Observational Data Challenge p53 Expression as a Surrogate Marker for TP53 Mutations in High-Risk Endometrial Cancer

Discordance between aberrant p53 protein expression and TP53 mutations was observed among patients with high-risk endometrial cancer, suggesting that p53 protein expression may not be a reliable surrogate for TP53 mutation status, according to findings from an observational cohort study presented during the 2025 SGO Winter Meeting.1

In the overall study population (n = 382), 66% of patients had abnormal p53 expression compared with 34% who had wild-type expression; 73% harbored TP53 mutations, and 27% had TP53-unmutated disease (r = .7).

“There were 2 discordant populations identified in our study, the first of which were TP53 nonmutated but had aberrant or abnormal p53 protein expression [n = 13],” presenting author Nusjasaubnusi Vue, MD, stated. “The other discordant population that we found in our study were TP53-mutated but had wild-type or normal p53 protein expression [n = 38].”

Vue is a second-year fellow in gynecologic oncology at the Allegheny Health Network in Allegheny, Pennsylvania.

Of note, 91 patients had both wild-type p53 expression and TP53 nonmutated disease. Among patients with wild-type p53 protein expression, 29.5% (n = 38) were also found to display TP53 mutations on tumor testing. Conversely, aberrant p53 expression was also observed in 13% of patients with TP53-nonmutated tumors (n = 13).

Additionally, 240 patients had both aberrant p53 expression and TP53 mutations. Among patients with aberrant p53 expression, 5.1%, had no mutations on tumor testing; 13.7% of patients with TP53 mutations were found to have wild-type or normal protein expression.

Study Background and Overview

The modern molecular classification of endometrial cancer encompasses 4 prognostic subgroups based on genomic abnormalities: POLE ultramutated; microsatellite-instability hypermutated; copy-number low; and copy-number high, characterized by frequent TP53 alterations.1,2

Prior research has demonstrated an 84.3% rate of agreement between p53 expression by immunohistochemistry (IHC) and the presence of TP53 mutations by next-generation sequencing (NGS). However, due to the 82% specificity of IHC testing, TP53 mutation status by NGS may be a more reliable prognostic indicator or classifier than p53 expression by IHC for patients with endometrial cancer. 1

The objective of this observational cohort was to investigate the frequency and concordance of aberrant p53 protein expression and TP53 mutations in high-risk mismatch repair proficient (pMMR) and POLE wild-type endometrial cancer. Data in the cohort study were obtained from the Endometrial Cancer Molecularly Targeted Therapy Consortium (EMCT2). Inclusion criteria for the observational cohort study included cancers with known TP53 mutational status and p53 protein expression. Patients with deficient DNA mismatch repair (dMMR) and POLE-mutated cancers were excluded from the study.

In the high-risk cohort, at a median follow-up was 23 months, the recurrence rate was 46%. The mean age at diagnosis was 65.08 years, and the majority of patients were diagnosed with stage III (34.7%) or IV (38.4%) endometrial cancer. The most common histologies were serous (34.7%), grade 2 endometroid (7.8%), and grade 3 endometrioid (11.0%). At the time of diagnosis, 85.9% of patients underwent surgery and 85% were treated with platinum-based chemotherapy in the first-line setting.

Among 278 patients in the study, 304 total mutations were identified. These included missense (69.4%), frameshift (9.2%), nonsense (12.5%), splice (4.6%), and other (4.3%) mutations.

Survival Outcomes According to TP53 Mutations and p53 Expression

Assessment of survival outcomes by p53 expression showed that the median progression-free survival (PFS) for was 20 months in patients with p53 wild-type disease (n = 129) and 17 months in those with p53-aberrant disease (n = 254; HR, 1.38; 95% CI, 0.99-1.92; P = .06). The median overall survival (OS) in patients with p53 protein expression was 44 months in those with p53 wild-type disease (n = 129) and 35 months in those with aberrant p53 expression (n = 254; HR, 1.19; 95% CI, 0.87-1.63; P = .27).

Concurrent analysis of survival outcomes according to TP53 mutation status showed that the median PFS was 19 months in those with TP53-nonmutated disease (n = 106) and 17 months in those with TP53-mutated disease (n = 277; HR, 1.45; 95% CI, 1.02-2.07; P = .04). The median OS was 63 months in those with TP53-nonmutated disease (n = 106) and 34 months in those with TP53-mutated disease (n = 277; HR, 1.60; 95% CI, 1.12-2.28; P = .01).

“When survival outcomes were compared using TP53 mutation status, there was a statistical significance depreciated in both PFS and OS,” Vue concluded in the presentation. “We found that TP53 mutation status did appear to have more prognostic or survival outcomes. As p53 is increasingly used as a predictive and prognostic biomarker, further research is necessary to understand its clinical relevance [for endometrial cancer].”

References

1. Vue N. Concordance and frequency of TP53 protein expression and gene sequence in mismatch repair proficient (pMMR) and POLE wild-type endometrial cancer: An endometrial cancer molecularly targeted therapy consortium (ECMT2) database study. Presented at: SGO Winter Meeting; January 30-February 1, 2025; Whistler, British Colombia, Canada. Oral Abstract 1.
2. Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73. doi:10.1038/nature12113