SAN ANTONIO—Increased post-neoadjuvant chemotherapy (NAC) tumor-infiltrating lymphocytes (TILs) are associated with increased survival in triple-negative breast cancer (TNBC), according to findings presented at the 2014 San Antonio Breast Cancer Symposium.

The findings seem to implicate RAS/MAPK pathway activation in TNBC immune evasion.

“Activation/alteration of the MEK pathway is associated lower TILs and may reflect a mechanism of immune evasion in cancer cells,” reported lead study author Justin M. Balko, PharmD, PhD, of Vanderbilt University, Nashville, TN.

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Using genetically manipulated mouse models, the study team also found evidence that combinatorial PD-L1 and MEK inhibition is therapeutic in vivo and “may be a viable clinical therapeutic strategy,” Dr. Balko reported.

Elevated TILs are associated with improved prognosis in patients with TNBC and HER2-positive breast cancer, but the molecular pathways modulating anti-tumor immune response are not as well-understood, he noted.

“To address this gap in knowledge, we analyzed TILs retrospectively in a cohort of clinically and molecularly characterized TNBCs with residual disease after neoadjuvant chemotherapy,” Dr. Balko said.

The team recently used post-NAC tumors from 112 patients with TNBC who had residual disease, and scored TILs for comparison with TIL samples from 39 matched baseline diagnostic biopsies, Dr. Balko reported.

Patients with TNBC low-TIL scores (0%-10%) had significantly worse recurrence-free survival rates than those with high (21%-70%) TIL scores (P = 0.0005).

“Genomic alterations in the residual disease were assayed using targeted next-generation sequencing (tNGS) while selected transcriptional signatures were evaluated by NanoString,” Dr. Balko reported.

MEK transcriptional activity score and genomic alterations in the RAS/MAPK pathway were each associated with lower post-NAC TILs (P = 0.0003 and P = 0.005, respectively), he said.

Tumor cell MEK activation might modulate immune recognition in part by upregulating major histocompatibility (MHC)-II genes, Dr. Balko suggested. “Co-expression of immune checkpoints such as PD-L1 lowers T-cell activation,” he noted, citing the study team’s in-vitro and genetically manipulated mouse models. “Anti-PD-1/PD-L1 therapy releases these negative interactions.”

Higher MEK activation is associated with decreased expression of tumor-specific MHC expression (for HLA-DR, P = 0.001), he noted—and inhibition of MEK enhances MHC-II expression in TNBC cells.

“In TNBC cell lines, chemical inhibition of MEK transcriptionally up-regulated MHC-I and MHC-II molecules, while simultaneously down-regulating mRNA expression of the immune checkpoint inhibitor PD-L1,” Dr. Balko and coauthors reported in an accompanying conference abstract.

“With additional mechanistic understanding, rational design of clinical trials combining MEK inhibitors with PD-L1 antibodies in TNBC may be warranted,” the researchers noted.


  1. Balko JM, Denkert C, Salgado R et al. S1-08. Presented at: San Antonio Breast Cancer Symposium 2014. Dec. 9-13, 2014; San Antonio, TX.