TY - JOUR
T1 - Independent prognostic value of ultra-sensitive quantification of tumor pre-treatment T790M subclones in EGFR mutated non-small cell lung cancer (NSCLC) treated by first/second generation TKI, depends on variant allele frequency (VAF)
T2 - Results of the French cooperative thoracic intergroup (IFCT) biomarkers France project
AU - on behalf of the French Cooperative Thoracic Intergroup (IFCT)
AU - Beau-Faller, Michèle
AU - Pencreach, Erwan
AU - Leduc, Charlotte
AU - Blons, Hélène
AU - Merlio, Jean Philippe
AU - Bringuier, Pierre Paul
AU - de Fraipont, Florence
AU - Escande, Fabienne
AU - Lemoine, Antoinette
AU - Ouafik, L'Houcine H.
AU - Denis, Marc
AU - Hofman, Paul
AU - Lacave, Roger
AU - Melaabi, Samia
AU - Langlais, Alexandra
AU - Missy, Pascale
AU - Morin, Franck
AU - Moro-Sibilot, Denis
AU - Barlesi, Fabrice
AU - Cadranel, Jacques
N1 - Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - Objectives: T790M mutations inEGFR-mutated non-small cell lung cancer (NSCLC) account for nearly 50% of acquired resistance mechanisms to EGFR-TKIs. Earlier studies suggested that tumor T790M could also be detected in TKI-naïve EGFR-mutated NSCLC. The aim of the study is to assess the prevalence and clinical significance of quantification of tumor pre-treatment T790M subclones. Materials and methods: We analyzed 366 EGFR-mutated NSCLC patients of the real-life IFCT Biomarkers France study with available pre-treatment formalin-fixed paraffin-embedded (FFPE) tumor DNA before treatment by first/second-generation EGFR-TKI. We used ultra-sensitive Droplet Digital Polymerase Chain Reaction (ddPCR) QX200 (BIO-RAD®, Hercules, CA, USA). All samples were tested in duplicate. Results: ddPCR identified T790M in 19/240 specimens (8%). T790M-positive and T790M-negative populations were not different for clinical baseline characteristics. T790M Variant Allele Frequency (VAF) was > 0.01% <0.1%, > 0.1% <1%, > 1% <10%, and >10% in five (26.3%), six (31.6%), six (31.6%), and two (10.5%) patients, respectively. T790M VAF was >0.1% in 11/13 (84%) patients with rapid (<3 months) or usual progression (3–20 months) compared to 0/3 with low progression (>20 months) (p = 0.02). In a Cox model, T790M mutation positivity was correlated with overall survival (OS) and progression-free survival (PFS) for 10% > VAF >1% (hazard ratio [HR] = 2.83, 95% confidence interval [CI] 1.13–7.07, p = 0.03; HR=3.62, 95%CI 1.43–4.92, p = 0.007, respectively) and for VAF >10% (HR = 19.14, 95%CI 4.35–84.26, p < 0.001; HR = 17.89, 95%CI 2.21–144.86, p = 0.007, respectively). Conclusion: Ultra-sensitive detection of tumor T790M mutation concerned 8% of EGFR-mutated TKI-naïve NSCLC patients and has a negative prognostic value only for T790M VAF over 1%.
AB - Objectives: T790M mutations inEGFR-mutated non-small cell lung cancer (NSCLC) account for nearly 50% of acquired resistance mechanisms to EGFR-TKIs. Earlier studies suggested that tumor T790M could also be detected in TKI-naïve EGFR-mutated NSCLC. The aim of the study is to assess the prevalence and clinical significance of quantification of tumor pre-treatment T790M subclones. Materials and methods: We analyzed 366 EGFR-mutated NSCLC patients of the real-life IFCT Biomarkers France study with available pre-treatment formalin-fixed paraffin-embedded (FFPE) tumor DNA before treatment by first/second-generation EGFR-TKI. We used ultra-sensitive Droplet Digital Polymerase Chain Reaction (ddPCR) QX200 (BIO-RAD®, Hercules, CA, USA). All samples were tested in duplicate. Results: ddPCR identified T790M in 19/240 specimens (8%). T790M-positive and T790M-negative populations were not different for clinical baseline characteristics. T790M Variant Allele Frequency (VAF) was > 0.01% <0.1%, > 0.1% <1%, > 1% <10%, and >10% in five (26.3%), six (31.6%), six (31.6%), and two (10.5%) patients, respectively. T790M VAF was >0.1% in 11/13 (84%) patients with rapid (<3 months) or usual progression (3–20 months) compared to 0/3 with low progression (>20 months) (p = 0.02). In a Cox model, T790M mutation positivity was correlated with overall survival (OS) and progression-free survival (PFS) for 10% > VAF >1% (hazard ratio [HR] = 2.83, 95% confidence interval [CI] 1.13–7.07, p = 0.03; HR=3.62, 95%CI 1.43–4.92, p = 0.007, respectively) and for VAF >10% (HR = 19.14, 95%CI 4.35–84.26, p < 0.001; HR = 17.89, 95%CI 2.21–144.86, p = 0.007, respectively). Conclusion: Ultra-sensitive detection of tumor T790M mutation concerned 8% of EGFR-mutated TKI-naïve NSCLC patients and has a negative prognostic value only for T790M VAF over 1%.
KW - Droplet digital PCR (ddPCR)
KW - EGFR mutation
KW - Non-small cell lung cancer (NSCLC)
KW - T790M
KW - Variant allele frequency (VAF)
UR - http://www.scopus.com/inward/record.url?scp=85076237428&partnerID=8YFLogxK
U2 - 10.1016/j.lungcan.2019.10.013
DO - 10.1016/j.lungcan.2019.10.013
M3 - Article
C2 - 31841714
AN - SCOPUS:85076237428
SN - 0169-5002
VL - 140
SP - 19
EP - 26
JO - Lung Cancer
JF - Lung Cancer
ER -