Abstract PR006: Correlation of immunohistochemistry with TP53 sequence and clinical outcomes in GOG-086P
Authors: Thiel Kristina W. , Devor Eric J. , Filiaci Virginia , Levine Douglas A. , Dao Fanny , Olvera Narciso , Mutch David , Aghajanian Carol , Leslie Kimberly K. 
Published: February 2021

Abstract
Introduction: GOG-086P was one of the first attempts to combine molecular inhibitors such as bevacizumab or temsirolimus with chemotherapy in patients with advanced endometrial cancer. An exploratory analysis of this study indicates that bevacizumab combined with chemotherapy is superior to temsirolimus plus chemotherapy in patients with TP53 mutated tumors as determined by next generation sequencing. The functional status of p53 in a tumor can be inferred by sequence analysis and/or by immunohistochemistry (IHC). In this next study of the GOG-086P cohort, we sought to determine whether p53 IHC alone or integrated with TP53 sequencing was similarly predictive of outcome and whether IHC was predictive of the sequence analysis. Methods: A total of 349 patients were enrolled on GOG-086P. Two hundred and forty-three patients have TP53 sequence data, and 213 have p53 protein expression data measured by IHC. Tumor histology and sequence data were correlated with p53 IHC categorizing each case as p53 negative or null, wild type (WT) or over-expressed (OE), and these variables were further correlated with progression-free survival (PFS) and overall survival (OS) in the chemotherapy + bevacizumab arms versus the chemotherapy + temsirolimus arm. Results: The majority of patients (118) had tumors with WT p53 protein expression by IHC and non-mutated or WT TP53 sequence, with expected concordance between IHC and sequence analysis. However, there were five discordant cases with OE p53 protein in the absence of a TP53 mutation. Fourteen patients had null IHC protein expression and a concordant TP53 sequence mutation expected to result in the total loss of protein. Four cases that were p53 null by IHC had a discordant WT TP53 sequence. Seventeen patients had tumors with a missense TP53 mutation but had WT p53 protein expression by IHC, reflecting a potential discordance between sequencing and IHC versus a missense mutation that did not result in loss of protein function. Six of these 17 discordant cases may be explained by co-mutations in TP53 and POLE or microsatellite instability where p53 proteins, though mutated, function more like WT. Reassuringly and as expected, high concordance was found in the 55 cases that had OE protein by IHC and a missense mutation in TP53. On integrated analysis, a TP53 mutation with p53 protein OE was associated with significantly lower hazard ratio for PFS (HR=0.41; 95% CI 0.22-0.83) and OS (HR=0.28; 95% CI 0.14-0.59), i.e., longer PFS and OS, for patients receiving bevacizumab + chemotherapy relative to temsirolimus + chemotherapy. Conclusions: Mutations in TP53, which are common in patients with advanced endometrial cancer, represent a developing platform upon which to design personalized treatment regimens. We demonstrate that IHC is often but not always predictive of the TP53 sequence. However, most cases with over-expressed p53 protein by IHC had a mutation in TP53, and bevacizumab + chemotherapy prolonged PFS and OS in such patients.
Citation Format: Kristina W. Thiel, Eric J. Devor, Virginia Filiaci, Douglas A. Levine, Fanny Dao, Narciso Olvera, David Mutch, Carol Aghajanian, Kimberly K. Leslie. Correlation of immunohistochemistry with TP53 sequence and clinical outcomes in GOG-086P [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PR006.