Ultra-sensitive EGFR T790M Detection as an Independent Prognostic Marker for Lung Cancer Patients Harboring EGFR del19 Mutations and Treated with First-generation TKIs

Abstract : PURPOSE: The detection of preexisting EGFR T790M subclones and the assessment of their clinical significance in the pretreatment of patients with EGFR T790M non-small cell lung cancer (NSCLC) remain unclear. EXPERIMENTAL DESIGN: A total of 179 tumor samples from patients treated or not with a first-generation tyrosine kinase inhibitor (TKI) was analyzed. The presence of ultra-low levels of preexisting EGFRT790M mutation was evaluated using ultra-sensitive droplet digital PCR (ddPCR) and the clinical implication of these mutations on first-generation TKI efficiency assessed. RESULTS: With a ddPCR linear performance of 0.999 and an analytical sensitivity of approximately 0.001%, we observed a 66% (99/150) overall incidence of ultra-low EGFR T790M mutation. Among 82 patients harboring EGFR activating mutations, the presence of a preexisting EGFR T790M mutation prior to any treatment was significantly associated with a longer progression-free survival (PFS; P = 0.009; log-rank test). Interestingly, longer PFS was linked to concomitant EGFR del19 and ultra-low EGFR T790M mutations. Moreover, the presence of both EGFR del19 and ultra-low EGFR T790M mutations was identified as the best fit for predicting the clinical outcome of patients treated with TKI compared with an ultra-low EGFR T790M mutation status or an activating mutation alone (P = 0.042 and P = 0.0071, respectively). CONCLUSIONS: We demonstrate that the detection of the ultra-low EGFR T790M mutation in TKI-naïve patients is not a rare event. We suggest that ddPCR should be used in clinical practice to distinguish patients who may respond to first- or third-generation TKIs.
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https://hal.umontpellier.fr/hal-02448987
Contributeur : Amandine Michel-Avella <>
Soumis le : mercredi 22 janvier 2020 - 15:53:02
Dernière modification le : jeudi 23 janvier 2020 - 01:40:15

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Julie Vendrell, Julien Mazieres, Romain Senal, Isabelle Rouquette, Xavier Quantin, et al.. Ultra-sensitive EGFR T790M Detection as an Independent Prognostic Marker for Lung Cancer Patients Harboring EGFR del19 Mutations and Treated with First-generation TKIs. Clinical Cancer Research, American Association for Cancer Research, 2019, 25 (14), pp.4280-4289. ⟨10.1158/1078-0432.CCR-18-2683⟩. ⟨hal-02448987⟩

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