ABSTRACT
Breast cancer is the most common malignancy and the leading cause of cancer death in females worldwide. Treatment is challenging, especially for those who are triple-negative. Increasing evidence suggests that diverse immune populations are present in the breast tumour microenvironment, which opens up avenues for personalised drug targets. Historically, our investigations into the immune constitution of breast tumours have been restricted to analyses of one or two markers at a given time. Recent technological advances have allowed simultaneous labelling of more than 35 markers and detailed profiling of tumour-immune infiltrates at the single-cell level, as well as determining the cellular composition and spatial analysis of the entire tumour architecture. In this review, we describe emerging technologies that have contributed to the field of breast cancer diagnosis, and discuss how to interpret the vast data sets obtained in order to effectively translate them for clinically relevant use.
Subject(s)
Breast Neoplasms/immunology , Breast Neoplasms/pathology , Fluorescent Antibody Technique , Immunohistochemistry , Tumor Microenvironment/immunology , Biomarkers, Tumor/immunology , Breast Neoplasms/diagnosis , Fluorescent Antibody Technique/methods , Humans , Immunohistochemistry/methods , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/pathology , Prognosis , Triple Negative Breast Neoplasms/immunology , Triple Negative Breast Neoplasms/pathologyABSTRACT
PURPOSE: The purpose of the study was to improve the understanding of NF1-associated breast cancer, given the increased risk of breast cancer in this tumour predisposition syndrome and the limited data. METHODS: We identified 18 women with NF1 and breast cancer at our institution. Clinical and pathologic characteristics of NF1-associated breast cancers were compared with 7132 breast cancers in patients without NF1 from our institutional database. Next generation sequencing was performed on DNA from blood and breast cancer specimens available. Blood specimens negative for NF1 mutation were subjected to multiplex ligation-dependent probe amplification (MLPA) to identify complete/partial deletions or duplications. Expression of neurofibromin in the NF1-associated breast cancers was evaluated using immunohistochemistry. RESULTS: There was a higher frequency of grade 3 (83.3% vs 45.4%, p = 0.005), oestrogen receptor (ER) negative (66.7% vs 26.3%, p < 0.001) and human epidermal growth factor receptor 2 (HER2)-positive (66.7% vs 23.4%, p < 0.001) tumours among NF1 patients compared to non-NF1 breast cancers. Overall survival was inferior in NF1 patients in multivariable analysis (hazard ratio 2.25, 95% CI 1.11-4.60; p = 0.025). Apart from germline NF1 mutations (11/16; 69%), somatic mutations in TP53 (8/10; 80%), second-hit NF1 (2/10; 20%), KMT2C (4/10; 40%), KMT2D (2/10; 20%), and PIK3CA (2/10; 20%) were observed. Immunohistochemical expression of neurofibromin was seen in the nuclei and/or cytoplasm of all specimens, but without any consistent pattern in the intensity or extent. CONCLUSIONS: This comprehensive series of NF1-associated breast cancers suggests that their aggressive features are related to germline NF1 mutations in cooperation with somatic mutations in TP53, KMT2C and other genes.
