Mutated p53 portends improvement in outcomes when bevacizumab is combined with chemotherapy in advanced/recurrent endometrial cancer: An NRG Oncology study

Abstract

Background: Successfully combining targeted agents with chemotherapy is an important future goal for cancer therapy. However, an improvement in patient outcomes requires an enhanced understanding of the tumor biomarkers that predict for drug sensitivity. NRG Oncology/Gynecologic Oncology Group (GOG) Study GOG-86P was one of the first attempts to combine targeted agents (bevacizumab or temsirolimus) with chemotherapy in patients with advanced endometrial cancer. Herein we performed exploratory analyses to examine the relationship between mutations in TP53, the most commonly mutated gene in cancer, with outcomes on GOG-86P.

Methods: TP53 mutational status was determined and correlated with progression-free survival (PFS) and overall survival (OS) on GOG-86P.

Results: Mutations in TP53 were associated with improved PFS and OS for patients that received bevacizumab as compared to temsirolimus (PFS: HR 0.48, 95% CI 0.31, 0.75; OS: HR: 0.61, 95% CI 0.38, 0.98). By contrast, there was no statistically significant difference in PFS or OS between arms for cases with WT TP53.

Conclusions: This exploratory study suggests that combining chemotherapy with bevacizumab, but not temsirolimus, may enhance PFS and OS for patients whose tumors harbor mutant p53. These data set the stage for larger clinical studies evaluating the potential of TP53 mutational status as a biomarker to guide choice of treatment for endometrial cancer patients. Clintrials.gov: NCT00977574.

Keywords: Bevacizumab; Chemotherapy; Endometrial cancer; p53.

Conflict of interest statement

Declaration of competing interest Kimberly K. Leslie: Dr. Leslie attests that she has no conflicts of interest. Virginia L. Filiaci: Dr. Filiaci is supported by institutional grants from NIH during the conduct of the study; Institutional contracts from GOG Foundation, Inc. outside the submitted work. Adrianne R. Mallen: Dr. Mallen reports no conflicts of interest. Kristina W. Thiel: Dr. Thiel is a co-founder of and holds equity in Immortagen, Inc. Eric J. Devor: Dr. Devor reports no conflict of interest. Katherine Moxley: Dr. Moxley attests that she has nothing to declare. Debra Richardson: Dr. Richardson reports that she serves on Advisory Boards for Genentech, Tesaro/GSK, AstraZeneca, Bayer, Deciphera, Mersana and Foundation Medicine. David Mutch: Dr. Mutch attests that he has no conflicts of interest. Angeles Alvarez Secord(:) Dr. Alvarez Secord discloses clinical trial grant funding received from AbbVie, Amgen, Astellas Pharma Inc., Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Eisai, Exelixis, Immutep Ltd., Incyte, Merck, PharmaMar, Roche/Genentech, Seattle Genetics, Inc., Tesaro/GSK, VBL Therapeutics and National Cancer Trial Network. Dr. Alvarez Secord has also received honoraria for Advisory Boards from Aravive, AstraZeneca, Clovis, Cordgenics, Eisai, Merck, Myriad, Oncoquest, Roche/Genentech and Tesaro/GSK within the past 24 months. Krishnansu S Tewari: Dr. Tewari served as a consultant and attended advisory boards for the manufacturers of bevacizumab (i.e., Genentech/Roche). Megan E McDonald: Dr. McDonald has no conflicts of interest to disclose. Cara Mathews: Dr. Mathews reports grants from National Institute of Health during the conduct of the study; grants from Syros, grants from Deciphera, grants from Astra Zeneca, grants from Astellas Pharma, grants from Tesaro/GSK, grants from Seattle Genetics and grants from Regeneron outside the submitted work. Casey Cosgrove: Dr. Cosgrove attests that she has no conflicts of interest. Summer Dewdney: Dr. Dewdney attests that she has nothing to declare. Yovanni Casablanca: Dr. Casablanca reports that spouse owns shares in Celsion (biotech company), but not related to this manuscript. Amanda Jackson: Peter G Rose: Dr. Rose attests that he has no conflicts of interest. Xun Clare Zhou: - Dr. Zhou attests that she has no conflicts of interest. Michael McHale: - Dr. McHale has no conflicts of interest to report. Heather Lankes: Dr. Lankes attests that she has no conflicts of interest. Douglas Levine: - Dr. Levine reports serving in a consulting/advisory role for Tesaro/GSK, Merck. Research funding to institution from Merck, Tesaro, Clovis Oncology, Regeneron, Agenus, Takeda, Immunogen, VBL Therapeutics, Genentech, Celsion, Ambry, Splash Pharmaceuticals. Founder Nirova BioSense, Inc. Carol Aghajanian: Dr. Aghajanian reports personal fees from Tesaro, personal fees from Immunogen, grants and personal fees from Clovis, grants from Genentech, grants from AbbVie, grants from Astra Zeneca, grants from Astra Zeneca, personal fees from Eisai/Merck, personal fees from Mersana Therapeutics, personal fees from Roche, personal fees from Abbvie, outside the submitted work.

Copyright © 2021. Published by Elsevier Inc.

Figures

Figure 1:. The majority ofTP53 mutations in GOG-86P dataset are in the DNA binding domain.

The frequency of mutated codons was calculated as the number of variants at each nucleotide position relative to the total number of variants detected in the dataset. Mutations that occurred in ≥4 samples are annotated in the graph. R248: 14 variants; R273: 11 variants; R175: 6 variants; Y220: 4 variants; D281: 4 variants. TAD: transactivation domain; PRD: proline-rich domain; DBD: DNA binding domain; OD: tetramerization domain; CTD: C-terminal domain.

Figure 2:. Tumors with mutant TP53 have worse outcomes as compared to tumors with WT TP53.

Kaplan-Meier survival plots of (A) PFS and (B) OS when all eligible cases on GOG-86P were subanalyzed by TP53 mutational status.

Figure 3:. TP53 mutational status is associated with improved PFS on bevacizumab-containing arms.

Kaplan-Meier survival plots of PFS when cases are sub-analyzed by TP53 mutational status (A, WT; B, Mutant TP53) on Arms 1 and 3 (bevacizumab-containing arms) vs. Arm 2 (temsirolimus-containing arm).

Figure 4:. TP53 mutational status is associated with improved OS on bevacizumab-containing arms.

Kaplan-Meier survival plots of OS when cases are sub-analyzed by TP53 mutational status (A, WT; B, Mutant TP53) on Arms 1 and 3 (bevacizumab-containing arms) vs. Arm 2 (temsirolimus-containing arm).