Immune modulation of pathologic complete response after neoadjuvant HER2-directed therapies in the NeoSphere trial

There is immune modulation of response to neoadjuvant trastuzumab and/or pertuzumab-containing therapies that is different with different regimens. Tumors with lower expression of immune markers benefit most from docetaxel/trastuzumab/pertuzumab (THP). PDL1 mRNA expression was associated with resistance. These findings support testing combinations of THP regimen with immune-checkpoint inhibitors. Background: To investigate in the NeoSphere trial the contribution of the immune system to pathologic complete response in the breast (pCRB) after neoadjuvant docetaxel with trastuzumab (TH), pertuzumab (TP), or both (THP), or monoclonal antibodies alone (HP). Patients and methods: Immune gene mRNA expression ( n = 350, 83.8%), lymphocyte infiltration ( TIL, n = 243, 58.3%), and PDL1 by immunohistochemistry ( n = 305, 73.1%) were correlated with pCRB. We studied five selected genes ( IFNG, PD1, PDL1, PDL2, CTLA4) and six immune metagenes corresponding to plasma cells ( IGG), T cells ( CD8A), antigen- presenting cells ( MHC2), and to MHC1 genes ( MHC1), STAT1 co- expressed genes ( STAT1), and interferon- inducible genes ( IF- I). Gene expression data from the NOAH trial were used for validation. Results: TIL as continuous variable and PDL1 protein expression were not significantly associated with pCRB. Expression of immune genes/metagenes had different association with pCRB after THP than after other therapies. With THP, higher expression of PD1 and STAT1, or any among PDL1, CTLA4, MHC1, and IF-I were linked with lower pCRB. In the combined TH/TP/HP treatment group, in multivariate analysis, higher expression of PD1, MHC2, and STAT1 were linked with pCRB, and higher PDL1, MHC1, or IF-I to lower pCRB. In the NOAH, a similar association of higher STAT1 with higher pCRB, and higher MHC1 and IF-I with lower pCRB was found for trastuzumab/chemotherapy but not for chemotherapy treatment only. Conclusions: The immune system modulates response to therapies containing trastuzumab and pertuzumab. Greatest benefit from THP is observed for low expression of some immune markers (i.e. MHC1, CTLA4). The involvement of PDL1 in resistance supports testing combinations of HER2-directed antibodies and immune-checkpoint inhibitors.