Survival Outcomes by <i>TP53</i> Mutation Status in Metastatic Breast Cancer.

Abstract

We sought to determine the significant genomic alterations in patients with metastatic breast cancer (MBC), and survival outcomes in common genotypes. 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. Significantly mutated genes (SMGs) varied by histology and tumor subtype, but <i>TP53</i> was a SMG in all three subtypes. The most SMGs in HR+ patients included <i>PIK3CA</i> (32%), <i>TP53</i> (29%), <i>GATA3</i> (15%), <i>CDH1</i> (8%), <i>MAP3K1</i> (8%), <i>PTEN</i> (5%), <i>TGFBR2</i> (4%), <i>AKT1</i> (4%), and <i>MAP2K4</i> (4%). <i>TP53</i> mutations were associated with shorter recurrence-free survival (P=0.004), progression-free survival (P=0.00057) and overall survival (P=0.003). Further, <i>TP53</i> status was prognostic among HR+ patients with <i>PIK3CA</i> mutations. <i>TP53</i> 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). SMGs differ by tumor subtype but <i>TP53</i> is significantly mutated in all three breast cancer subtypes. <i>TP53</i> mutations are associated with poor prognosis in HR+ breast cancer. <i>TP53</i> mutations should be considered in the design and interpretation of precision oncology trials.