Impact of KRAS and TP53 Co-Mutations on Outcomes After First-Line Systemic Therapy Among Patients With STK11-Mutated Advanced Non-Small-Cell Lung Cancer

Abstract

Purpose: The STK11 gene encodes a serine/threonine protein kinase that regulates cell polarity and functions as a tumor suppressor. Patients with non-small-cell lung cancer (NSCLC) and STK11 mutations often have other co-mutations. We evaluated the impact of KRAS and TP53 co-mutations on outcomes after first-line systemic therapy for patients with metastatic or recurrent NSCLC that harbors STK11 mutations.

Methods: We conducted a retrospective review of patients with metastatic NSCLC and STK11 mutations treated at the University of Pennsylvania. STK11 mutations were identified through next-generation sequencing (NGS) in tissue or plasma. Cox proportional hazard models were used to determine the relationship between STK11 co-mutations and survival outcomes. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS).

Results: From February 2013 to December 2016, samples from 1,385 patients with NSCLC were analyzed by NGS; of these, 77 patients (6%) harbored an STK11 mutation (n = 56, tissue; n = 21, plasma). Of the 62 patients included, 18 had an STK11 mutation alone, 19 had STK11/KRAS, 18 had STK11/TP53, and seven had STK11/KRAS/TP53. Patients with STK11/KRAS co-mutations had a worse median PFS (2.4 months) compared with STK11 alone (5.1 months; log-rank P = .048), STK11/TP53 (4.3 months; log-rank P = .043), and STK11/KRAS/ TP53 (13 months; log-rank P = .03). Patients with STK11/KRAS co-mutation experienced shorter median OS (7.1 months) compared with STK11 alone (16.1 months; log-rank P < .001), STK11/TP53 (28.3 months; log-rank P < .001), and STK11/KRAS/TP53 (22 months; log-rank P = .025).

Conclusion: Among patients with advanced NSCLC and STK11 mutations treated with first-line systemic therapy, co-mutation with KRAS was associated with significantly worse PFS and OS. By contrast, co-mutation of STK11 with TP53 conferred a better prognosis.

FIG 1.

Flowchart of the study cohort. NGS, next-generation sequencing; NSCLC, non–small-cell lung cancer.

FIG 2.

Distribution of STK11, KRAS and TP53 mutations. (A) Columns represent individual patients with mutation type specified by color; missense mutations in STK11 were found in six patients, but specific point mutations were not identified. Five missense mutations were in splice sites, and one was a deletion in exon 5. (B) Lollipop plots mapping specific mutation location (x-axis) and frequency (y-axis) for STK11, KRAS and TP53. aa, amino acids.

FIG 3.

Progression-free survival (PFS) and overall survival (OS) by STK11 co-mutation status. Kaplan-Meier curves of (A) PFS and (C) OS of patients with stage IV or recurrent disease and tumors with STK11 mutation. (*) STK11/KRAS versus STK11/KRAS/TP53, log-rank P = .03. Kaplan-Meier curves of (B) PFS and (D) OS of patients with stage IV or recurrent disease and tumors with disease-associated STK11 mutation. (†) STK11/KRAS versus STK11/TP53, log-rank P = .01.

Fig A1.

Kaplan-Meier curves of (A) progression-free survival (PFS) and (B) overall survival (OS) of patients with stage IV or recurrent disease and tumors with STK11 mutations stratified by STK11 mutation location.