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

Inna Chervoneva1, Amy R Peck2, Yunguang Sun2

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JCO Precision Oncology
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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.

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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.