Abstract 73P
Background
We recently reported that high cancer cell protein levels of PD-L2 in patients (pts) with treatment-naïve estrogen receptor-positive breast cancer (ER+ BC), was an independent predictor of shorter progression-free survival in two distinct cohort of pts (1). These findings suggest that PD-L2 may help improve BC pt selection for PD-1 inhibitors. We therefore initiated efforts to determine baseline expression patterns of PD-L1 and PD-L2 in BC.
Methods
PD-L1 and PD-L2 protein levels in cancer cells and tumor-infiltrating immune cells were prospectively analyzed by immunohistochemistry (IHC) using validated antibodies in diagnostic core biopsies of 28 consecutive pts diagnosed with localized or locoregional ER+/HER2- BC or TNBC. Percent positivity of PD-L1 and PD-L2 in cancer cells and immune cells was determined by a breast pathologist.
Results
PD-L1 and PD-L2 expression patterns in BC differed in several ways. First, PD-L1-positivity in immune cells was higher than in cancer cells (median=5.0% vs. 0.05%; p=0.002), whereas PD-L2-positivity was higher in cancer vs. immune cells (median=20% vs. 5.0%; p=0.001). Second, there was no significant correlation between PD-L1 and PD-L2 expression, neither across all cases (N=28), nor within ER+ (N=20) or TNBC (N=8) cases. Third, PD-L1 positivity in cancer cells and immune cells were positively correlated in TNBC (rho=0.72, p=0.045) but not in ER+ BC. Conversely, PD-L2 positivity was positively correlated in ER+ BC (rho=0.62, p=0.004) but not in TNBC. TNBC diverged from ER+ BC by displaying higher PD-L1 positivity in immune cells (median=20.0% vs. 1.0%; p=0.004). By the conventional cutpoint for positivity of ≥1% for PD-L1 and PD-L2 in cancer cells or immune cells, all TNBC tumors were PD-L1-positive (8/8), with 7 also being PD-L2-positive. Of the 20 ER+ cases, 15 were PD-L2-positive, of which only 8 were also PD-L1-positive.
Conclusions
PD-L1 and PD-L2 proteins show divergent expression and are not correlated in BC. Discordant PD-L2 and PD-L1 expression may be more common in ER+ BC than in TNBC. This progress justifies efforts to explore PD-L2 as a complementary marker to PD-L1 for improved prediction of responses to PD-1 inhibitors, which may also benefit pts with aggressive ER+ BC. Reference: 1.JCO Precis Oncol 7:e2100498, 2023.
Clinical trial identification
Tumor specimens from diagnostic core biopsies from our ongoing phase II clinical trial (NCT04243616) of neoadjuvant chemotherapy and PD-1 inhibitor (cemiplimab; Regeneron Pharmaceuticals Inc) were used for these analyses
Legal entity responsible for the study
The authors.
Funding
National Center for Advancing Translational Sciences, National Institutes of Health Awards KL2TR001438.
Disclosure
L.N. Chaudhary: Other, Personal, Advisory Board: Puma Biotechnology, Seattle Genetics, Gilead Sciences, AstraZeneca, Novartis; Other, Institutional, Research Grant: Regeneron Pharmaceuticals. All other authors have declared no conflicts of interest.