Serial Plasma Comprehensive Genomic Profiling Captures Therapy Resistance and Guides Management of Non-Small Cell...

Area of Science:

• Oncology
• Genomics
• Precision Medicine

Background:

• Plasma comprehensive genomic profiling (pCGP) is established in non-small cell lung cancer (NSCLC) care.
• The utility of serial pCGP for managing oncogene-driven NSCLC post-progression is less documented.
• This study focuses on the clinical value of serial pCGP in EGFR-mutant NSCLC.

Purpose of the Study:

• To assess the clinical utility of serial pCGP in NSCLC management.
• To investigate evolving co-mutation patterns and resistance mechanisms in EGFR-mutant NSCLC using serial pCGP.
• To determine the impact of pCGP on treatment decisions, especially when tissue biopsy is not feasible.

Main Methods:

• Retrospective analysis of 718 NSCLC patients undergoing pCGP between 2015-2022.
• Programmatic extraction of clinical-genomic data from Johns Hopkins Lung Cancer Precision Medicine Center.
• Analysis of variant annotation, actionability, and co-mutation patterns across serial pCGP, focusing on EGFR-mutant NSCLC.

Main Results:

• pCGP informed management in 13% of patients, primarily by identifying actionable mutations when tissue testing was unavailable.
• In EGFR-mutant NSCLC, serial pCGP revealed PI3K pathway alterations (11%) and resistance mutations like BRAF V600E and MET exon 14 skipping (3% each) after TKI therapy.
• Among 31 EGFR-mutant NSCLC patients with actionable findings after TKI progression, 18 (58%) were matched to targeted therapies.

Conclusions:

• Serial pCGP is valuable for guiding treatment decisions in NSCLC patients.
• In EGFR-mutant NSCLC, pCGP at progression effectively identifies actionable drivers of therapy resistance.
• This enables timely therapeutic interventions, improving patient management.