ctDNA analysis reveals different molecular patterns upon disease progression in patients treated with osimertinib
Autor: Romero, Atocha; Serna-Blasco, Roberto; Alfaro, Cristina; Sánchez-Herrero, Estela; Barquín, Miguel; Turpín, María del Carmen; Chico, Sofía; Sanz-Moreno, Sandra; Rodriguez-Festa, Alejandro; Laza-Briviesca, Raquel; Cruz-Bermudez, Alberto; Calvo, Virginia; Royuela, Ana; Provencio, Mariano
Resumen: Background: Several clinical trials have demonstrated the efficacy and safety of osimertinib in advanced nonsmall-cell lung cancer (NSCLC). However, there is significant unexplained variability in treatment outcome.
Methods: Observational prospective cohort of 22 pre-treated patients with stage IV NSCLC harboring
the epidermal growth factor receptor (EGFR) p.T790M resistance mutation and who were treated with
osimertinib. Three hundred and twenty-six serial plasma samples were collected and analyzed by digital PCR
(dPCR) and next-generation sequencing (NGS).
Results: The median progression-free survival (PFS), since the start of osimertinib, was 8.9 [interquartile
range (IQR): 4.6–18.0] months. The median treatment durations of sequential gefitinib + osimertinib,
afatinib + osimertinib and erlotinib + osimertinib treatments were 30.1, 24.6 and 21.1 months, respectively.
The p.T790M mutation was detected in 19 (86%) pre-treatment blood samples. Undetectable levels of the
original EGFR-sensitizing mutation after 3 months of treatment were associated with superior PFS (HR:
0.2, 95% CI: 0.05–0.7). Likewise, re-emergence of the original EGFR mutation, alone or together with the
p.T790M mutation was significantly associated with shorter PFS (HR: 8.8, 95% CI: 1.1–70.7 and HR: 5.9,
95% CI: 1.2–27.9, respectively). Blood-based monitoring revealed three molecular patterns upon progression
to osimertinib: sensitizing+/T790M+/C797S+, sensitizing+/T790M+/C797S–, and sensitizing+/T790M–/
C797S–. Median time to progression in patients showing the triplet pattern (sensitizing+/T790M+/C797S+)
was 12.27 months compared with 4.87 months in patients in whom only the original EGFR sensitizing was
detected, and 2.17 months in patients showing the duplet pattern (sensitizing+/T790M+). Finally, we found
that mutations in exon 545 of the PIK3CA gene were the most frequent alteration detected upon disease
progression in patients without acquired EGFR-resistance mutations.
Conclusions: Different molecular patterns identified by plasma genotyping may be of prognostic
significance, suggesting that the use of liquid biopsy is a valuable approach for tumor monitoring.
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