PD-L1 and MEK inhibition may be synergistic in triple-negative breast cancer

SAN ANTONIO — MHC-I/II and PD-L1 expression appeared to have opposing effects on the immune system in patients with triple-negative breast cancer who had residual disease after neoadjuvant chemotherapy, according to study results presented at the San Antonio Breast Cancer Symposium.

These findings suggest that combined PD-L1 and MEK inhibition may have a synergistic antitumor effect in triple-negative breast cancer, researchers said.

Justin M. Balko

“Increased tumor-infiltrating lymphocytes have been shown to predict favorable patient prognosis in triple-negative and HER-2–positive breast cancers in a variety of different disease states, including in the adjuvant setting,” Justin M. Balko, PharmD, PhD, assistant professor of medicine and cancer biology at Vanderbilt University in Nashville, Tenn., said during a presentation. “Increased tumor-infiltrating lymphocytes in pretreatment biopsies can also predict pathological complete response in the neoadjuvant setting, and in patients who lack a pathological complete response to neoadjuvant chemotherapy, increased tumor infiltrating lymphocytes in residual disease can predict improved RFS and OS.”

Balko and colleagues sought to evaluate tumor genomic alterations that might be associated with tumor infiltrating lymphocytes (TILs) in residual triple-negative breast cancer, as this may help identify why some patients have a more active anti-tumor immune reaction.

Researchers evaluated TILs in 114 patients with triple-negative breast cancer who had residual disease after treatment with neoadjuvant chemotherapy. The analysis also included evaluable data from 39 matched baseline biopsies.

Increased levels of TILs in patients post-neoadjuvant chemotherapy were associated with favorable RFS (P=.0001) and OS (P=.0016). Each percent increase in TIL concentration was associated with a 3.4% relative risk reduction for relapse and a 2.8% relative risk reduction for death.

In a multivariate analysis controlled for stage, age, node status and residual disease tumor cellularity, the association between increased TILs and favorable outcomes persisted for RFS (P=.0008) and OS (P=.007).

Researchers also noted TIL levels decreased with neoadjuvant chemotherapy in paired samples, but this change was not statistically significant (P=0.07).

Results of next-generation sequencing indicated the presence of lower TIL levels in residual disease samples were associated with genetic alteration in the Ras/MAPK pathways, including KRAS, BRAF and RAF1 amplifications and NF1 truncations (P=.005). Genetic alterations in the cell cycle pathway — such as CCND1-3, CDK4, CDK6, CCNE1, RB, AURKA and CDKN2A alternations — also were associated with lower TILs (P=.05).

The investigators also identified an inverse correlation between a gene signature of Ras/MAPK activation and TILs in residual disease samples (P=.00028), although the total number of alterations was not associated with TILs. These findings suggest the association between TIL levels and Ras/MAPK deregulation may be pathway specific.

Cell line analyses indicated MEK inhibition up-regulated MHC-I and MHC-II molecules while simultaneously up-regulating the expression of the immune checkpoint PD-L1 on the tumor cell surface.

“In the antitumor immune milieu, the secretion of interferon gamma in the tumor cell can induce MHC and PD-L1 expression,” Balko said. “The Ras/MAP kinase pathway can work to inactive the expression of these molecules. The expression of both of these molecules can be suggested to having opposing effects on the immune system, where MHC-I/II antigen presentation can promote anti-tumor immunity, while the co-expression of PD-L1 can thwart this and cause an immune invasion. Given this information, we reasoned that co-treatment with a MEK inhibitor and anti–PD-L1 neutralizing antibody might have co-synergistic activity in breast cancer.”

In a mouse model of breast cancer, the investigators demonstrated the combination treatment of MEK and PD-L1 inhibition caused complete tumor regression in all mice tested, and they remained tumor free 20 to 30 days after treatment, Balko said.

For more information:

Balko JM. Abstract #S1-08. Presented at: San Antonio Breast Cancer Symposium; Dec. 9-13, 2014; San Antonio.

Disclosure: The researchers report no relevant financial disclosures.