What is the treatment approach for gallbladder cancer identified through Next-Generation Sequencing (NGS)?

Treatment Approach for Gallbladder Cancer Identified Through Next-Generation Sequencing

For gallbladder cancer patients with advanced disease suitable for systemic treatment, perform comprehensive NGS molecular profiling on tissue biopsies to identify actionable targets including ERBB2, FGFR2, NTRK, IDH1, BRAF, and PIK3CA, as this guides targeted therapy selection and is recommended by current ESMO guidelines. 1

When to Perform NGS Testing

• Obtain tissue for NGS at initial diagnosis via ERCP/PTC-guided biopsies or EUS-guided fine needle biopsy, ensuring adequate tissue for both diagnostic pathology and molecular profiling 1
• Perform NGS on formalin-fixed paraffin-embedded tumor tissue, which is well-suited for tissue biopsies 1
• Consider liquid biopsies using cell-free circulating DNA only if insufficient tumor tissue is available for NGS 1
• For patients at high risk for recurrence (node-positive, margin-positive, vascular invasion, or multifocal disease), perform molecular profiling at diagnosis even if initially resectable 1

Essential Gene Panel Components

The NGS panel must include at minimum:

• Hotspot mutations: IDH1, ERBB2 (HER2), BRAF 1
• Gene fusions: FGFR2 and NTRK genes, preferably interrogated at RNA level using panel-based methods that identify both known and unknown fusion partners 1
• DNA-based testing: FGFR2 breakpoints involving exons 17 and 18 1
• Microsatellite instability (MSI): Via immunohistochemistry for MLH1, MSH2, MSH6, and PMS2, or DNA-based microsatellite analysis 1
• Additional targets based on emerging evidence: PIK3CA, CDKN2A/B, TP53 2, 3

The technology should employ hybrid capture or anchored multiplex PCR, with discussion with molecular pathologist strongly recommended 1

Treatment Algorithm Based on NGS Results

For Resectable Disease After NGS Profiling

• T1a disease with R0 resection and negative nodes: Observation alone is acceptable 4, 5
• T1b and beyond: Extended cholecystectomy with en bloc hepatic resection (segments IVb and V minimum), regional lymphadenectomy, and bile duct resection if involved to achieve R0 status 4, 6
• High-risk features (node-positive, R1/R2 resection): Adjuvant gemcitabine plus cisplatin provides approximately 4 months survival benefit 4, 6

For Advanced/Unresectable Disease with Actionable Targets

Match therapy to molecular findings:

• ERBB2 (HER2) amplification/overexpression (13-18.5% of cases): Consider HER2-directed therapy, as ERBB2 alterations are associated with better tumor differentiation and represent an ESCAT tier target 1, 2, 3
• FGFR2 fusions: ESCAT tier I target, ready for routine use with approved FGFR inhibitors 1
• IDH1 mutations: ESCAT tier I target, ivosidenib approved for IDH1-mutated disease 1
• NTRK fusions: ESCAT tier I target with approved TRK inhibitors 1
• BRAF V600E mutations: ESCAT tier II target, extent of benefit under investigation 1
• PIK3CA mutations (14-20% of cases): PI3K/mTOR pathway alterations present in 33-37% of patients, consider PI3K inhibitors in clinical trials 2, 3
• High TMB (≥10 mutations/Mb, present in ~17% of cases): Consider immune checkpoint inhibitors 2
• MSI-high status: ESCAT tier I for immune checkpoint inhibitors 1

For Patients Without Actionable Targets

• First-line: Gemcitabine plus cisplatin remains standard of care, providing 3.6-4 months survival benefit 4, 5
• Cisplatin contraindicated: Gemcitabine plus oxaliplatin as alternative 5
• Second-line after progression: Fluoropyrimidine-based chemotherapy or clinical trial enrollment 1, 5

Frequency of Actionable Alterations

Research demonstrates that 76-83% of gallbladder cancer patients harbor at least one actionable alteration that could guide personalized treatment, making NGS profiling highly clinically relevant 2, 3, 7

The most common alterations identified are:

• TP53 (57-73%) 2, 3
• CDKN2A/B (25-26%) 2, 3
• ERBB2 (13-18.5%) 2, 3
• PIK3CA (14-20%) 2, 3
• ARID1A (14%) 1

Critical Pitfalls to Avoid

• Never delay tissue acquisition for NGS profiling in patients with biliary obstruction—obtain biopsies during ERCP/PTC procedures for both diagnosis and molecular profiling simultaneously 1
• Do not perform single-gene testing when NGS panels are available, as parallel sequencing is preferred and more cost-effective 1
• Avoid relying solely on biliary brush cytology, which has limited sensitivity—core biopsies are mandatory for adequate tissue and NGS 1
• Do not delay systemic therapy while waiting for NGS results in rapidly progressing disease—initiate gemcitabine/cisplatin and adjust based on results 4
• For potentially resectable tumors, make EUS-FNA decisions in multidisciplinary setting due to very low but real risk of needle tract seeding 1

Practical Implementation Considerations

• Discuss preferred technology (NGS, RNA sequencing, IHC) with molecular pathologist based on targets and available material 1
• Turnaround time for NGS is typically 10-14 days—plan treatment timeline accordingly 1
• Approximately 30-40% of patients with gallbladder cancer harbor potentially actionable molecular aberrations 1
• Consider enrollment in biomarker-driven clinical trials, as only 21% of biliary tract protocols historically utilized targeted therapies based on genomics 7