles 2
• Fibroblast growth factor receptor 4 (FGFR4) inhibition with integrated translational research 2
• FLT-3, c-KIT, and RET kinase pathways as secondary targets 5

Resistance Mechanisms and Sequential Therapy

Disease stabilization with sorafenib lasts only months due to resistance development, with no biomarkers available for monitoring 6. Research should address:

• Mechanisms of acquired resistance to tyrosine kinase inhibitors and checkpoint inhibitors 6
• Optimal sequencing strategies for first-line atezolizumab/bevacizumab followed by second-line TKIs (sorafenib, lenvatinib, cabozantinib, regorafenib) 1
• Post-progression survival enhancement through sequential treatment protocols 7
• Combination approaches targeting different pathway levels simultaneously to prevent resistance 6

Integration with Locoregional Therapies

Combination of molecular therapy with surgical or locoregional approaches requires systematic investigation 6. Key research topics:

• Molecular therapy combined with transarterial chemoembolization (TACE) for intermediate-stage disease 1
• Lenvatinib with stereotactic body radiotherapy (SBRT) for portal vein tumor thrombosis 1
• Sorafenib or lenvatinib with external beam radiation for locally advanced disease 1
• Transarterial radioembolization (TARE) with systemic therapy combinations currently under investigation 1

Child-Pugh B Patient Population

Real-world studies show similar adverse event rates but shorter overall survival in Child-Pugh B patients, representing an underserved population 1. Research needs include:

• Safety and efficacy profiles of molecular agents in Child-Pugh B cirrhosis 1
• Dose modification strategies to balance efficacy and tolerability 8
• Segmental treatment approaches for patients with bilirubin >2-3 mg/dL 1

Tumor Microenvironment Modulation

Understanding the tumor microenvironment and field effect in adjacent non-tumoral tissue defines patient subgroups with different outcomes 1. Research should explore:

• Gene profiling of adjacent non-tumoral tissue to predict prognosis 1
• Proliferation versus non-proliferation molecular subclasses and their treatment implications 1
• Inflammation class characterization and targeted interventions 1

Critical Methodological Considerations

Phase III randomized controlled trials remain essential, as observational studies provide less robust evidence 1. Research design should:

• Incorporate translational endpoints with tumor and blood biomarker collection 2
• Include quality-of-life assessments alongside survival outcomes 1
• Account for viral etiology differences (HBV versus HCV) in treatment response 1
• Exclude patients with >50% liver involvement or main portal vein invasion when appropriate for safety 1