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High PD-L2 Predicts Early Recurrence of ER-Positive Breast Cancer

T-cell–mediated cytotoxicity is suppressed when programmed cell death-1 (PD-1) is bound by PD-1 ligand-1 (PD-L1) or PD-L2. Although PD-1 inhibitors have been approved for triple-negative breast cancer, the lower response rates of 25%-30% in estrogen receptor–positive (ER+) breast cancer will require...

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Detalles Bibliográficos
Autores principales: Chervoneva, Inna, Peck, Amy R., Sun, Yunguang, Yi, Misung, Udhane, Sameer S., Langenheim, John F., Girondo, Melanie A., Jorns, Julie M., Chaudhary, Lubna N., Kamaraju, Sailaja, Bergom, Carmen, Flister, Michael J., Hooke, Jeffrey A., Kovatich, Albert J., Shriver, Craig D., Hu, Hai, Palazzo, Juan P., Bibbo, Marluce, Hyslop, Terry, Nevalainen, Marja T., Pestell, Richard G., Fuchs, Serge Y., Mitchell, Edith P., Rui, Hallgeir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wolters Kluwer Health 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9928763/
https://www.ncbi.nlm.nih.gov/pubmed/36652667
http://dx.doi.org/10.1200/PO.21.00498
Descripción
Sumario:T-cell–mediated cytotoxicity is suppressed when programmed cell death-1 (PD-1) is bound by PD-1 ligand-1 (PD-L1) or PD-L2. Although PD-1 inhibitors have been approved for triple-negative breast cancer, the lower response rates of 25%-30% in estrogen receptor–positive (ER+) breast cancer will require markers to identify likely responders. The focus of this study was to evaluate whether PD-L2, which has higher affinity than PD-L1 for PD-1, is a predictor of early recurrence in ER+ breast cancer. METHODS: PD-L2 protein levels in cancer cells and stromal cells of therapy-naive, localized or locoregional ER+ breast cancers were measured retrospectively by quantitative immunofluorescence histocytometry and correlated with progression-free survival (PFS) in the main study cohort (n = 684) and in an independent validation cohort (n = 273). All patients subsequently received standard-of-care adjuvant therapy without immune checkpoint inhibitors. RESULTS: Univariate analysis of the main cohort revealed that high PD-L2 expression in cancer cells was associated with shorter PFS (hazard ratio [HR], 1.8; 95% CI, 1.3 to 2.6; P = .001), which was validated in an independent cohort (HR, 2.3; 95% CI, 1.1 to 4.8; P = .026) and remained independently predictive after multivariable adjustment for common clinicopathological variables (HR, 2.0; 95% CI, 1.4 to 2.9; P < .001). Subanalysis of the ER+ breast cancer patients treated with adjuvant chemotherapy (n = 197) revealed that high PD-L2 levels in cancer cells associated with short PFS in univariate (HR, 2.5; 95% CI, 1.4 to 4.4; P = .003) and multivariable analyses (HR, 3.4; 95% CI, 1.9 to 6.2; P < .001). CONCLUSION: Up to one third of treatment-naive ER+ breast tumors expressed high PD-L2 levels, which independently predicted poor clinical outcome, with evidence of further elevated risk of progression in patients who received adjuvant chemotherapy. Collectively, these data warrant studies to gain a deeper understanding of PD-L2 in the progression of ER+ breast cancer and may provide rationale for immune checkpoint blockade for this patient group.