High PD-L2 expression predicts early ER-positive breast cancer recurrence
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High PD-L2 expression occurred in as many as one-third of previously untreated, ER-positive breast tumors and independently predicted early breast cancer recurrence, according to study results published in JCO Precision Oncology.
The findings indicate a need for additional research to gain further understanding of PD-L2 expression in the progression of ER-positive breast cancer, researchers concluded.
Rationale and methods
“We felt that it would be important to investigate the levels of the immune checkpoint protein PD-L2 in breast cancer because so much attention has been focused on PD-L1,” Hallgeir Rui, MD, PhD, Wisconsin Breast Cancer Showhouse endowed professor of breast cancer research in the department of pathology at Medical College of Wisconsin, told Healio. “Research by others has shown that PD-L2 binds to PD-1 even more strongly than PD-L1, further justifying tumor analyses of PD-L2.”
PD-1 inhibitors received approval last year for triple-negative breast cancer, Rui said, although markers will be needed to identify likely responders among patients with ER-positive disease.
“Patients now have access to PD-1 inhibitors unless the tumors are ER-positive,” he said. “The purpose of the study was to evaluate whether PD-L2 is a predictor for early recurrence in ER-positive breast cancer.”
Researchers used quantitative immunofluorescence histocytometry to retrospectively measure levels of PD-L2 protein in cancer cells and stromal cells among patients with treatment-naive, localized or locoregional ER-positive breast cancers. They sought to compare the association between PD-L2 expression and PFS in the main study cohort (n = 684) and an independent validation cohort (n = 273).
All patients underwent standard-of-care adjuvant therapy without immune checkpoint inhibitors.
Results
Researchers identified high PD-L2 expression in as many as one-third of patients in the cohort.
Results showed an association of high PD-L2 expression in cancer cells with shorter PFS (HR = 1.8; 95% CI, 1.3-2.6), which researchers further validated in an independent cohort (HR = 2.3; 95% CI, 1.1-4.8) and remained independently predictive after adjustment for common clinicopathologic variables (HR = 2; 95% CI, 1.4-2.9).
Results of a subanalysis including an independent cohort of patients treated with adjuvant chemotherapy (n = 197) additionally showed that high levels of PD-L2 in cancer cells appeared associated with shorter PFS in univariate (HR = 2.5; 95% CI, 1.4-4.4) and multivariable analyses (HR = 3.4; 95% CI, 1.9 to 6.2).
Implications
The findings suggest certain patients with ER-positive breast cancer may benefit from PD-1 inhibitors and provide a rationale to look for responding tumors among these patients, Rui told Healio.
“Motivated by this progress, the research team has initiated a phase 2 clinical trial, led by Lubna Chaudhary, MD, to test a PD-1 inhibitor in patients with ER-positive or ER-negative breast cancer that expresses either PD-L1 or PD-L2,” he said. “We hope that this initial trial can provide initial evidence that combined analysis of PD-L1 and PD-L2 will more accurately identify patients likely to benefit from PD-1 inhibitors. We know that measurement of PD-L1 alone is an inadequate predictor of response. There is also currently no established test for PD-L2 in the clinic. Therefore, it is important that patients advocate for themselves and request full development of that type of test.”
For more information:
Hallgeir Rui, MD, PhD, can be reached at hrui@mcw.edu.
Perspective
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Azka Ali, MD
Immune checkpoint inhibitors target the programmed cell death-1 (PD-1), or programmed cell death ligand-1 or -2 (PD-L1, PD-L2), which are overexpressed in certain cancer cells. These include agents that block PD-1 receptor interactions with PD-L1 or antibodies that target PD-L1 binding to PD-1 and, in turn, suppress T cell-mediated cell kill. PD-1 or PD-L1 blockade has shown to be effective in several tumor types, including triple-negative and ER-positive breast cancer. Preclinical research has shown that PD-L2 has much higher affinity for PD-1 than PD-L1. Therefore, there has been interest in understanding the association of PD-L2 expression and breast cancer-related outcomes.In this retrospective study, levels of PD-L2 protein were measured by immunohistochemistry in local recurrence of ER-positive breast cancer, and these levels correlated with disease recurrence. Investigators showed that high levels of PD-L2 were associated with shorter PFS. It is yet to be seen if this association is clinically meaningful, and if immune checkpoint inhibitors can be utilized to decrease the risk for recurrence among these patients. The research team is planning to test the concept by measuring levels of PD-L1 or PD-L2 in ER-positive patients and using a PD-1 inhibitor to understand the clinical benefit and to further provide a proof of concept. The results of that concept would be interesting and potentially could be practice changing. However, as of right now, it remains unclear if PD-L2 should be routinely tested in patients.
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