Evidence-Based Liquid Biopsy Knowledge
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Gastric Cancer

ctDNA Enables Early Recurrence Detection and Molecular Profiling for Targeted Therapies

Clinical Overview

Gastric and gastroesophageal junction (GEJ) adenocarcinomas are aggressive malignancies with high recurrence rates of 40-60% following curative-intent surgery and adjuvant therapy. The treatment landscape has expanded significantly with targeted therapies and immunotherapy, making molecular profiling essential for optimal treatment selection.

ctDNA testing provides dual clinical utility: MRD monitoring for early recurrence detection with 2-8 month lead time before imaging, and molecular genotyping to identify actionable biomarkers including HER2 amplification (10-20%), CLDN18.2 expression, FGFR2b amplification (5-10%), MSI-H status (4-8%), and PD-L1 expression. These biomarkers guide selection of targeted therapies with demonstrated survival benefits in randomized trials.

Clinical Utility of ctDNA in Gastric Cancer

  • MRD detection: 2-8 month lead time before radiographic progression; sensitivity 50-88% depending on stage
  • Prognostic stratification: HR 7.3-18 for recurrence in ctDNA-positive vs ctDNA-negative patients
  • HER2 genotyping: 10-20% prevalence; trastuzumab improves OS by 2.7 months (ToGA: HR 0.74)
  • CLDN18.2 genotyping: Zolbetuximab trials show HR 0.75-0.77 for OS improvement
  • FGFR2b genotyping: 5-10% prevalence; bemarituzumab under investigation in clinical trials
  • MSI-H identification: 4-8% prevalence; pembrolizumab achieves ~50% ORR
  • PD-L1 assessment: CheckMate 649 showed nivolumab HR 0.71 in CPS ≥5 patients
  • Non-invasive alternative: Avoids repeat endoscopy or biopsy of metastatic sites

ctDNA Testing Methodology

ctDNA testing in gastric cancer employs both tumor-informed and tumor-agnostic approaches depending on clinical application:

Tumor-Informed Approach (Baseline-Based)

Methodology: Uses a baseline sample (tissue biopsy or baseline plasma) to identify patient-specific mutations, then tracks those mutations at MRD monitoring timepoints.

Clinical Applications:

  • Postoperative MRD monitoring for recurrence detection
  • Treatment response assessment in metastatic disease
  • Higher sensitivity than tumor-agnostic approaches (50-88% depending on stage)

Technical Approach: Targeted sequencing or next-generation sequencing of patient-specific variants identified at baseline.

Tumor-Agnostic Approach (No Baseline)

Methodology: Tests directly at clinical timepoint without prior baseline profiling, using fixed gene panels to detect common cancer mutations.

Clinical Applications:

  • Molecular genotyping for treatment selection (HER2, CLDN18.2, FGFR2b, MSI-H, PD-L1)
  • Useful when tissue biopsy is unavailable or insufficient
  • Enables biomarker assessment at diagnosis or progression

Technical Approach: Gene panel testing covering actionable biomarkers in gastric cancer.

Key Distinction: The difference is whether baseline profiling was performed (tumor-informed) versus testing without prior knowledge of the patient's mutation profile (tumor-agnostic). Both approaches can use fixed gene panels; the distinction is about baseline profiling, not panel design.

MRD Detection: Clinical Utility

Clinical Context: After curative-intent treatment, detecting microscopic residual disease identifies patients at high risk for recurrence, enabling earlier intervention or clinical trial enrollment.

MRD Detection Performance:

  • Sensitivity: 50-88% depending on disease stage (higher in advanced vs early-stage disease)
  • Lead Time: 2-8 months before radiographic detection of recurrence
  • Hazard Ratio: 7.3-18 for recurrence in ctDNA-positive vs ctDNA-negative patients
  • Stage-Dependent Detection: Detection rates higher in locally advanced and metastatic disease compared to early-stage gastric cancer

Clinical Significance: The 2-8 month lead time represents a window where recurrence exists but is invisible on imaging. Hazard ratios of 7.3-18 indicate that detectable ctDNA identifies patients at substantially elevated risk for recurrence. This powerful risk stratification enables consideration of early salvage therapy, clinical trial enrollment, or intensified surveillance strategies.

Evidence from Clinical Studies

Postoperative MRD Monitoring:

  • Tumor-informed approaches achieve highest sensitivity for MRD detection
  • Serial monitoring improves detection compared to single timepoints
  • Successfully detects recurrence across all patterns (peritoneal, hepatic, lymph node, distant metastases)
  • ctDNA dynamics correlate with treatment response and clinical outcomes

Stage-Specific Performance:

  • Advanced-stage disease: Higher ctDNA detection rates due to greater tumor burden
  • Early-stage disease: Lower sensitivity; may require more sensitive assays or serial sampling
  • Peritoneal disease: Detection can be challenging due to limited vascular access

Current Clinical Status: MRD detection has strong prognostic value with hazard ratios demonstrating substantial risk stratification. However, interventional trials testing whether ctDNA-guided treatment intensification improves outcomes are needed to establish clinical utility beyond prognosis.

Genotyping: Clinical Utility for Treatment Selection

Molecular genotyping via ctDNA identifies actionable biomarkers that guide selection of targeted therapies with demonstrated survival benefits in gastric cancer.

1. HER2 Amplification

Clinical Context: HER2 amplification or overexpression occurs in 10-20% of gastric/GEJ adenocarcinomas, with higher prevalence in GEJ tumors and intestinal-type histology. HER2-targeted therapy is standard of care in first-line metastatic disease.

HER2 in Gastric Cancer:

  • Prevalence: 10-20% of gastric/GEJ adenocarcinomas
  • Higher prevalence: GEJ tumors, intestinal-type histology, well-differentiated tumors
  • Detection: ctDNA can identify HER2 amplification, monitor HER2 status changes, and detect resistance mechanisms
  • Targeted Therapies: Trastuzumab, trastuzumab deruxtecan

ToGA Trial: Trastuzumab in HER2+ Gastric Cancer

The ToGA trial (Bang et al. Lancet 2010) established trastuzumab as standard of care in HER2-positive advanced gastric/GEJ cancer:

  • Study Design: Phase 3 randomized trial of chemotherapy with or without trastuzumab in HER2-positive disease
  • Overall Survival: 13.8 months (trastuzumab + chemotherapy) vs 11.1 months (chemotherapy alone)
  • Hazard Ratio: 0.74 (26% reduction in mortality risk, p=0.0046)
  • Response Rate: 47% vs 35%
  • Clinical Impact: Established HER2 as first predictive biomarker in gastric cancer

Trastuzumab Deruxtecan (Second-Line):

  • Antibody-drug conjugate for patients progressing on trastuzumab
  • Objective response rate ~51% in HER2-positive gastric cancer
  • Median overall survival ~12 months in heavily pre-treated patients

ctDNA Application: ctDNA testing enables non-invasive HER2 assessment, monitors HER2 status changes during treatment (HER2 amplification can be lost or gained), and detects resistance mechanisms to guide therapy switching.

Reference: Bang et al. Lancet 2010

2. CLDN18.2 Expression

Clinical Context: Claudin 18.2 (CLDN18.2) is a tight junction protein with restricted expression in gastric epithelium. CLDN18.2-positive tumors can be targeted with zolbetuximab, a first-in-class anti-CLDN18.2 monoclonal antibody.

CLDN18.2 in Gastric Cancer:

  • Expression: Present in subset of gastric/GEJ adenocarcinomas, particularly diffuse-type histology
  • Detection: Traditionally assessed by immunohistochemistry; emerging plasma-based approaches under investigation
  • Targeted Therapy: Zolbetuximab (CLDN18.2-targeted monoclonal antibody)

Zolbetuximab Clinical Trials

SPOTLIGHT Trial (Shitara et al. Lancet 2023):

  • Study Design: Phase 3 trial of zolbetuximab + mFOLFOX6 vs placebo + mFOLFOX6 in CLDN18.2-positive, HER2-negative gastric/GEJ cancer
  • Overall Survival: 14.9 months vs 12.5 months
  • Hazard Ratio: 0.75 (25% reduction in mortality risk, p=0.0053)
  • Progression-Free Survival: 10.6 months vs 8.7 months (HR 0.75, p=0.0066)

GLOW Trial (Shah et al. Lancet 2023):

  • Study Design: Phase 3 trial of zolbetuximab + CAPOX vs placebo + CAPOX in CLDN18.2-positive, HER2-negative disease
  • Overall Survival: 14.4 months vs 12.2 months
  • Hazard Ratio: 0.77 (23% reduction in mortality risk, p=0.0053)
  • Progression-Free Survival: 8.2 months vs 6.8 months (HR 0.68, p<0.0001)

Clinical Significance: Both trials demonstrated consistent survival benefits with zolbetuximab in CLDN18.2-positive gastric cancer. The similar hazard ratios (0.75-0.77) across different chemotherapy backbones support the therapeutic value of CLDN18.2 targeting.

ctDNA Application: While CLDN18.2 is traditionally assessed by tissue immunohistochemistry, research is ongoing to develop plasma-based approaches for CLDN18.2 assessment, which would enable non-invasive biomarker testing.

References: Shitara et al. Lancet 2023, Shah et al. Lancet 2023

3. FGFR2b Amplification

Clinical Context: Fibroblast growth factor receptor 2b (FGFR2b) amplification occurs in 5-10% of gastric cancers, particularly diffuse-type histology. FGFR2b amplification represents an actionable target under investigation in clinical trials.

FGFR2b in Gastric Cancer:

  • Prevalence: 5-10% of gastric/GEJ adenocarcinomas
  • Higher prevalence: Diffuse-type histology, poorly cohesive carcinomas
  • Detection: ctDNA can identify FGFR2b amplification and monitor during treatment
  • Targeted Therapy: Bemarituzumab (FGFR2b-targeted monoclonal antibody)

Bemarituzumab Clinical Development

FIGHT Trial (Wainberg et al. Lancet Oncol 2022):

  • Study Design: Phase 2 trial of bemarituzumab + mFOLFOX6 vs placebo + mFOLFOX6 in FGFR2b-positive gastric/GEJ cancer
  • Clinical Activity: Demonstrated encouraging activity in FGFR2b-overexpressing tumors
  • Biomarker Dependency: Efficacy strongly associated with high FGFR2b expression levels
  • Current Status: Phase 3 trials (FORTITUDE-101, FORTITUDE-102) ongoing

Clinical Significance: FGFR2b amplification represents a molecularly defined subset of gastric cancer with a potential targeted therapy. Identification of FGFR2b-positive patients enables clinical trial enrollment and, if ongoing trials are positive, will guide future treatment selection.

ctDNA Application: ctDNA testing can identify FGFR2b amplification non-invasively, particularly useful when tissue is limited or in metastatic disease where repeat biopsy may be challenging. Plasma genotyping enables monitoring of FGFR2b status during treatment.

Reference: Wainberg et al. Lancet Oncol 2022

4. Microsatellite Instability (MSI-H/dMMR)

Clinical Context: MSI-H/dMMR status indicates mismatch repair deficiency, creating hypermutated tumors highly responsive to immune checkpoint inhibitors. MSI-H gastric cancers show excellent responses to immunotherapy, often without requiring cytotoxic chemotherapy.

MSI-H in Gastric Cancer:

  • Prevalence: 4-8% of advanced gastric cancer (higher in early-stage and Asian populations)
  • Clinical Association: Better baseline prognosis, excellent immunotherapy response
  • Detection: ctDNA can identify MSI-H status via next-generation sequencing
  • Immunotherapy: Pembrolizumab (tissue-agnostic approval for MSI-H solid tumors)

Pembrolizumab in MSI-H Gastric Cancer

  • Objective Response Rate: ~50% with single-agent pembrolizumab
  • Durability: Responses often durable, with prolonged disease control
  • Clinical Advantage: May avoid cytotoxic chemotherapy in highly responsive subset
  • Tissue-Agnostic Indication: Pembrolizumab approved for MSI-H solid tumors regardless of primary site

ctDNA Application: ctDNA testing enables MSI-H assessment alongside comprehensive genomic profiling, particularly valuable when tissue is insufficient for multiple biomarker tests or when repeat sampling is needed.

Reference: Kim et al. Nat Med 2018

5. PD-L1 Expression

Clinical Context: PD-L1 expression (measured by Combined Positive Score, CPS) predicts benefit from immune checkpoint inhibitors. Immunotherapy-chemotherapy combinations are now standard first-line therapy in PD-L1-positive gastric cancer.

PD-L1 and Immunotherapy:

  • Biomarker: PD-L1 CPS (Combined Positive Score) with thresholds at ≥1, ≥5, or ≥10
  • Standard Combinations: Nivolumab + chemotherapy, pembrolizumab + chemotherapy
  • Detection: Traditionally assessed by tissue immunohistochemistry

CheckMate 649: First-Line Nivolumab Standard

CheckMate 649 (Janjigian et al. Lancet 2021) established immunotherapy-chemotherapy as first-line standard:

  • Overall Survival (CPS ≥5): 14.4 months (nivolumab + chemotherapy) vs 11.1 months (chemotherapy)
  • Hazard Ratio (CPS ≥5): 0.71 (29% reduction in mortality, p<0.0001)
  • Overall Survival (CPS ≥1): 13.8 months vs 11.6 months
  • Hazard Ratio (CPS ≥1): 0.77 (p<0.0001)

KEYNOTE-062: Pembrolizumab-Based Strategies

  • Pembrolizumab + chemotherapy: OS benefit in CPS ≥1 patients
  • Single-agent pembrolizumab non-inferior to chemotherapy in CPS ≥10

Clinical Application: PD-L1 testing is standard of care for first-line treatment selection. While traditionally assessed by tissue immunohistochemistry, research is ongoing into plasma-based PD-L1 assessment methods.

Reference: Janjigian et al. Lancet 2021

Clinical Summary

ctDNA testing in gastric cancer provides prognostic risk stratification through MRD monitoring and actionable biomarker information through molecular genotyping, guiding treatment selection in an era of expanding targeted and immunotherapeutic options.

Clinical Recommendations

MRD Monitoring (Prognostic Value):

  • Sensitivity: 50-88% depending on stage (higher in advanced vs early-stage disease)
  • Lead Time: 2-8 months before radiographic recurrence detection
  • Risk Stratification: HR 7.3-18 for recurrence in ctDNA-positive vs ctDNA-negative patients
  • Best Practice: Tumor-informed approach with serial monitoring for highest sensitivity
  • Current Status: Strong prognostic value; interventional trials testing treatment guidance needed

Molecular Genotyping (Actionable Biomarkers):

  • HER2 amplification (10-20%): Trastuzumab + chemotherapy improves OS by 2.7 months (ToGA: HR 0.74)
  • CLDN18.2 expression: Zolbetuximab shows HR 0.75 (SPOTLIGHT) and HR 0.77 (GLOW) for OS
  • FGFR2b amplification (5-10%): Bemarituzumab trials ongoing; identifies clinical trial candidates
  • MSI-H (4-8%): Pembrolizumab achieves ~50% ORR; may avoid cytotoxic chemotherapy
  • PD-L1 CPS ≥5: Nivolumab + chemotherapy shows HR 0.71 (CheckMate 649)
  • Clinical Advantage: Non-invasive alternative to repeat endoscopy or metastatic site biopsy

Integrated Treatment Approach:

  • HER2-positive: Trastuzumab + chemotherapy first-line; trastuzumab deruxtecan second-line
  • CLDN18.2-positive, HER2-negative: Zolbetuximab + chemotherapy emerging standard
  • FGFR2b-positive: Consider bemarituzumab clinical trials
  • MSI-H: Pembrolizumab monotherapy or combination
  • PD-L1 CPS ≥1 (HER2-negative): Immunotherapy + chemotherapy combinations
  • Comprehensive Profiling: Simultaneous multi-biomarker testing optimizes treatment selection

Bottom Line: Gastric cancer demonstrates dual ctDNA utility: MRD monitoring provides powerful prognostic stratification (HR 7.3-18, lead time 2-8 months), while molecular genotyping identifies actionable targets (HER2, CLDN18.2, FGFR2b, MSI-H, PD-L1) that guide therapies with demonstrated survival benefits. As the treatment landscape expands with novel targeted agents, ctDNA-based molecular profiling offers non-invasive biomarker assessment to optimize personalized therapy selection. Key limitations include lower sensitivity in early-stage disease and the need for interventional trials to demonstrate that ctDNA-guided treatment decisions improve clinical outcomes.

References

  1. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687-697.
  2. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2023;401:1655-1668.
  3. Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastro-oesophageal junction adenocarcinoma: the randomised, phase 3 GLOW trial. Lancet. 2023;401:1669-1681.
  4. Wainberg ZA, Enzinger PC, Kang YK, et al. Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol. 2022;23:1430-1440.
  5. Kim ST, Cristescu R, Bass AJ, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med. 2018;24:1449-1458.
  6. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398:27-40.

Evidence summary as of January 2026 | Document Version: 2.0