Survival Outcomes by TP53 Mutation Status in Metastatic Breast Cancer

Abstract

Purpose: We sought to determine the significant genomic alterations in patients with metastatic breast cancer (MBC), and survival outcomes in common genotypes.

Patients and methods: High-depth next generation sequencing was performed for 202 genes in tumor and normal DNA from 257 patients with MBC, including 165 patients with ER/PR+ HER2- (hormone receptor positive, HR+ positive), 32 patients with HER2+ and 60 patients with triple negative (ER/PR/HER2-) cancer. Kaplan Meier survival analysis was performed in our discovery set, in breast cancer patients analyzed in The Cancer Genome Atlas, and in a separate cohort of 98 patients with MBC who underwent clinical genomic testing.

Results: Significantly mutated genes (SMGs) varied by histology and tumor subtype, but TP53 was a SMG in all three subtypes. The most SMGs in HR+ patients included PIK3CA (32%), TP53 (29%), GATA3 (15%), CDH1 (8%), MAP3K1 (8%), PTEN (5%), TGFBR2 (4%), AKT1 (4%), and MAP2K4 (4%). TP53 mutations were associated with shorter recurrence-free survival (P=0.004), progression-free survival (P=0.00057) and overall survival (P=0.003). Further, TP53 status was prognostic among HR+ patients with PIK3CA mutations. TP53 mutations were also associated with poorer overall survival in the 442 HR+ breast cancer patients in the TCGA (P=0.042) and in an independent set of 96 HR+ MBC who underwent clinical sequencing (P=0.0004).

Conclusions: SMGs differ by tumor subtype but TP53 is significantly mutated in all three breast cancer subtypes. TP53 mutations are associated with poor prognosis in HR+ breast cancer. TP53 mutations should be considered in the design and interpretation of precision oncology trials.

Fig 1.

Frequency of the most common alterations in the cohort (T200) versus The Cancer Genome Atlas (TCGA). (A) Overall mutation frequency. (B) Overall copy number alteration (CNA) frequency. (C) Human epidermal growth factor receptor 2–negative (HER2–) hormone receptor–positive (HR+) breast cancer mutation frequency. (D) HER2– HR+ breast cancer CNA frequency. (E) Triple-negative breast cancer (TNBC) mutation frequency. (F) TNBC CNA frequency.

Fig 2.

Heat map and bar plot of the alterations in the 50 most commonly altered genes from patients with hormone receptor–positive breast cancer. The samples are presented in order, with the most common alterations on the left. amp, amplification; del, deletion; mut, mutation.

Fig 3.

Kaplan-Meier survival analysis for patients with hormone receptor–positive (HR+) metastatic breast cancer (MBC) by TP53 genotype. (A) Recurrence-free survival for patients with HR+ MBC. (B) Recurrence-free survival for patients with HR+ MBC with TP53 mutations by TP53 mutation type (missense v other). (C) Overall survival for patients with HR+ MBC by TP53 mutation status. (D) Progression-free survival on first-line endocrine therapy for patients with HR+ MBC. (E) Overall survival for patients with HR+ PIK3CA-mutant MBC by TP53 mutation status. (F) Progression-free survival for patients with HR+ PIK3CA-mutant MBC by TP53 mutation status. MUT, mutant; WT, wild type.

Fig 4.

Kaplan-Meier survival analysis for patients with hormone receptor–positive metastatic breast cancer by TP53 genotype in validation cohorts. (A) Recurrence-free survival in The Cancer Genome Atlas by TP53 mutation status. (B) Overall survival in an independent cohort of 98 patients with hormone receptor–positive metastatic breast cancer by TP53 mutation status. MUT, mutant; WT, wild type.