In early-stage HER2+ breast cancer (BC), de-escalation of systemic treatment remains a challenge. New biomarkers into risk scoring will help improvement in this field. We aim to develope a prognostic signature based on 2 miRNAs (A, B), quantitative and qualitative clinical variables in HER2+ BC patients.
A retrospective patients’ cohort (n= 45) who received standard treatment for localized disease was selected. We calculated a prognostic signature for disease-free survival (DFS) by principal components analysis combining pathological data (Ki67 and axillary lymph node status) and expression of miRNAs. Multiple DFS prognostic signatures were calculated and goodness of fit was evaluated by Akaike’s Information Criterion to perform Cox model selection. Signature was dichotomized into high risk and low risk using maximally selected Log-Rank statistics by Hothorn and Lausen, as method for optimal cut-off. Target genes were predicted and functional enrichment analysis was performed with KEGG and validated by western blot after miRNA mimics transfection.
MiR-A and B were strongly correlated (r=0.84) and their expression was higher in primary tumor of patients who relapsed (miR-A p= 0.004, miR-B p= 0.018). Our signature was significantly associated with relapse (HR 1.72; CI 95%: 1.24–2.38; p<0.01, AIC=114). Median DFS of the high risk was 44 months while it was not reached in low risk after 67 months of median follow-up (HR 8.39; p=0.005, AIC=111). Significant differences in survival between both groups were found (p< 0.001). This signature was not applicable in other BC subtypes. Functional enrichment analysis returned 55 significant pathways. Interestingly, P53, apoptosis and DNA damage were in the top 5 enriched pathways. Protein expression of predicted targets from these pathways was decreased after miRNA overexpression.
Both miRNA are related to main biological pathways associated to BC. Our prognostic signature identifies patients with early-stage HER2+ BC who might be candidates for de-escalated systemic treatment. This signature was able to classify patients for DFS in high or low risk groups at the moment of BC diagnosis. Further investigations to validate the value of this signature are on-going.
Clinical trial identification
Legal entity responsible for the study
INCLIVA Biomedical Research Institute.
Spanish Ministry of Economy and Competitiveness and Feder Funds.
All authors have declared no conflicts of interest.