Patients with ovarian clear cell carcinoma harboring PPP2R1A mutations showed significantly improved survival when treated with immunotherapy compared with those without PPP2R1A mutations, according to study findings published in Nature.
Preclinical findings from the study also suggested that targeting PPP2R1A could also be an effective therapeutic approach following immunotherapy for these patients. The gene may be an important biomarker and possible target for additional cancer types beyond ovarian cancer as well.
“Developing effective immunotherapies for ovarian cancer, including rare subtypes like ovarian clear cell carcinoma, remains a significant unmet clinical need,” said co-senior author Amir Jazaeri, MD, Professor of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center. “Our study is the first to demonstrate the clinical importance of PPP2R1A mutations, and it opens the door to new strategies that could benefit many more patients.”
Study Methods and Findings
Researchers explored responses to immune checkpoint inhibition in a cohort of 34 patients with treatment-resistant ovarian clear cell carcinoma from a phase II clinical trial. The study included treatment with the PD-L1 inhibitor durvalumab and the CTLA-4 inhibitor tremelimumab.
The analysis of the cohort showed that patients with PPP2R1A gene mutations had significantly prolonged progression-free and overall survival. The median overall survival was 66.9 months for PPP2R1A-mutated patients compared with 9.2 months for patients not expressing this mutation.
From there, the researchers also looked at two more independent cohorts: one of patients with endometrial cancer, and the other comprised of more than 9,000 patients who received immunotherapy treatments for various cancer types. The findings of improved survival in those with PPP2R1A mutations were confirmed in these cohorts as well.
Translational analysis of tumors with PPP2R1A mutations that were treated with immunotherapy showed enhanced IFNγ signaling, tertiary lymphoid structures at baseline, and enhanced immune infiltration and expansion of CD45RO+CD8+ T cells in the tumor microenvironment.
Both in vitro and in vivo preclinical analysis showed that PPP2R1A could be targeted through pharmacological inhibition or genetic modification and it would lead to improved survival, regardless of the form of immunotherapy used in the combination approach.
“Not only did we identify a new biomarker in ovarian cancer, but we also confirmed [its] survival benefits in other cancer types,” Dr. Jazaeri said. “Since PPP2R1A mutations are relatively uncommon, we believe the same benefits may be possible by targeting the PPP2A pathway—using drugs, and we currently are evaluating this in a clinical trial at MD Anderson.”
Disclosure: The study was supported by grants from the National Institutes of Health/National Cancer Institute, and other organizations. For full disclosures of the study authors, visit nature.com.
