Study identification and selection
Detailed process of the performed literature searches was illustrated in a flow chart (Fig.1). A total of 1656 relevant articles were identified initially through database searching from Pubmed, Embase, Medline, The Cochrane library, and Web of science up to May 15, 2019. Additional 12 articles were identified through references reading. 306 articles were excluded for duplicates. Following a title/abstract screening and a full text reviewing by all the authors, 15 studies [29–32,37–38,44,46–52,58] were included for final analysis.
Characteristics of the included studies
The characteristics of the 15 studies were summarized in Table 1. The studies were carried out in 7 diﬀerent countries (including USA, Italy, Canada, Germany, UK, China, and Korea) and were published between the year 2013 to 2019. 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 standardized EGFR-TKIs or ALK-TKIs targeted therapy. The technique of gene detection in most studies (11/15) was next generation sequencing (NGS) with which full genome profiling were conducted. Among all, 14 studies used tissue samples for gene detection [29–32,37–38,44,46–52,58], except for study by Tsui DWY et al.  in which blood samples were collected for gene detection. With respect to type of study, study by Aisner et al.  and Tsui DWY et al.  were performed prospectively, and study by Christopoulos P  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 [50–52], 3 for OS [29–31], 9 for both PFS and OS.
All 1342 patients included were stratified according to TP53 mutation status. Totally, 475 patients were TP53-positive cases and 867 were TP53-wild type cases. Among all patients included, 1049 in 11 studies [29–32,37–38,44,46–48, 58] 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%. All these 293 patients were lung adenocarcinoma patients with ALK-rearrangement and were treated with ALK-TKIs in all lines setting (postoperative adjuvant treatment, first line treatment, second line treatment and other conditions) [49–52]. Driver gene alterations and targeted drugs in the studies included were shown in detail in Table 2.
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 [42,46,32,37,58]; the remaining 6 studies included patients with all NSCLC types (adenocarcinoma, squamous carcinoma, adeno-squamous carcinoma, neuroendocrine carcinoma, poorly differentiated carcinoma, ect) [29,30,31,38,46,47]. 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 [30,38,44,46,47]; the remaining 670 patients received EGFR-TKIs treatment in all lines setting (postoperative adjuvant treatment, first line treatment, second line treatment and other conditions).
Notably, patients in study by Youjin Kim et al.  were divided in two independent groups according to different EGFR TKIs treatments: group1, 1st/2nd-generation EGFR TKIs (first-line treatment); group 2, 3rd-generation EGFR-TKIs following initial EGFR-TKIs failure (second-line treatment). Similarly, patients in study by Kron A et al.  were also grouped based on types of ALK-TKIs therapy-patients with first generation ALK-TKIs or next generation ALK-TKIs (ceritinib/alectinib/brigatinib). Prognosis and clinical outcomes of patients in different groups in these two studies were presented independently. Therefore, survival information (PFS/OS with HR and 95%CI) of patients in these two studies were extracted separately accordingly, as shown in Table1.
Methodological quality assessment
The NewcastleOttawa scale scores of the 15 eligible studies were all above 6 (7.73 on average), indicating high quality of studyTable 3).
Taken together, when compared with the TP53 mutation group, the wildtype group was associated with significantly longer PFS (HR,1.88, 95% CI: 1.59–2.23, P<0.001) (Fig. 2a) and longer OS (HR = 1.92, 95% CI: 1.55–2.38, P<0.001) (Fig. 2b) values. No heterogeneity was observed among the included studies regarding either PFS（I2 = 0.0%, P = 0.792) or OS (I2 = 0.0%, P = 0.515). Generally, these findings showed that TP53 mutations were associated with reduced responsiveness and poor prognosis of patients with advanced NSCLC who received targeted therapy of EGFR-TKIs or ALK-TKIs.
To comprehensively explore the association between TP53 mutation and survival of patients with EGFR- TKIs or ALK-TKIs treatments, subgroup analyses were performed based on type of targeted drugs (EGFR-TKIs or ALK-TKIs) (Fig. 3); treatment line of targeted therapy (first line or all lines) (Fig. 4); histopathological type of tumor (ADC or all NSCLC subtypes) (Fig. 5). For patients with EGFR-TKIs therapy in 11 studies, TP53 mutations were associated with higher risk of disease progression (pooled HR for PFS: 1.76, 95% CI: 1.44–2.16, P<0.001; heterogeneity: I2 = 0.0%, P = 0.768), and death (pooled HR for OS:1.83, 95% CI: 1.47–2.29, P<0.001; heterogeneity: I2 = 0.0%, P = 0.727) (Fig. 3 a,b). For 293 patients who harbored ALK oncogenic mutations and underwent ALK-TKIs therapy, the pooled HR for PFS was 2.20 (95% CI: 1.62–3.00, P<0.001; heterogeneity: I2 = 0.0%, P = 0.657) (Fig. 3a); data concerning the overall survival in patients with ALK-TKIs therapy was only available in study by Kron A et al, in which 93 patients were under treatment with first-generation ALK inhibitors and 33 patients were under treatment with next-generation ALK inhibitors. Pooled HR for OS of these two groups of patients was 3.92 (95%CI: 1.19–12.92, P = 0.025; heterogeneity: I2 = 48.4%, P = 0.164) (Fig. 3b).
With regard to type of tumor, concurrent TP53 mutations were poor prognostic factors in patients with both ADC (Pooled HR for PFS = 1.97, 95% CI:1.61–2.41, P<0.001, heterogeneity: I2 = 0.0%, P = 0.755; Pooled HR for OS = 1.81, 95% CI: 1.33–2.46, P<0.001, heterogeneity: I2 = 0.0%, P = 0.435) and all NSCLC subtypes (Pooled HR for PFS = 1.70, 95% CI:1.25–2.31, P = 0.001, heterogeneity: I2 = 0.0%, P = 0.518; Pooled HR for OS = 2.03, 95% CI: 1.51–2.73, P<0.001, heterogeneity: I2 = 0.0%, P = 0.413) (Fig. 4a,b). When the analysis was restricted to line of targeted therapy, TP53 mutations were associated with reduced PFS and OS in patients with both first-line targeted therapy (pooled HR for PFS: 1.69, 95% CI: 1.25–2.27, P = 0.001, heterogeneity: I2 = 0.0%, P = 0.473; pooled HR for OS: 1.94, 95% CI: 1.36–2.76, P<0.001, heterogeneity: I2 = 0.0%, P = 0.484) (Fig. 5a,b) and those who received EGFR-TKIs treatments in all lines setting (pooled HR for PFS: 1.99, 95% CI: 1.62–2.44, P = 0.001, heterogeneity: I2 = 0.0%, P = 0.817; pooled HR for OS: 1.93, 95% CI: 1.45–2.58, P<0.001, heterogeneity: I2 = 9.1%, P = 0.360) (Fig. 5c,d).
Since all patients included in our study who received ALK-TKIs therapy were diagnosed as ADCs and received ALK-TKIs as all line treatments, so we further performed subgroup analysis in patients with EGFR-TKIs therapy based on pathological type of cancer, and treatment line. In the subgroup of patients with adenocarcinoma, the pooled HR for PFS was 1.81 (95% CI: 1.39–2.37, P<0.001; heterogeneity: I2 = 0.0%, P = 0.638); the pooled HR for OS was 1.61 (95%CI: 1.15–2.25, P<0.001; heterogeneity: I2 = 0.0%, P = 0.848). In addition, for those 5 studies investigating the impact of TP53 mutational status on clinical efficacy of EGFR-TKIs in all NSCLCs generally, the pooled HR for PFS (HR = 1.70, 95% CI 1.25–2.31, P<0.001; heterogeneity: I2 = 0.0%, P = 0.518); the pooled HR for OS (HR = 2.03, 95% CI 1.51–2.73, P<0.001; heterogeneity: I2 = 0.0%, P = 0.413) (Fig. 6 a, b).
When stratifying patients according to treatment line, the observed results indicated that TP53 mutations were associated with a significantly reduced PFS and OS in patients who received EGFR-TKIs treatment in the first-line setting and those who received EGFR-TKIs treatment in all lines generally. For patients who received first/second generation of EGFR-TKIs as first line therapy, the pooled HR for PFS (HR = 1.69, 95% CI 1.25–2.27, P<0.001; heterogeneity: I2 = 0.0%, P = 0.473), and the pooled HR for OS (HR = 1.94, 95% CI 1.36–2.76, P<0.001; heterogeneity: I2 = 0.0%, P = 0.484); In the remaining 6 studies which included NSCLC patients treated with EGFR-TKIs therapy regardless of the treatment lines (first line/second line/ postoperative treatments), the pooled HR for PFS (HR = 1.83, 95% CI 1.39–2.41, P<0.001; heterogeneity: I2 = 0.0%, P = 0.749), The pooled HR for OS (HR = 1.76, 95% CI 1.32–2.35, P<0.001; heterogeneity: I2 = 0.0%, P = 0.644) (Fig. 6 c, d).
These findings suggested that the concurrent mutations of TP53 predict a poor prognosis as well as increased risk of disease progression and death in patients with advanced NSCLC undergoing targeted TKIs therapy in all subgroups that we listed.
Sensitivity analysis demonstrated that the heterogeneity and overall effect were not significantly altered by omitting any study in all groups mentioned above. (Additional file 1–11). Thus, a negative correlation between mutated TP53 and the prognosis of patients with advanced NSCLC undergoing EGFR-TKIs or ALK-TKIs therapy existed after any study was excluded from our meta-analysis.
The Begg’s funnel plots revealed an almost symmetrical distribution in terms of overall PFS and overall OS of the 15 studies included in this meta-analysis (Fig.7), and Egger’s tests indicated no evidence of publication bias (overall PFS, P = 0.057; overall OS, P = 0.077).