Background
Our group and others previously demonstrated that endometrial carcinoma (EC) is comprised of four molecular subtypes that are biologically distinct, diagnostically reproducible, and highly significantly prognostic. Among these subtypes, p53 abnormal (p53abn) EC is by far the deadliest, with over 50% of patients succumbing to disease within 5 years. Recent clinical trials demonstrated that patients with p53abn EC responded to immune checkpoint inhibition combined with chemotherapy.1 2 Furthermore, trials of PARP inhibitors and HER2 targeted therapies have shown promise in EC.3 4 However, the immune cell response to p53abn EC and associations to these targetable pathways have yet to be thoroughly investigated.
Methods
We built tissue microarrays from 256 treatment-naïve p53abn EC samples gathered from across Canada (approved by the University of British Columbia research ethics board; approval number H18-01652). Guided artificial intelligence analysis (HALO2 software) of multiplex immunofluorescent panels identified the cell types and density, functional status, and tissue localization of the immune infiltrate using the following markers: (1) CD3, CD8, FOXP3, CD20, CD79a, and CK; (2) PD1, PD-L1, IDO-1, CD8, CD68, and CK. Shallow whole genome sequencing identified homologous recombination deficient and HER2 amplified cases. Immune density and status were compared to clinical data and molecular genotypes using multivariate Cox proportional-hazard analysis.
Results
Mixture modeling divided p53abn EC into lymphocyte-high and lymphocyte-low subsets, with intraepithelial lymphocytes highly correlated to stromal lymphocytes. The lymphocyte-high subset was associated with longer overall and disease-specific survival in multivariate analysis, particularly in advanced stage disease and patients that received no subsequent chemotherapy. Lymphocyte-high cases failed to associate with homologous recombination deficient mutational signatures or HER2 amplification. In lymphocyte-high cases, macrophages and tumor cells expressed increased PDL1, and CD8 T cells expressed increased PD1, indicating active anti-tumor immunity in this group.
Conclusions
p53abn EC can be subdivided based on an immune signature that correlates with improved survival in advanced stage tumors and in patients that received no subsequent chemotherapy. The lymphocyte-high group failed to correlate with homologous recombination deficiency signatures or HER2 amplification. These findings may allow for improved selection of p53abn EC patients for treatment with immune checkpoint inhibitors, chemotherapy, PARP inhibitors, and HER2 targeted therapies, leading to improved outcomes and reduced adverse effects.
References
Eskander RN, Sill MW, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023 Jun 8;388(23):2159–2170.
Mirza MR, S Sharma, et al. 740MO Dostarlimab + chemotherapy for the treatment of primary advanced or recurrent endometrial cancer (pA/rEC): analysis of progression free survival (PFS) and Overall Survival (OS) outcomes by molecular classification in the ENGOT-EN6-NSGO/GOG-3031/RUBY Trial. Annals of Oncology. 2023 Oct (34) S507. https://doi.org/10.1016/j.annonc.2023.09.1919.
Westin SN, Labrie M, et al. Phase Ib dose expansion and translational analyses of olaparib in combination with capivasertib in recurrent endometrial, triple-negative breast, and ovarian cancer. Clin Cancer Res. 2021 Dec 1;27(23):6354–6365.
Meric-Bernstam F, Makker V, et al. Efficacy and safety of trastuzumab deruxtecan in patients with her2-expressing solid tumors: primary results from the DESTINY-PanTumor02 Phase II trial. J Clin Oncol. 2024 Jan 1;42(1):47–58.
Ethics Approval
Ethics approval was provided by The University of British Columbia Research Ethics board; approval number H18-01652. All participants provided written informed consent.