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. 2018:2018:PO.18.00107.
doi: 10.1200/PO.18.00107. Epub 2018 Aug 31.

Influence of TP53 Mutation on Survival in Patients With Advanced EGFR-Mutant Non-Small-Cell Lung Cancer

Charu Aggarwal  1 , Christiana W Davis  1 , Rosemarie Mick  1 , Jeffrey C Thompson  1 , Saman Ahmed  2 , Seth Jeffries  1 , Stephen Bagley  1 , Peter Gabriel  1 , Tracey L Evans  1 , Joshua M Bauml  1 , Christine Ciunci  1 , Evan Alley  1 , Jennifer J D Morrissette  1 , Roger B Cohen  1 , Erica L Carpenter  1 , Corey J Langer  1
Affiliations

Influence of TP53 Mutation on Survival in Patients With Advanced EGFR-Mutant Non-Small-Cell Lung Cancer

Charu Aggarwal et al. JCO Precis Oncol. 2018.

Abstract

Purpose: TP53 mutation (MT) in epidermal growth factor receptor (EGFR) -MT non-small cell lung cancer (NSCLC) is associated with poor response to targeted therapy; however, its impact on survival is not clearly established.

Patients and methods: We performed an analysis of patients with stage IV EGFR MT NSCLC with available gene sequencing data. Associations between baseline characteristics; molecular profile, including TP53 MT; and survival outcomes were assessed.

Results: We identified 131 consecutive patients with EGFR MT; 81 (62%) had a TP53 MT, and 55 (42%) had other coexisting oncogenic MTs. Emergent EGFR T790M MT was observed in 42 patients (32%). Overall survival (OS) was longer for younger patients (P = .003), never smokers (P = .002), those with Eastern Cooperative Oncology Group performance status 0 to 1 (P = .004), and emergent T790M MT (P = .018). TP53 MT (P = .021) and other coexisting oncogenic MTs (P = 0.011) were associated with inferior OS. In a multivariable regression analysis adjusted for age, smoking, Eastern Cooperative Oncology Group performance status, and the presence of TP53 MT (P = .063) and other coexisting MTs (P = .064) did not achieve statistical significance. Patients with EGFR T790M/TP53 double MT had worse OS compared with patients with T790M MT alone (46.4 months v 82.9 months). In our series, five patients transformed to small-cell lung cancer (5.6%). All had TP53 MT. In four patients, allelic fraction of TP53 MT increased at the time of transformation.

Conclusion: The presence of TP53 and other coexisting MTs in EGFR MT NSCLC were associated with inferior OS, including patients with emergent T790M MT. An increase in TP53 mutation allelic fraction may potentially be a useful clinical predictor of small-cell transformation.

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Conflict of interest statement

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Figures

Fig 1.
Fig 1.
CONSORT diagram. (*) Patients had concurrent tissue and plasma NGS (next-generation sequencing) performed (n = 42); tissue NGS results were used for analyses. (†) At event of clinical progression of NSCLC (non–small-cell lung cancer). (‡) Including 38 patients treated with an oral TKI (tyrosine kinase inhibitor ) before progression of disease. EGFR, epidermal growth factor receptor; MT, mutant; SCLC, small-cell lung cancer.
Fig 2.
Fig 2.
(A) Distribution of epidermal growth factor receptor (EGFR). (B) TP53 mutations (MTs; 131 patients had EGFR MTs and 81 had TP53 MTs). (C) Prevalence of coexisting MTs in the entire cohort, and in patients with TP53 MT, 55 patients were found to have coexisting MTs, 37 of whom also harbored a TP53 MT. (D) Comutation plot and list of all patients with TP53 MTs and other coexisting oncogenic MTs. (*) One patient had a de novo EGFR T790M mutation. Prepared using http://www.cbioportal.org/oncoprinter.jsp#. WT, wild type.
Fig 3.
Fig 3.
Kaplan-Meier curves of overall survival (OS). (A) Kaplan-Meier curve representing OS of patients with stage IV disease at diagnosis and tumors with TP53 mutation (MT; n = 81) and TP53 wild-type (WT) cohorts (n = 50). (B) Kaplan-Meier curve representing OS of patients with stage IV disease at diagnosis and tumors with coexisting MT (n = 55) and without coexisting MT (n = 76). (C) Kaplan-Meier curve representing OS of patients with stage IV disease at diagnosis and tumors with TP53 exon 8 MT (n = 18) and TP53 MT other than exon 8 (n = 63). (D) OS for four subgroups depending on TP53 MT status and the presence of T790M MT. Neg, negative.
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