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Gregory J. Riely, MD, PhD
Gregory J. Riely, MD, PhD
Posted: Friday, February 23, 2024
Resistance to BRAF inhibition in patients with advanced non–small cell lung cancer (NSCLC) may not be driven by BRAF V600E mutations, according to Françoise Farace, PhD/HDR, of Gustave Roussy, Université Paris-Saclay, Villejuif, and colleagues. In fact, single circulating tumor cell (CTC) sequencing in matched tissue obtained from four patients with NSCLC indicated that just 1 of 26 cells were considered to be BRAF V600E–mutant. The findings of this study were published in the British Journal of Cancer.
“Extensive tumor genomic heterogeneity was found in CTCs compared to tumor biopsies and circulating free DNA at failure to BRAF inhibition in BRAF V600E–mutant NSCLC, including relevant alterations that may represent potential treatment opportunities,” stated the study investigators.
CTCs and DNA were examined in seven patients with advanced NSCLC at the time of treatment failure. Matched tumor tissue was obtained from four of these patients. Fluorescence-activated cell sorting was used following enrichment, immunofluorescence, and sequencing to determine mutations and copy number–alteration analyses. BRAF V600E was found in 100% of tumor biopsies and approximately 71% of circulating free DNA samples.
CTC mutations appeared to be mainly associated with mitogen-activated protein kinase–independent pathways, and less than 1% of cells were found to be BRAF V600E–mutated. Matched tumor biopsies contained the majority of copy number alterations but were almost exclusively found within tumor cells. Mitogen-activated protein kinase, cell cycle, DNA repair, and immune response pathways were altered in CTCs. However, analyses of tumor cell biopsies did not detect alterations in these pathways within circulating free DNA. Additionally, driver alterations in clinically relevant genes were found to reoccur in CTCs.
Disclosure: For full disclosures of the study authors, visit nature.com.
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