December 2019: HLA class I evaluation in breast cancer patients from GeparTrio trial

Interactions between cancer cells and the host immune system are important for development, evolution, and progression of cancer. Furthermore, they can modulate treatment response and survival of patients offering new approaches for cancer therapy. Therefore, clinical application of cancer immunotherapy requires a better understanding of tumor immunogenicity and the tumor microenvironment. Human leucocyte antigen (HLA) class I molecules are expressed on the surface of all nucleated cells and are encoded by the human leukocyte antigens HLA-A, HLA-B, and HLA-C. Their function is to present antigens to CD8+ cytotoxic T lymphocytes to recognize and eliminate infected or tumor cells. Their loss or downregulation is frequently found in tumors resulting in reduced T cell responses and worse prognosis. Aim of this study was to evaluate the potential of HLA class I heavy chain (HC) expression for prediction of response to neoadjuvant chemotherapy.

To this end, the HLA class I HC expression was evaluated in 863 biopsies obtained from breast cancer patients treated with anthracycline/taxane-based neoadjuvant chemotherapy within the GeparTrio trial. In parallel, the expression of HLA-A was analyzed using a microarray cohort of 320 breast cancer patients from the MD Anderson Cancer Center to validate the findings and investigate correlation with clinical outcome, tumorinfiltrating lymphocytes (TILs), and immune cell metagenes. In HR+/HER2− breast cancer, HLA class I HC expression was associated with increased TILs and better response to chemotherapy (7% vs. 14% pCR rate, p=0.029), but shorter disease-free survival (hazard ratio (HR) 1.6 [95%CI 1.1–2.4]; p=0.024). The effect was significant in a multivariate model adjusted for clinical and pathological variables (HR 1.7 [95%CI 1.1–2.6]; p=0.016) and was confirmed by analysis of HLA-A in a microarray cohort. HLA-A was correlated to most immune cell metagenes. There was no association with response or survival in triple-negative or HER2+ disease. The study demonstrated that HLA class I expression can be used to predict worse outcome in HR+/HER2- breast cancer. This outcome is a complex function of resistance and sensitivity to neoadjuvant cytotoxic therapy, adjuvant endocrine treatment, and tumor immunogenicity. In addition, the findings confirm the negative prognostic role of lymphocytes in hormone receptor-positive breast cancer and point at a subtype-specific and potentially treatment-specific role of tumor-immunological processes in breast cancer with different implications in triple-negative and hormone receptor-positive disease.

Sinn BV, Weber KE, Schmitt WD, et al. Human leucocyte antigen class I in hormone receptor-positive, HER2-negative breast cancer: association with response and survival after neoadjuvant chemotherapy. Breast Cancer Res. 2019;21:142.
Link in PubMed