Completing Biomarker Testing When Tissue Is Insufficient: Liquid Biopsy, Timing, and Patient Counseling

When comprehensive tissue next-generation sequencing (NGS) fails, liquid biopsy should be the reflex strategy, especially in stage IV disease, where tissue-plasma concordance is high. Dr. Wu notes that in William's case, the limited tissue panel (EGFR, ALK, ROS1, KRAS, BRAF) was negative, which does not rule out an actionable driver. Critically, most limited tissue panels do not include full HER2 (ERBB2) sequencing, so a negative limited panel can be falsely reassuring.

Dr. Wu reviews the National Comprehensive Cancer Network (NCCN) framework for non-squamous advanced NSCLC, which designates EGFR, ALK, ROS1, KRAS, BRAF, NTRK, MET exon 14, and RET as Category 1 biomarkers. HER2 mutation testing, HER2 immunohistochemistry, and NRG1 are listed but are not Category 1—another reason comprehensive NGS is essential rather than a piecemeal approach.

His preferred workflow: order tissue NGS and plasma NGS in parallel at the first visit, so a complementary liquid result is available if tissue is inadequate. A nuance for early-stage disease—tissue-plasma concordance is lower in stage I, so in resectable cases he prefers waiting for a surgical or adequate biopsy specimen for tissue NGS.

On counseling, Dr. Wu acknowledges the tension: Patients want to start treatment immediately. He frames the wait as a search for a more personalized, targeted option. For highly symptomatic patients, he often uses Option B, one cycle of carboplatin/pemetrexed without pembrolizumab while awaiting NGS, which preserves future immunotherapy decisions if a driver is found.