Lung Cancer Whole-Genome Sequencing, Treatment Decisions, and Clonal Hematopoiesis

Dr. Raez discusses IASLC 2025 data, now published in the Journal of Thoracic Oncology, representing important progress for lung cancer's MRD research, which has historically lagged behind gastrointestinal and genitourinary cancers.

He traces technological evolution from initial approaches using 16 truncal mutations through whole-exome sequencing to current whole-genome sequencing with enhanced techniques improving sensitivity and specificity.

This study enrolled 216 post-surgical patients with stage I to III disease, conducting 2 key analyses.

The landmark analysis (immediately post-surgery, pre-treatment) showed that ctDNA-negative patients had significantly improved disease-free and overall survival.

The second analysis, conducted after completing adjuvant immunotherapy and chemotherapy, showed that patients remaining ctDNA-positive had worse relapse-free and overall survival.

Sensitivity was approximately 89%.

Dr. Raez references a complementary ASCO presentation by Dr. Julia Rotow using similar technology to guide therapy in metastatic lung cancer: patients receiving immunotherapy alone were monitored via MRD testing after 2 months, with persistently positive results triggering escalation to immunotherapy plus chemotherapy, showing significant survival improvement.

Regarding adjuvant osimertinib (EGFR-mutant resected NSCLC) and durvalumab following chemoradiation (stage III NSCLC), Dr. Raez notes osimertinib isn't universally successful, with some patients developing resistance mutations (C797S and others) that MRD monitoring could potentially detect.

Similarly, despite durvalumab following the PACIFIC protocol representing best available stage III treatment, only approximately half of patients are cured; MRD monitoring could identify non-responders earlier, enabling escalation strategies rather than waiting years to recognize treatment failure.

Regarding clonal hematopoiesis of indeterminate potential (CHIP), Dr. Raez confirms this represents a significant challenge: acquired somatic mutations originating from hematopoietic cells rather than tumor tissue that can be indistinguishable from tumor-derived mutations without verification.

Tumor-informed testing reduces but doesn't eliminate this problem, whereas tumor-naïve testing lacks tissue-based verification, increasing false-positive rates.

CHIP-related false-positives can trigger unnecessary imaging, additional testing, and significant patient psychological distress, representing a critical barrier requiring resolution before MRD becomes standard of care.