Dynamics of multiple resistance mechanisms in plasma DNA during EGFR‐targeted therapies in non‐small cell lung cancer

Abstract

Tumour heterogeneity leads to the development of multiple resistance mechanisms during targeted therapies. Identifying the dominant driver(s) is critical for treatment decision. We studied the relative dynamics of multiple oncogenic drivers in longitudinal plasma of 50 EGFR‐mutant non‐small‐cell lung cancer patients receiving gefitinib and hydroxychloroquine. We performed digital PCR and targeted sequencing on samples from all patients and shallow whole‐genome sequencing on samples from three patients who underwent histological transformation to small‐cell lung cancer. In 43 patients with known EGFR mutations from tumour, we identified them accurately in plasma of 41 patients (95%, 41/43). We also found additional mutations, including EGFR T790M (31/50, 62%), TP53 (23/50, 46%), PIK3CA (7/50, 14%) and PTEN (4/50, 8%). Patients with both TP53 and EGFR mutations before treatment had worse overall survival than those with only EGFR. Patients who progressed without T790M had worse PFS during TKI continuation and developed alternative alterations, including small‐cell lung cancer‐associated copy number changes and TP53 mutations, that tracked subsequent treatment responses. Longitudinal plasma analysis can help identify dominant resistance mechanisms, including non‐druggable genetic information that may guide clinical management.

Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: a meta-analysis

“…306 articles were excluded for duplicates. Following a title/abstract screening and a full text reviewing by all the authors, 15 studies [26][27][28][29][34][35][41][42][43][44][45][46][47][48][49] were included for final analysis.…”

“…In total, 3786 lung cancer patients who accepted genomic profiling for one or more targeted gene were included in our study. Among all patients, 1342 patients were diagnostic as EGFR-or ALK-mutated advanced NSCLC (IIIB/IV/recurrent stage) and were treated with for study by Tsui DWY et al [43] in which blood samples were collected for gene detection. With respect to type of study, study by Aisner et al [26] and Tsui DWY et al [43] were performed prospectively, and study by Christopoulos P [47] were designed as both prospective and retrospective study, all the remaining 13 studies were retrospective studies.…”

“…Among all patients, 1342 patients were diagnostic as EGFR-or ALK-mutated advanced NSCLC (IIIB/IV/recurrent stage) and were treated with for study by Tsui DWY et al [43] in which blood samples were collected for gene detection. With respect to type of study, study by Aisner et al [26] and Tsui DWY et al [43] were performed prospectively, and study by Christopoulos P [47] were designed as both prospective and retrospective study, all the remaining 13 studies were retrospective studies. As for the survival outcomes, 15 eligible studies were divided into 3 datasets: 3 for PFS [46-48], 3 for OS [26][27][28], 9 for both PFS and OS.…”

“…Totally, 475 patients were TP53-positive cases and 867 were TP53-wild type cases. Among all patients included, 1049 in 11 studies [26][27][28][29][34][35][41][42][43][44][45][46][47][48][49] harbored EGFR active mutations (mainly EGFR Exon19 deletions and Exon 21 L858R mutations) and received EGFR-TKIs therapy (first generation EGFR-TKIs---gefitinib, erlotinib; second generation EGFR-TKIs---afatinib, dacomitinib; third generation EGFR-TKIs--osimertinib, olmutinib). Four studies with 293 patients investigated the impact of TP53 mutational status on outcome of patients with activating ALK rearrangements (mainly EML4-ALK fusions) receiving ALK-TKIs therapy (first generation ALK-TKIs----crizotinib; next generation ALK-TKIs---ceritinib, alectinib, brigatinib, ect), percent of TP53 concurrent mutations in ALK-rearranged advanced NSCLC in these four studies ranged from 23.44%-60%.…”

“…Percent of TP53 concurrent mutations in EGFR-mutated advanced NSCLC in these 11 studies ranged from 25.91%-60%. In terms of the pathology type of tumor, 9 studies focused on ADC only or over 96% of patients included were ADC patients [29,34,39,42,49]; the remaining 6 studies included patients with all NSCLC types (adenocarcinoma, squamous carcinoma, adeno-squamous carcinoma, neuroendocrine carcinoma, poorly differentiated carcinoma, ect) [26,27,28,35,42,43]. When it comes to treatment lines, 379 out of 1049 patients in 5 studies received first line treatment of first-or second-generation EGFR-TKIs [27,35,41,42,43]; the remaining 670 patients received EGFR-TKIs treatment in all lines setting (postoperative adjuvant treatment, first line treatment, second line treatment and other conditions).…”