NK cell infiltrates and HLA class I expression in primary HER2+ breast cancer predict and uncouple pathological response and disease-free survival

Purpose: We investigated the value of tumor-infiltrating NK cells (TI-NK) and HLA class I tumor expression as biomarkers of response to neoadjuvant anti-HER2 antibody-based treatment in breast cancer. Experimental Design: TI-NK cells and HLA-I were determined by immunohistochemistry in pre-treatment tumor biopsies from two cohorts of HER2-positive breast cancer patients [discovery cohort (n=42) and validation cohort (n=71)]. TIL were scored according to international guidelines. Biomarker association with pathological complete response (pCR) and disease-free survival (DFS) was adjusted for prognostic factors. Gene set variation analysis was used for determining immune-cell populations concomitant to NK cell enrichment in HER2-positive tumors from the TCGA (n=190). Results: TI-NK cells were significantly associated with pCR in the discovery cohort as well as in the validation cohort (p<0.0001), independently of clinicopathological factors. A ≥3 TI-NK cells/50xHPF cut off predicted pCR in the discovery and validation cohort [OR 188 (11-3154); OR 19.5 (5.3-71.8)]. Presence of TI-NK cells associated with prolonged DFS in both patient cohorts [HR 0.07 (0.01-0.6), p=0.01; HR 0.3 (0.08-1.3), p=0.1]. NK-, activated dendritic- and CD8 T-cell gene expression signatures positively correlated in HER2-positive tumors, supporting the value of NK cells as surrogates of effective anti-tumor immunity. Stratification of patients by tumor HLA-I expression identified patients with low and high relapse risk independently of pCR. Conclusions: This study identifies baseline TI-NK cells as an independent biomarker with great predictive value for pCR to anti-HER2 antibody-based treatment and points to the complementary value of tumor HLA-I status for defining patient prognosis independently of pCR.

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