Journal
EUROPEAN JOURNAL OF CANCER
Volume 48, Issue 1, Pages 12-23Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2011.06.025
Keywords
Bimodal expression; Immune therapy; CT-X antigens; Prognostic markers; Subtypes of breast cancer; Microarray analysis
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Funding
- H.W. & J. Hector-Stiftung, Mannheim
- Margarete Bonifer-Stiftung, Bad Soden
- BANSS-Stiftung, Biedenkopf
- Dr. Robert Pfleger-Stiftung, Bamberg
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Background: Molecular markers displaying bimodal expression distribution can reveal distinct disease subsets and may serve as prognostic or predictive markers or represent therapeutic targets. Oestrogen (ER) and human epidermal growth factor receptor 2 (HER2) receptors are strongly bimodally expressed genes in breast cancer. Material and methods: We applied a novel method to identify bimodally expressed genes in 394 triple negative breast cancers (TNBC). We identified 133 bimodally expressed probe sets (128 unique genes), 69 of these correlated to previously reported metagenes that define molecular subtypes within TNBC including basal-like, molecular-apocrine, claudin-low and immune cell rich subgroups but 64 probe sets showed no correlation with these features. Results: The single most prominent functional group among these uncorrelated genes was the X chromosome derived Cancer/Testis Antigens (CT-X) including melanoma antigen family A (MAGE-A) and Cancer/Testis Antigens (CTAG). High expression of CT-X genes correlated with worse survival in multivariate analysis (HR 2.02, 95% CI 1.27-3.20; P = 0.003). The only other significant variable was lymph node status. The poor prognosis of patients with high MAGE-A expression was ameliorated by the concomitant high expression of immune cell metagenes (HR 1.87, 95% CI 0.96-3.64; P = 0.060), whereas the same immune metagene had lesser prognostic value in TNBC with low MAGE-A expression. Conclusions: MAGE-A antigen defines a very aggressive subgroup of TNBC; particularly in the absence of immune infiltration in the tumour microenvironment. These observations suggest a therapeutic hypothesis; TNBC with MAGE-A expression may benefit the most from further augmentation of the immune response. Novel immune stimulatory drugs such as (anti-cytotoxic T-lymphocyte antigen-4 CTLA-4) directed therapies provide a realistic opportunity to directly test this hypothesis in the clinic. (C) 2011 Elsevier Ltd. All rights reserved.
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