TP53 Sequencing and p53 Immunohistochemistry Predict Outcomes When Bevacizumab Is Added to Frontline Chemotherapy in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT00977574.

FIG 1.

Concordance between p53 expressions by IHC with mutation in TP53. (A) Examples of WT p53 staining (both low and high patterns), null p53, and overexpression of p53. Also shown are cases with equivocal staining for p53 and focal regions of p53 overexpression. (B) Overall distribution of p53 expression by IHC in cases with available data. (C) Percent of cases with WT p53 staining, null staining, or OE by histology. (D) Concordance on the basis of the absence (WT) or presence of a TP53 mutation with p53 expression by IHC. (E) Concordance on the basis of the specific type of TP53 mutation. IHC, immunohistochemistry; OE, overexpressed; WT, wild-type.

FIG 2.

Comparison of HRs for bevacizumab plus chemotherapy versus temsirolimus plus chemotherapy by TP53 mutational status, expression by IHC, or integrated sequencing/IHC analysis. Forest plots of (A) PFS and (B) OS. Also show are HR and 95% CI. Significantly improved HRs are indicated in red. GOF, gain of function; HR, hazard ratio; IHC, immunohistochemistry; NGS, next-generation sequencing; OS, overall survival; PFS, progression-free survival; sVUF, somatic variants of unknown function; WT, wild-type.

FIG 3.

p53 overexpression by IHC predicts for response to bevacizumab plus chemotherapy. (A) Kaplan-Meier curves for PFS (left) and OS (right) on the basis of p53 status by IHC. (B) Kaplan-Meier curves for PFS (left) and OS (right) for cases with p53 overexpression by IHC by treatment arm. IHC, immunohistochemistry; OE, overexpressed; OS, overall survival; PFS, progression-free survival; WT, wild-type.

FIG 4.

Integrated analysis of p53 using IHC and sequencing data improves the prediction of response to bevacizumab plus chemotherapy. (A) Decision tree for integrated analysis of p53 by IHC and sequencing. Kaplan-Meier curves for (B) PFS and (C) OS for the integrated categories independent of treatment. Kaplan-Meier curves for (D) PFS and (E) OS for the integrated category of p53^OE/TP53^mut by treatment arm. IHC, immunohistochemistry; OE, overexpressed; OS, overall survival; PFS, progression-free survival.

FIG 5.

A potential clinical management schema supported by the findings from GOG-86P. For ease and feasibility, tumor testing for p53 status can begin with standard IHC. If p53 is highly expressed in the nuclei of 80% of more of tumor cells, our data indicate that bevacizumab, when added to chemotherapy in the upfront setting, significantly improves PFS and OS. If the immunostaining is negative entirely, or null, we cannot make a strong recommendation because of the low number of cases, but we are aware that some p53 null cases appeared to benefit on the bevacizumab arms of GOG-86P. Therefore, we recommend weighing the risk of bevacizumab, including hypertensive complications, in each individual patient before adding bevacizumab to upfront chemotherapy. If immunostaining is modest and not uniform, this suggests a WT p53 expression pattern. Our data suggest no clear benefit by adding bevacizumab to chemotherapy upfront. If p53 immunostaining is indeterminant, which may occur due to high cellular heterogeneity of p53 expression, cytoplasmic instead of nuclear staining or other conditions, we recommend sequencing TP53. If results reveal a mutation (^aother than the known SNP at P72), consideration should be given for adding bevacizumab to chemotherapy upfront. Note that tumors that coexpress POLE and TP53 mutations or potentially those with microsatellite instability or mismatch repair deficiency comprise a special category, and at this time, the data do not inform management. IHC, immunohistochemistry; OS, overall survival; PFS, progression-free survival; SNP, single nucleotide polymorphism; WT, wild-type.