Can evaluation of mismatch repair defect and TILs increase the number of triple-negative breast cancer patients eligible for immunotherapy?

Abstract

BackgroundProgrammed-cell-death-ligand 1 (PD-L1) inhibitor treatment is approved for metastatic/recurrent, PD-L1 positive, triple-negative breast cancer (TNBC) and solid tumors with mismatch repair (MMR) defect regardless of PD-L1 status. The analytical validity of PD-L1 has been questioned and adding evaluation of tumor-infiltrating lymphocytes (TILs) may identify patients likely to respond to immunotherapy. We investigated the association between MMR-deficiency and PD-L1 in TNBC; aiming to identify PD-L1 negative, TNBC patients that may be candidates for anti-PD-L1 immunotherapy. MethodologyParaffin-embedded tumor material from 44 TNBC patients was included. In 38 cases, immunohistochemical-staining´s on whole-slide sections were successful for all four MMR proteins (MSH2, MSH6, MLH1 and PMS2) and PD-L1 in 36 cases. MMR-status was categorized as positive (pMMR), heterogeneous (hMMR) or deficient (dMMR). Tumor-infiltrating lymphocytes (TILs) were evaluated on H&E sections. ResultsMMR stainings showed substantial intratumor heterogeneity. Four of 38 cases (11%) were recorded as dMMR with loss of ≥ 1 MMR-protein and 19 cases (50%) showed heterogeneous expression or partial loss (hMMR) of ≥ 1 MMR-protein. Three of 22 PD-L1 negative cases were dMMR (14%) and ten cases hMMR (45%). 16 of 22 PD-L1 negative cases (73%) showed high TILs. ConclusionsA substantial proportion of PD-L1 negative, TNBC patients showed complete/partial loss of MMR and/or high TILs indicating that supplementing PD-L1 examination with these biomarkers may identify TNBC-patients that may be selected for immunotherapy.