<i>TP53</i> Mutations and Phosphatidylinositol 3-Kinase/AKT Pathway Alterations Are Key Determinants of Breast Cancer Outcome Independent of Subtype and Stage.

Abstract

Breast cancer (BC) is a heterogeneous disease with genetic alterations influencing prognosis and treatment response. <i>TP53</i> mutations (<i>TP53</i>muts) are present in approximately 30% of BC, but their prognostic impact remains controversial. In addition, the phosphatidylinositol 3-kinase (PI3K)/Ak strain transforming (AKT) pathway is frequently altered and represents a promising therapeutic target for BC. Understanding the combined prognostic impact of <i>TP53</i>mut and PI3K/AKT pathway alterations across BC subtypes remains underexplored. This retrospective cohort study integrated clinical and genomic data from 4,265 patients with BC from the Molecular Taxonomy of Breast Cancer International Consortium (n = 2,509) and the Memorial Sloan Kettering Cancer Center (n = 1,756). Genetic profiling identified <i>TP53</i>mut and PI3K/AKT pathway alterations (<i>AKT1</i>, <i>AKT2</i>, <i>AKT3</i>, <i>PIK3CA</i>, <i>PTEN</i>, <i>RICTOR</i>). Survival outcomes were assessed using Kaplan-Meier survival analysis and multivariable Cox proportional hazards models. In 3,807 patients with available gene alteration status, <i>TP53</i>mut was associated with younger age, higher tumor grade, advanced stage, and aggressive subtypes (<i>P</i> < .001). <i>TP53</i>mut was associated with worse survival independent of subtype, stage, age, and grade (hazard ratio [HR], 1.43 [95% CI, 1.24 to 1.66]; <i>P</i> < .0001). The type of <i>TP53</i>mut has also been found to be prognostic in BC. PI3K/AKT pathway alterations were more frequent in <i>TP53</i>mut tumors and independently associated with worse survival (HR, 1.18 [95% CI, 1.03 to 1.35]; <i>P</i> = .0173). The combined presence of <i>TP53</i>mut and PI3K/AKT alterations resulted in the worst survival outcomes (HR, 1.61 [95% CI, 1.32 to 1.97]; <i>P</i> < .0001). <i>TP53</i>mut status is a critical prognostic factor in BC, independent of subtypes and stage, and its adverse impact is amplified by PI3K/AKT pathway alterations. These findings emphasize the integration of genetic profiling into routine clinical practice to refine treatment strategies and identify potential therapeutic targets for this high-risk population.