Abstract
Disease outcomes of HER2+ breast cancers have dramatically changed after targeted therapies, such as trastuzumab, came to clinical practice but predictive factors for trastuzumab sensitivity and resistance are frequently unknown. Current work included metastatic breast cancer patients (n = 48), who were treated with trastuzumab and had pre-treatment tumour samples available. The tumours were immunostained for T-cell (CD3, CD8), natural killer (NK)-cell (CD56) and macrophage (CD68) markers and quantitative analysis of the immune cells was carried out using a computer-assisted image analysis in different tumour locations. High number of CD3 and CD8 positive T-cells was associated with significant survival benefit in the center of the tumour (CT) (p = 0.007, p = 0.001) but not in the invasive margin. The number of NK-cells and macrophages in the CT showed non-significant tendency towards improved survival. In subgroup analyses, high density of CD8 CT cells was associated with significant survival benefit in non-bone only disease, in TX or T1-3, and in ER+ tumours (p = 0.006, p = 0.003, p = 0.001). Moreover, high CD8 CT cell density associated significantly with long trastuzumab interruption periods in response. The results suggest important prognostic and predictive role of tumour infiltrating lymphocytes in center of the tumours in metastatic HER2+ breast cancer.
Highlights
Immune system has suppressive and promoting effects on cancer development and progression, and both innate and adaptive immune cells are found in the tumour microenvironment[1]
Trastuzumab mode-of-action is related to both target signalling inhibition and immune activation (ADCC) and both altered signalling pathways and immunological status of the tumour could be related to drug responses
Alterations abolishing the signal transduction inhibition of trastuzumab, such as p95 variant of Human epidermal growth factor receptor 2 (HER2), PI3KCA, and PTEN, and compromised host immunoactivation have shown some correlation to trastuzumab resistance[29]
Summary
Immune system has suppressive and promoting effects on cancer development and progression, and both innate and adaptive immune cells are found in the tumour microenvironment[1]. Tumour infiltration of lymphocytes ( T-cells and natural killer (NK)-cells) have been associated with an improved survival rates in breast, colorectal, and gastric cancers[2,3,4,5,6,7]. More accurate, quantitative data on the significance of different immune cell types in different tumour locations would be required to reliably identify potential predictive markers for trastuzumab therapy. In this current work, we examined the possible prognostic and predictive value of tumour infiltrating lymphocytes in metastatic HER2 positive breast cancers treated with trastuzumab. Using this method gives many advantages, such as accuracy, reproducibility, objectivity and time efficiency compared to manual counting methods[2,26]
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