Early assessment of KRAS mutation in cfDNA correlates with risk of progression and death in advanced non-small-cell lung cancer

• Published in: British journal of cancer 2020-07, Vol.123 (1), p.81-91
• Main Authors: Zulato, Elisabetta, Attili, Ilaria, Pavan, Alberto, Nardo, Giorgia, Del Bianco, Paola, Boscolo Bragadin, Andrea, Verza, Martina, Pasqualini, Lorenza, Pasello, Giulia, Fassan, Matteo, Calabrese, Fiorella, Guarneri, Valentina, Amadori, Alberto, Conte, PierFranco, Indraccolo, Stefano, Bonanno, Laura
• Format: Article
• Language: English
• Subjects: 631/67/1612/1350; 631/67/1857; Aged; Biomarkers, Tumor - genetics; Biomedical and Life Sciences; Biomedicine; Biopsy; Cancer Research; Carcinoma, Non-Small-Cell Lung - blood; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell death; Cell-Free Nucleic Acids - genetics; Chemotherapy; Cohort Studies; Disease Progression; Drug Resistance; Epidemiology; Female; Genotyping; Humans; Immune checkpoint inhibitors; K-Ras protein; Lung cancer; Male; Middle Aged; Molecular Medicine; Mutation; Mutation - genetics; Neoplasm Staging; Non-small cell lung carcinoma; Oncology; Plasma; Proto-Oncogene Proteins p21(ras) - genetics; Small cell lung carcinoma
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-0833-7

Background Liquid biopsy has the potential to monitor biological effects of treatment. KRAS represents the most commonly mutated oncogene in Caucasian non-small-cell lung cancer (NSCLC). The aim of this study was to explore association of dynamic plasma KRAS genotyping with outcome in advanced NSCLC patients. Methods Advanced NSCLC patients were prospectively enrolled. Plasma samples were collected at baseline (T1), after 3 or 4 weeks, according to treatment schedule (T2) and at first radiological restaging (T3). Patients carrying KRAS mutation in tissue were analysed in plasma with droplet digital PCR. Semi-quantitative index of fractional abundance of mutated allele (MAFA) was used. Results KRAS -mutated cohort included 58 patients, and overall 73 treatments ( N  = 39 chemotherapy and N  = 34 immune checkpoint inhibitors) were followed with longitudinal liquid biopsy. Sensitivity of KRAS detection in plasma at baseline was 48.3% (95% confidence interval (CI): 35.0–61.8). KRAS mutation at T2 was associated with increased probability of experiencing progressive disease as best radiological response (adjusted odds ratio: 7.3; 95% CI: 2.1–25.0, p  = 0.0016). Increased MAFA (T1–T2) predicted shorter progression-free survival (adjusted hazard ratio (HR): 2.1; 95% CI: 1.2–3.8, p  = 0.0142) and overall survival (adjusted HR: 3.2; 95% CI: 1.2–8.4, p  = 0.0168). Conclusions Longitudinal analysis of plasma KRAS mutations correlated with outcome: its early assessment during treatment has great potentialities for monitoring treatment outcome in NSCLC patients.