Another prognostic marker that can predict added efficacy of therapy in this case bevacizumab.
The status of p53 in a tumor can be inferred by next-generation sequencing (NGS) or by immunohistochemistry (IHC). We examined the association between p53 IHC and sequence and whether p53 IHC alone, or integrated with TP53 NGS, predicts the outcome.
From GOG-86P, a randomized phase II study of chemotherapy combined with either bevacizumab or temsirolimus in advanced endometrial cancer, 213 cases had p53 protein expression data measured by IHC and TP53 NGS data. An analysis was designed to integrate p53 expression by IHC with the presence or absence of a TP53 mutation. These variables were further correlated with progression-free survival (PFS) and overall survival (OS) in the chemotherapy plus bevacizumab arms versus the chemotherapy plus temsirolimus arm.
In the analysis of p53 IHC, the most striking treatment effect favoring bevacizumab was in cases where p53 was overexpressed (PFS hazard ratio [HR]: 0.46, 95% CI, 0.26 to 0.88; OS HR: 0.31, 95% CI, 0.16 to 0.62). On integrated analysis, patients with TP53 missense mutations and p53 protein overexpression had a similar treatment effect on PFS (HR: 0.41, 95% CI, 0.22 to 0.83) and OS (HR: 0.28, 95% CI, 0.14 to 0.59) favoring bevacizumab plus chemotherapy relative to temsirolimus plus chemotherapy. Concordance between TP53 NGS and p53 IHC was 88%. Concordance was 92% when cases with TP53 mutations and POLE mutations or mismatch repair deficiency were removed.
IHC for p53 alone or when integrated with sequencing for TP53 identifies a specific, high-risk tumor genotype/phenotype for which bevacizumab is particularly beneficial in improving outcomes when combined with chemotherapy.
For patients with local recurrences of endometrial cancer, XRT alone is extremely effective, and the addition of cisplatin does not offer any benefit while increasing toxicity. These patients with low-grade and vaginal recurrences have a good prognosis and most should be treated with XRT alone.
Initial results from the DUO-E study in metastatic endometrial cancer. The preliminary report suggests that maintenance durvalumab and maintenance durvalumab + olaparib were superior to standard observation after systemic carbo/taxol. As the trial data matures, the question will be: is this in all patients or driven by those with dMMR or HDR mutations?
This is another possibility for maintenance therapy. It will require further study.
An interesting study where the authors performed a post hoc analysis of randomized trials using molecular classification of endometrial cancers. There was good evidence to omit RT for those with POLE mutations and def-MMR. There seems to be a higher degree of benefit in those with a p53 mutation.
Large phase III study of carbo/taxol+pembro x 6 followed by pembro alone x 14 cycles in metastatic endometrial cancer. There was a benefit in both pMMR and dMMR patients, although the magnitude was unsurprisingly higher in those with dMMR. OS results are still pending, and carcinosarcoma-type histology was excluded. This combination has been approved and is on NCCN as a cat-1 recommendation.
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