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Purpose: Increased appreciation of the human epidermal growth factor receptor-2 (HER2/neu) signalling pathway has led to the development of targeted therapeutic agents used in conjunction with chemotherapy to improve outcomes for HER2 overexpressing (HER2+) breast cancer. For neoadjuvant therapy, response rates can be unpredictable - novel biomarkers predicting effectiveness are required to enhance oncological outcomes for these patients, and microRNA may prove effective. Our objective was to identify microRNA (miRNA) expression patterns predictive of response to neoadjuvant chemotherapy (NAC) and/or anti-HER2 targeted therapies in patients being treated for early-stage HER2+ breast cancer. Methods: A search was performed of the PUBMED, SCOPUS, Web of Science, and EMBASE in accordance to Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Results: Overall, 15 studies including 1335 patients were included. These studies highlighted an expression profile of 73 miRNA and their ability to predict tumour response to neoadjuvant therapies was correlated. Results from 11 studies were in relation to circulatory miRNA and 4 studies included data from tumour tissue. Overall, upregulation and downregulation of 41 miRNA and 29 miRNA, respectively, predicted differential response to neoadjuvant therapy. Expression levels of 3 miRNA (miR-21, miR-210, and miR-376c-3p) were inconclusive in predicting therapeutic response, while 'aberrant' expression of circulating miR-199a predicted pathological complete response (pCR) to NAC. Conclusions: This systematic review outlines expression patterns of a number of miRNA which correlate with response to NAC and/or anti-HER2 therapies. Future translational research evaluating predictive biomarkers of primary response to neoadjuvant therapy in HER2+ breast cancer may consider these results.
RESUMO
BACKGROUND: Human epidermal growth factor receptor-2 (HER2) is overexpressed in 20-25% of breast cancers. Complete eradication of disease following neoadjuvant therapies and chemotherapy has been referred to as pathological complete response (pCR). AIMS: To determine clinicopathological predictors of pCR to neoadjuvant therapies and to evaluate pCR as a surrogate to enhanced survival. METHODS: Consecutive female patients with HER2 positive (HER+) breast cancer managed surgically in a single institution between 2005 and 2015 were included. Descriptive statistics and binary logistic regression were used to determine predictors of pCR. Appraisal of pCR as a predictor of survival was performed using Kaplan-Meier curves and Cox regression analysis. RESULTS: 451 patients were included with a mean age of 56.6 ± 13.4 years (range 23-95). Disease-free (DFS) and overall survival (OS) was 82.3% (371/451) and 82.6% (376/451) respectively with a median follow-up of 108.0 months (range 3-184.0). 118 were treated in the neoadjuvant setting (26.2%): tumour size <50 mm (Odds Ratio (OR): 12.156, P = 0.023) and progesterone receptor negativity (OR: 2.762, P = 0.008) independently predicted breast pCR, while ductal carcinoma (OR: 3.203, P = 0.030) and grade 3 disease (OR: 2.788, P = 0.018) predicted axillary pCR. Both breast and axillary pCR predicted enhanced DFS (Hazard Ratio (HR): 0.470 & HR: 0.449) and OS (HR: 0.383 & HR: 0.307). Axillary pCR independently predicted improved OS (HR: 0.326). CONCLUSION: pCR is sensitive biomarker and surrogate to survival outcomes in HER2+ breast cancer. Patients likely to achieve pCR may be predicted from traditional clinicopathological characteristics and molecular parameters.