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High PD-L2 Predicts Early Recurrence of ER-Positive Breast Cancer
Inna Chervoneva1, Amy R Peck2, Yunguang Sun2
1Division of Biostatistics, Thomas Jefferson University, Philadelphia, PA.
Purpose:
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.
Insights
High programmed cell death-1 ligand-2 (PD-L2) expression in estrogen receptor-positive breast cancer predicts early recurrence. This finding may guide future immune checkpoint inhibitor therapies for this patient group.
Area of Science:
- Oncology
- Immunology
Background:
- T-cell-mediated cytotoxicity is suppressed by the interaction of programmed cell death-1 (PD-1) with its ligands, PD-L1 and PD-L2.
- While PD-1 inhibitors show promise in triple-negative breast cancer, their efficacy in estrogen receptor-positive (ER+) breast cancer is limited, necessitating predictive biomarkers.
Purpose of the Study:
- To investigate whether PD-L2, a ligand with higher affinity for PD-1 than PD-L1, can serve as a predictor of early recurrence in ER+ breast cancer.
Main Methods:
- Quantitative immunofluorescence histocytometry was used to measure PD-L2 protein levels in cancer and stromal cells of therapy-naive ER+ breast cancers.
- Progression-free survival (PFS) was analyzed retrospectively in a main cohort (n=684) and an independent validation cohort (n=273).
Main Results:
- High PD-L2 expression in cancer cells was significantly associated with shorter PFS in both the main (HR, 1.8; P=.001) and validation cohorts (HR, 2.3; P=.026).
- This association remained independently predictive after multivariable adjustment (HR, 2.0; P<.001).
- In ER+ patients receiving adjuvant chemotherapy, high PD-L2 levels in cancer cells predicted shorter PFS in both univariate (HR, 2.5; P=.003) and multivariable analyses (HR, 3.4; P<.001).
Conclusions:
- Approximately one-third of treatment-naive ER+ breast tumors exhibit high PD-L2 expression, which independently predicts poor clinical outcomes.
- Elevated risk of progression was observed in patients with high PD-L2 who received adjuvant chemotherapy.
- These findings suggest PD-L2 as a potential biomarker and warrant further investigation into its role in ER+ breast cancer progression and its implications for immune checkpoint blockade therapy.
