In an analysis from an NRG Oncology/Gynecologic Oncology Group phase II study (GOG-86P) reported in the Journal of Clinical Oncology, Thiel et al looked at outcomes in patients with advanced endometrial cancer treated with bevacizumab added to front-line chemotherapy. The investigators found that p53 overexpression on immunohistochemistry alone and with combined p53 overexpression and presence of TP53 mutation identified on next-generation sequencing were associated with benefit in these patients.
The analysis involved patients in the trial randomly assigned to receive bevacizumab or temsirolimus in addition to carboplatin/paclitaxel chemotherapy. A total of 213 patients had p53 protein expression data from IHC and TP53 NGS data. Overexpression of p53 on IHC, defined as uniform and intense nuclear staining in ≥ 80% of tumor cell nuclei, was identified in 60 patients (28%). TP53 mutations were identified on NGS in 85 patients (40%), including missense variants in 66 (31%) and truncating variants in 19 (9%).
Both progression-free survival (hazard ratio [HR] = 0.46, 95% confidence interval [CI] = 0.26–0.88) and overall survival (HR = 0.31, 95% CI = 0.16–0.62) were significantly improved in patients with p53 overexpression in the bevacizumab vs temsirolimus group.
On an integrated analysis, patients with both TP53 missense mutations and p53 protein overexpression in the bevacizumab vs temsirolimus group had significantly improved progression-free survival (HR = 0.41, 95% CI = 0.22–0.83) and overall survival (HR = 0.28, 95% CI = 0.14–0.59).
Concordance between TP53 NGS and p53 IHC findings was 88%; concordance increased to 92% when cases with TP53 mutation and POLE mutation or mismatch repair deficiency were excluded from analysis.
The investigators concluded, “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. … Determining p53 status by IHC is a fast, cost-effective, and reliable method that can be easily integrated into clinical management of advanced endometrial cancer.”
Kimberly K. Leslie, MD, of The University of New Mexico Comprehensive Cancer Center, Albuquerque, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the National Institutes of Health, National Cancer Institute, Department of Defense, and others. For full disclosures of the study authors, visit ascopubs.org.
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