An Anaplastic Lymphoma Kinase Pathway Signature is associated with Cell De-differentiation, Neoadjuvant Response and Recurrence Risk in Breast Cancer

Abstract The role of ALK signaling in the pathogenesis of breast cancer (BC) is not clear. Previously we generated a gene signature for ALK pathway based on the difference of gene expression profiles between tumor cells with activated and inactive ALK pathway. Here, this signature was used to compute ALK pathway activity in BC samples from 42 microarray datasets, and the associations between ALK pathway score and the clinical outcome were examined by logistic regression and survival analysis. Our results indicated that high ALK pathway activity was a significant risk factor for the presence of higher-grade breast cancer with loss of ER and PR expression in the 42 datasets (n= 6381). ALK pathway activity was also positively associated with pathological complete response (pCR) in 15 datasets annotated with patient’s neoadjuvant response information (n= 2093, overall OR 1.67, p=2.00E-12), and with recurrence risk in 30 datasets annotated with patient’s survival information (n= 4678, overall HR 1.21, p=3.31E-08). The associations of ALK pathway activity with pCR and recurrence were more significant in HER2 negative and grade 1&2 tumors than in HER2 positive and grade 3 tumors. Notably, the association between ALK and tumor recurrence was statistically significant in patient with age>50 but not ≤50 years old, in patient with positive but not negative lymph node and in patients with residual disease but not pCR following neoadjuvant chemotherapy. These data indicate that ALK may be involved in BC tumorigenesis and ALK pathway signature represents a novel biomarker for BC clinical management.