Esophageal Cancer

Why ctDNA Matters in Esophageal Cancer

• MRD detection: Identifies recurrence 3-7 months before imaging with high prognostic value (HR 6.9-17.0 for ctDNA-positive vs ctDNA-negative patients)
• Histology-specific genotyping: HER2 amplification in 15-30% of adenocarcinoma guides trastuzumab therapy; squamous cell carcinoma has distinct molecular profile
• Non-invasive profiling: Avoids risks of repeat endoscopy or biopsy in post-radiation/post-surgical anatomy
• Treatment response monitoring: Emerging data support ctDNA clearance as biomarker for adjuvant immunotherapy benefit

Tumor-Informed (Baseline-Based) Approach

How it works: Uses a baseline sample (surgical tissue or pre-treatment blood) to identify the patient's specific tumor mutations. These identified mutations are then tracked at MRD monitoring timepoints using targeted sequencing.

Performance in esophageal cancer:

• Sensitivity: 60-90% depending on histology and disease burden
• Lead time: 3-7 months before radiographic recurrence
• Prognostic value: HR 6.9-17.0 for recurrence in ctDNA-positive vs ctDNA-negative patients
• Histology differences: Higher detection rates in adenocarcinoma compared to squamous cell carcinoma

When to use: Postoperative MRD surveillance in patients who underwent curative-intent surgery, particularly those with residual pathologic disease or high-risk features. Baseline tumor profiling from surgical specimen enables personalized mutation tracking.

Direct Plasma Testing with Fixed Panels

How it works: Analyzes ctDNA from blood draw at time of advanced disease diagnosis using fixed gene panels covering actionable mutations. No prior tissue sequencing required.

Key targets in esophageal cancer:

• HER2 amplification (adenocarcinoma): 15-30% prevalence in EAC; guides trastuzumab therapy (ToGA trial: HR 0.74)
• MSI-H status: Rare (<5%) but identifies pembrolizumab candidates
• PD-L1 expression/TMB: Complements tissue PD-L1 testing for immunotherapy selection
• PIK3CA mutations: Present in both histologies but more common in adenocarcinoma (16%)

When to use: At diagnosis of metastatic disease or unresectable locally advanced disease, particularly when tissue biopsy is technically difficult, insufficient, or unsafe in post-radiation anatomy. Most useful for adenocarcinoma HER2 testing.

Key Clinical Evidence

Azad et al. (Gastroenterology 2020): MRD detection after chemoradiotherapy in localized esophageal cancer

• Study design: Tumor-informed ctDNA tracking in 45 patients with localized esophageal cancer treated with chemoradiotherapy
• Lead time: Median 3.5 months (range 2.1-13.1 months) before radiographic recurrence
• Prognostic value: Detectable posttreatment ctDNA strongly predicted recurrence
• Clinical implication: Provides window for potential intervention before radiographic progression

Ococks et al. (Ann Oncol 2021): Longitudinal tracking of 97 esophageal adenocarcinomas

• Study design: Comprehensive longitudinal ctDNA analysis throughout treatment course
• Key finding: ctDNA dynamics correlated with treatment response and outcome
• Detection rate: ctDNA detected in majority of patients with active disease
• Clinical utility: Demonstrated feasibility of real-world serial ctDNA monitoring

CheckMate 577 ctDNA Analysis (Kelly et al. N Engl J Med 2021): ctDNA clearance with adjuvant nivolumab

• Trial design: Phase 3 trial of adjuvant nivolumab vs placebo in resected esophageal cancer with residual pathologic disease
• ctDNA clearance rate: 89% with nivolumab vs 62.5% with placebo
• Clinical correlation: ctDNA clearance associated with improved disease-free survival
• Implication: ctDNA may serve as early pharmacodynamic marker of immunotherapy benefit

HER2-Targeted Therapy: ToGA Trial Evidence

Trial design: Phase 3 randomized trial of trastuzumab plus chemotherapy vs chemotherapy alone in HER2-positive gastric/gastroesophageal junction adenocarcinoma (N=584)

Results (Bang et al. Lancet 2010):

• Overall survival: 13.8 months (trastuzumab + chemo) vs 11.1 months (chemotherapy alone)
• Hazard ratio: 0.74 (95% CI 0.60-0.91, p=0.0046)
• Benefit in high HER2 expression: OS 16.0 vs 11.8 months (HR 0.65) in IHC 3+ or IHC 2+/FISH+ subgroup
• Clinical impact: Established HER2 testing as essential for adenocarcinoma treatment planning

Second-line options: Trastuzumab deruxtecan demonstrated activity in HER2-positive disease progressing on trastuzumab, further emphasizing importance of HER2 testing.

ctDNA advantage: Non-invasive HER2 assessment particularly valuable when repeat endoscopic biopsy is technically difficult or unsafe in post-radiation anatomy, or when tissue is insufficient for comprehensive testing.

Immunotherapy Selection: PD-L1 and MSI-H

CheckMate 649 (Janjigian et al. N Engl J Med 2021): First-line nivolumab + chemotherapy in gastric/GEJ adenocarcinoma

• PD-L1 CPS ≥5 population: OS 14.4 vs 11.1 months (HR 0.71)
• PD-L1 CPS ≥10 population: Greater benefit, OS 15.4 vs 11.1 months (HR 0.68)
• Clinical implication: PD-L1 testing guides first-line immunotherapy use

KEYNOTE-590 (Sun et al. JAMA Oncol 2021): First-line pembrolizumab + chemotherapy in esophageal/GEJ cancer

• Overall population: OS 12.4 vs 9.8 months (HR 0.73)
• PD-L1 CPS ≥10: Enhanced benefit, OS 13.9 vs 8.8 months (HR 0.62)
• Esophageal adenocarcinoma: Consistent benefit across histologies

MSI-H/dMMR testing: Rare in esophageal adenocarcinoma (<5%) but identifies exceptional responders to pembrolizumab monotherapy, making testing worthwhile despite low prevalence.

Key Differences from Adenocarcinoma

Alteration	Adenocarcinoma (EAC)	Squamous Cell (ESCC)	Clinical Impact
HER2 amplification	15-30%	<5%	Trastuzumab therapy primarily for adenocarcinoma
TP53 mutations	~50%	>90%	No current targeted therapy; prognostic marker
NOTCH1 mutations	Rare	20-25%	Distinct ESCC feature; no approved therapy
PIK3CA mutations	~16%	~20%	Investigational PI3K inhibitors in trials
PD-L1 expression	Variable	Variable	Guides immunotherapy in both histologies

Key Clinical Points

MRD Detection After Curative Treatment:

• Performance: 60-90% sensitivity with 3-7 month lead time before imaging
• Prognostic value: HR 6.9-17.0 for recurrence in ctDNA-positive vs ctDNA-negative patients
• Histology differences: Higher detection rates in adenocarcinoma vs squamous cell carcinoma
• Methodology: Tumor-informed approach using baseline sample (tissue or blood) to identify mutations for tracking
• Limitation: Prognostic value established; predictive value for treatment decisions requires prospective trials

Molecular Genotyping - Adenocarcinoma:

• HER2 amplification (15-30%): Trastuzumab + chemotherapy improves OS (ToGA: HR 0.74, OS 13.8 vs 11.1 months)
• PD-L1 CPS ≥10: Enriches for immunotherapy benefit (CheckMate 649, KEYNOTE-590)
• MSI-H (<5%): Rare but identifies exceptional pembrolizumab responders
• PIK3CA mutations (16%): Investigational PI3K inhibitors in development
• Clinical utility: Greatest value when tissue insufficient or unsafe to obtain for HER2 testing

Molecular Genotyping - Squamous Cell Carcinoma:

• Distinct molecular profile: High TP53 (>90%), NOTCH1 (20-25%), low HER2 (<5%)
• Limited HER2 role: HER2-targeted therapy rarely applicable unlike adenocarcinoma
• Immunotherapy-based treatment: PD-L1 testing guides chemotherapy-immunotherapy combinations
• Investigational targets: PIK3CA inhibitors in trials; no approved targeted therapy beyond immunotherapy

Clinical Decision Framework:

• Curative-intent setting: MRD testing for risk stratification in high-risk postoperative patients (residual pathologic disease)
• Advanced adenocarcinoma: HER2 testing essential (tissue preferred, ctDNA when tissue limited)
• Advanced squamous carcinoma: PD-L1 testing for immunotherapy selection; limited additional genotyping utility
• Both histologies: Consider MSI-H testing despite low yield; guides immunotherapy monotherapy option