P53 non-disruptive mutation is a negative predictive factor in EGFR M+ NSCLC treated with TKI

Griesinger, Frank; Netchaeva, Maria; Lüers, A; Prenzel, R; Scriba, D.; Willborn, K.; Stropiep, Ursula; Hallas, Cora; Falk, Markus; Tiemann, Markus; Neemann, Nicole; Heukamp, Lukas C.; Roeper, J.

doi:10.1093/annonc/mdw383.32

Cited by 3 publications

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“…In our study, TP53 concurrent mutations were associated with a markedly shorter time to progression and OS on initial EGFR-TKIs, as well as reduced DCR and ORR to TKI therapy. In addition, we found that non-disruptive mutations of the p53 gene are an independent factor of shorter survival in advanced NSCLC with a possible predictive negative value of response to TKIs; the same conclusions could be seen in two previously published studies 30 , 31. However, the molecular pathogenesis is still unclear.…”

Section: Discussionsupporting

confidence: 81%

“…Given that different types of TP53 genetic mutations tend to have different effects on the functionality of the protein, we classified TP53 mutations into disruptive/non-disruptive, missense/non-missense mutations as well as mutations in different sites based on previous studies (Table 5). 5 , 29 – 31 In contrast to TP53 disruptive mutations, TP53 non-disruptive mutations demonstrate greater potency in shortening mPFS and OS of the patients (PFS: 6.3 versus 14.0 months, P =0.028; HR 2.38, 95% CI 1.06–5.32, P <0.030; OS: 35.0 versus 52.5 months, P =0.008; HR 5.00, 95%CI 1.38–18.18, P =0.008) when compared with TP53-wt controls (Figure 2A and B, Tables S2 and S3 ). Similar conclusions could be made on TP53 non-missense mutations: patients with non-missense mutations showed shorter PFS and OS (mPFS: 6.3 versus 14 months, P =0.041; HR 2.01, 95% CI 1.00–4.05, P =0.046; mOS: 21.2 versus 52.5 months, P =0.001; HR 5.53, 95% CI 1.79–16.95 P =0.001) than that of TP53-wt cases (Figure 2C and D, Tables S2 and S3 ).…”

Section: Resultsmentioning

confidence: 99%

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<p>Concurrent TP53 mutations predict poor outcomes of EGFR-TKI treatments in Chinese patients with advanced NSCLC</p>

Hou¹,

Qin²,

Yu³

et al. 2019

CMAR

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Purpose: The study investigated the impact of TP53 mutations on the clinical efficacy of first-generation EGFR-tyrosine kinase inhibitors (TKIs) in Chinese patients with advanced or recurrent non-small-cell lung cancer (NSCLC). Patients and methods: Tissues from 163 NSCLC patients at the Affiliated Hospital of Qingdao University were analyzed by next-generation sequencing (NGS) to determine the mutational status of EGFR and concurrent genetic alterations. TP53 mutations were evaluated in relation to baseline patient characteristics and treatment outcomes (progression-free survival [PFS], overall survival [OS], objective response rate [ORR] and disease control rate [DCR]). Results: Among 163 patients with advanced NSCLC, 77 were identified as EGFR-mutant (47.2%). Six patients who did not receive TKI treatment were excluded. Among the remaining 71 patients with EGFR genetic alterations, the frequency of pathogenic TP53 mutations was 60.6% (43/71), while other concurrent mutations were rare events. Markedly shorter median PFS (mPFS) (6.5 versus 14.0 months, P =0.025) and median OS (mOS) (28.0 versus 52.0 months, P =0.023) were observed in TP53-mut patients than in TP53-wt controls. The overall DCR and ORR of TP53-mutant patients were both lower than those of the TP53-wt cases (DCR: 76.7% versus 89.3%, P =0.160; ORR: 25% versus 28%, P =0.374). Differences in prognosis were significant, especially in the subgroup of patients with TP53 non-missense mutations, non-disruptive mutations, mutations in exon 6, mutations in exon 7 and mutations in the non-DBD region among all TP53 mutations. Conclusion: TP53 mutations reduce responsiveness to TKIs and worsen the prognosis of EGFR-mutant NSCLC patients, especially for those with non-missense mutations and non-disruptive mutations, as well as mutations in exon 6, exon 7 and non-DBD region, thus acting as an independent predictor of poor outcome in advanced NSCLC patients treated with first-generation TKI therapy. Our study also suggests that TP53 mutation might be involved in primary resistance to EGFR-TKIs in Chinese NSCLC patients.

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Section: Discussionsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

<p>Concurrent TP53 mutations predict poor outcomes of EGFR-TKI treatments in Chinese patients with advanced NSCLC</p>

Hou¹,

Qin²,

Yu³

et al. 2019

CMAR

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“…The functional significance of TP53 nondisruptive mutations remains elusive; however, experimental evidence has suggested that they often are associated with gain‐of‐functional activities with PD and poor clinical outcomes 41‐43 . It is important to note that the presence of nondisruptive TP53 mutations was found to be significantly associated with poor prognosis in patients with metastatic EGFR ‐mutant NSCLC who were treated with EGFR TKIs, which is consistent with the current study findings regarding the predictive role of disruptive TP53 mutations in patients with R/M‐ESCC who were treated with EGFR TKIs 44,45 …”

Section: Discussionsupporting

confidence: 87%

Phase 2 study of afatinib among patients with recurrent and/or metastatic esophageal squamous cell carcinoma

Hong

Heo

Lee

et al. 2020

Cancer

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BACKGROUND: The objective of the current study was to investigate the clinical activity of, safety of, and predictive biomarkers for afatinib, an irreversible pan-ErbB kinase inhibitor, in patients with recurrent and/or metastatic esophageal squamous cell carcinoma (R/M-ESCC). METHODS: Patients with R/M-ESCC that was refractory to platinum-based chemotherapy were enrolled in the current multicenter, single-arm, phase 2 study and received afatinib at a dose of 40 mg/day. The primary endpoint was the objective response rate. Secondary endpoints included progression-free survival, overall survival, the disease control rate, and the safety profile. To identify predictive biomarkers, single-nucleotide variations, short insertions/deletions, and somatic copy number alterations were assessed using whole-exome sequencing and their associations with clinical outcomes were analyzed. RESULTS: Among 49 enrolled patients, the objective response rate and disease control rate were 14.3% and 73.3%, respectively. With a median follow-up of 6.6 months, the median progression-free survival and overall survival were 3.4 months and 6.3 months, respectively. Treatment-related adverse events were noted to have occurred in 33 patients (67.3%), with the majority being of grade 1 to 2 (adverse events were graded and recorded based on the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). Whole-exome sequencing demonstrated that the ESCC genomes of patients who demonstrated a response to afatinib were enriched with genomic alterations of TP53 and epidermal growth factor receptor (EGFR). As a predictive marker, a score derived from TP53 disruptive mutations and EGFR amplifications and/ or missense mutations demonstrated a significant association with the response to afatinib. The score based on the mutational status of EGFR and TP53 achieved a performance of an area under the curve of 0.86 in predicting the sensitivity of afatinib. CONCLUSIONS: The results of the current study demonstrated that afatinib can confer modest clinical benefits with manageable toxicity in patients with platinum-resistant R/M-ESCC. Identification of TP53 alterations and EGFR amplifications may serve as predictive markers with which to identify patients with R/M-ESCC who may benefit from afatinib. Cancer 2020;126:4521-4531.

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“…Our data confirm that EGFR mutated cancers have different mutational backgrounds and raise the question of the clinical impact of intertumor heterogeneity to predict first line response and secondary resistance mechanisms. Previous works suggested links between TP53 mutations [15] or sub-groups of TP53 mutations and low OS or PFS [20][21][22]. Here no association between TP53 mutations (or mutation subgroups) and clinical data was identified, contrasting with results published by Griesinger et al that suggested an impact of non-disruptive mutations on PFS.…”

Section: Discussioncontrasting

confidence: 82%

PTEN, ATM, IDH1 mutations and MAPK pathway activation as modulators of PFS and OS in patients treated by first line EGFR TKI, an ancillary study of the French Cooperative Thoracic Intergroup (IFCT) Biomarkers France project

et al. 2021

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P53 non-disruptive mutation is a negative predictive factor in EGFR M+ NSCLC treated with TKI

Cited by 3 publications

References 0 publications

<p>Concurrent TP53 mutations predict poor outcomes of EGFR-TKI treatments in Chinese patients with advanced NSCLC</p>

<p>Concurrent TP53 mutations predict poor outcomes of EGFR-TKI treatments in Chinese patients with advanced NSCLC</p>

Phase 2 study of afatinib among patients with recurrent and/or metastatic esophageal squamous cell carcinoma

PTEN, ATM, IDH1 mutations and MAPK pathway activation as modulators of PFS and OS in patients treated by first line EGFR TKI, an ancillary study of the French Cooperative Thoracic Intergroup (IFCT) Biomarkers France project

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