BJMO - volume 11, issue 2, march 2017
M. Mariñas , P. Valdiviezo BSc, C.H. Saravia BSc, F. Vallenas MD, PhD, L. Bravo MD, MSc, J. M. Araujo BSc, D. Bretel MD, R. Velazco BSc, H. L. Gómez MD, PhD, J. A. Pinto MSc
Toll-like receptors are key players of the innate immunity that recognise foreign patterns and have been related to cancer aggressiveness in several cancers, including breast cancer. Previously, TLR4 was associated with resistance to taxanes in breast cancer model.
Objective: The aim of this work was to characterise the expression of toll-like receptors in breast cancers and evaluate them as predictive and prognostic biomarkers.
Methods: A publicly available dataset of breast cancer in the neoadjuvant setting profiled with the Affymetrix platform H133A (GSE25066) was evaluated. Expression levels were log2 transformed and median centred. Toll-like receptors gene expression (TLR1-TLR9) was associated with clinical features and prognosis of breast cancer in terms of distant metastasis-free survival. Using levels of expression of genes involved in TLR4 signalling we developed a prognostic signature.
Results: Expression of TLR1, TLR2 and TLR5 were enriched in the basal subtype. Toll-like receptors expressions were not related with pathologic complete response. The univariate analysis identified to TLR1 (HR=5.9; 95%CI: 1.7–20.9; P=0.006), TLR4 (HR=10.9; 95%CI: 2.5–46.8; P=0.001) and TLR6 (HR=6.4; 95%CI: 1.7–23.2; P=0.005) statistically related with the distant recurrence-free survival. Due to the relevance of TLR4, we evaluated 37 genes involved in its pathway. The dataset was divided into discovery and validation cohorts. The multivariate analysis with the stepwise method selected five genes that were independent prognostic factors. Using the regression coefficients, we developed a prognostic signature: (0.279xIRAK1 + –0.421xIRF3 + –0.548xNFKB1 + 0.404xNEMO + 0.336xTRIMS). The prognostic signature was able to identify patients at different risk in the validation cohort.
Conclusion: Although toll-like receptors are not related to pathologic complete response, TLR4 signalling pathway is related to the outcome in neoadjuvant chemotherapy with anthracyclines and taxanes.
(BELG J MED ONCOL 2017;11(2):68–74)