Strong CD8+ lymphocyte infiltration in combination with expression of HLA class I is associated with better tumor control in breast cancer patients treated with neoadjuvant chemotherapy.

PURPOSE: Tumor-infiltrating lymphocytes (TILs) are associated with pathological complete response (pCR) and survival after neoadjuvant chemotherapy (NAC) in patients with early breast cancer. We investigated the prognostic and predictive role of TILs, macrophages, and HLA class 1 expression after NAC with or without the potentially immune modulating compound zoledronic acid (ZA). METHODS: Baseline tumor biopsies from 196 patients in the NEOZOTAC trial were analyzed for CD8 (cytotoxic T-cells), FoxP3 (regulatory T-cells), CD68 (macrophages), and HLA class I (HCA2/HC10) expression by immunohistochemistry and subsequently related to pCR and disease-free survival (DFS). RESULTS: A strong intratumoral CD8+ infiltration or expression of HLA class 1 by cancer cells was associated with a higher pCR rate (p < 0.05). Clinical benefit of high CD8+ T-cell infiltration was found when cancer cells expressed HLA class 1 (pCR: 21.8% vs. 6.7%, p = 0.04) but not when HLA class 1 expression was lost or downregulated (pCR: 5.9% vs. 0%, p = 0.38). Interaction analyses revealed survival benefit between HLA class 1 expression and strong CD8+ T-cell infiltration, whereas in the absence or downregulation of HLA class 1 expression, high levels of CD8+ T-cells were associated with survival disadvantage (p for interaction 0.01; hazard ratio 0.41, 95% CI 0.15-1.10, p = 0.08 and hazard ratio 7.67, 95% CI 0.88-66.4, p = 0.07, respectively). Baseline immune markers were not related to ZA treatment. CONCLUSIONS: Strong baseline tumor infiltration with CD8+ T-cells in the presence of tumoral HLA class 1 expression in patients with HER2-negative breast cancer is related to a higher pCR rate and a better DFS after NAC.

Expression of cell adhesion molecules and prognosis in breast cancer.

BACKGROUND: Cell adhesion molecules (CAMs) play an important role in the process of metastasis. The prognostic value of tumour expression of N-cadherin, E-cadherin, carcinoembryonic antigen (CEA) and epithelial CAM (Ep-CAM) was evaluated in patients with breast cancer. METHODS: A tissue microarray of the patient cohort was stained immunohistochemically for all markers and analysed by microscopy. Expression was classified into two categories, with the median score as cut-off level. For CEA, the above-median category was further subdivided in two subgroups based on staining intensity (low or high intensity). RESULTS: The cohort consisted of 574 patients with breast cancer with a median follow-up of 19 years. Below-median expression of E-cadherin (P = 0·015), and above-median expression of N-cadherin (P = 0·004), Ep-CAM (P = 0·046) and CEA (P = 0·001) all resulted in a shorter relapse-free period. Multivariable analysis revealed E-cadherin and CEA to be independent prognostic variables. Combined analysis of CEA and E-cadherin expression showed a 3·6 times higher risk of relapse for patients with high-intensity expression of CEA, regardless of E-cadherin expression, compared with patients with below-median CEA and above-median E-cadherin tumour expression (hazard ratio 3·60, 95 per cent confidence interval 2·12 to 6·11; P < 0·001). An interaction was found between expression of these two CAMs (P < 0·001), suggesting a biological association. CONCLUSION: Combining E-cadherin and CEA tumour expression provides a prognostic parameter with high discriminative power that is a candidate tool for prediction of prognosis in breast cancer.