TP53 Alterations Predict Rapid Treatment Resistant Evolution in Patients With EFGR-Mutated NSCLC

Patients with epidermal growth factor receptor (EFGR)-mutated non-small cell lung cancer (NSCLC) and TP53-mutated tumors exhibited a rapid progression of resistance to various treatments, regardless of treatment mechanism, according to an analysis of data collected from the Dana-Farber Cancer Institute.

“TP53 alterations seem to be the genomic event most consistently associated with poor outcomes across different studies. Nevertheless, the mechanism for why TP53 alterations associate with worse outcomes remains underexplored,” explained Natalie I. Vokes, MD, Department of Thoracic and Head and Neck Medical Oncology and Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, and colleagues.

The retrospective study identified 269 patients, 185 of which proved response-assessable with pre-treatment specimens, with targetable EGFR-mutated NSCLS who had been treated at the Dana-Farber Cancer Institute between 2005 and 2019.

 Among these patients TP53 alterations predicted decreases in first-line progression-free survival and overall survival. Even in patients who exhibited initial positive response to radiographic treatment, TP53 alterations were associated with worse outcomes and faster acquisition of treatment resistance mechanisms. Exposure to therapy and tobacco added additional mutational burden and increased mutagenesis in patients with TP53-mutated tumors as well.

Among all available samples in the cohort (n = 311), TP53-mutated samples had a higher tumor mutational burden (TMB) with a median of 8.47 vs 6.84 in those samples without TP53 mutations, (p = 0.00051), and a higher copy-number alteration (CNA) load, with a median of 0.136 vs 0.077 (p = 0.0014). When treated with targeted tyrosine kinase inhibitors (TKI), tumors with TP53 alterations yielded a pronounced increase in TMB in post- versus pre-treatment samples (median 9.68 vs 7.60, p = 5.228E—5). CNA load remained unaffected by TKI treatment.

“Our analysis further defines the effects of concurrent mutations on outcomes in EGFR-mutated NSCLC, suggesting an important role for TP53 mutations in facilitating the acquisition of resistance,” concluded Vokes et al, adding, “Our analyses further suggest that the deleterious effects of other concurrent mutations may be contingent on TP53 mutation status and should be studied in this context.”

Source: 

Vokes NI, Chambers E, Nguyen T, et al. Concurrent TP53 Mutations Facilitate Resistance Evolution in EGFR-Mutant Lung Adenocarcinoma. J Thorac Oncol. 2022;17(6):779-792. doi:10.1016/j.jtho.2022.02.011