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Plasma miRNA Levels for Predicting Therapeutic Response to Neoadjuvant Treatment in HER2-positive Breast Cancer: Results from the NeoALTTO Trial

Serena Di Cosimo, Valentina Appierto, Sara Pizzamiglio, Paola Tiberio, Marilena V Iorio, Florentine Hilbers, Evandro De Azambuja, Lorena De La Pena, Miguel Izquierdo, Jens Huober, José Baselga, Martine Piccart, Filippo G De Braud, Giovanni Apolone, Paolo Verderio & Maria Grazia Daidone

abstract

PURPOSE
To investigate the potential of circulating-miRNAs (ct-miRNA) as noninvasive biomarkers to predict the efficacy of single/dual HER2-targeted therapy in the NeoALTTO study.

EXPERIMENTAL DESIGN
Patients with plasma samples at baseline (T0) and/or after 2 weeks (T1) of treatment were randomized into training ( = 183) and testing ( = 246) sets. RT-PCR-based high-throughput miRNA profiling was employed in the training set. After normalization, ct-miRNAs associated with pathologic complete response (pCR) were identified by univariate analysis. Multivariate logistic regression models were implemented to generate treatment-specific signatures at T0 and T1, which were evaluated by RT-PCR in the testing set. Event-free survival (EFS) according to ct-miRNA signatures was estimated by Kaplan-Meier method and Cox regression model.

RESULTS
In the training set, starting from 51 ct-miRNAs associated with pCR, six signatures with statistically significant predictive capability in terms of area under the ROC curve (AUC) were identified. Four signatures were confirmed in the testing set: lapatinib at T0 and T1 [AUC 0.86; 95% confidence interval (CI), 0.73-0.98 and 0.71 (0.55-0.86)], respectively; trastuzumab at T1 (0.81; 0.70-0.92); lapatinib + trastuzumab at T1 (0.67; 0.51-0.83). These signatures were confirmed predictive after adjusting for known variables, including estrogen receptor status. ct-miRNA signatures failed to correlate with EFS. However, the levels of ct-miR-140-5p, included in the trastuzumab signature, were associated with EFS (HR 0.43; 95% CI, 0.22-0.84).

CONCLUSIONS
ct-miRNAs discriminate patients with and without pCR after neoadjuvant lapatinib- and/or trastuzumab-based therapy. ct-miRNAs at week two could be valuable to identify patients responsive to trastuzumab, to avoid unnecessary combination with other anti-HER2 agents, and finally to assist deescalating treatment strategies.
   
citation Di Cosimo S, Appierto V, Pizzamiglio S, Tiberio P, Iorio M V, Hilbers F, de Azambuja E, de la Pena L, Izquierdo M, Huober J, Baselga J, Piccart M, de Braud F G, Apolone G, Verderio P, Daidone M G. Plasma miRNA Levels for Predicting Therapeutic Response to Neoadjuvant Treatment in HER2-positive Breast Cancer: Results from the NeoALTTO Trial. Clin Cancer Res 2019; 25:3887-3895.
   
type journal paper/review (English)
date of publishing 27-02-2019
journal title Clin Cancer Res (25/13)
ISSN electronic 1557-3265
pages 3887-3895
PubMed 30814109
DOI 10.1158/1078-0432.CCR-18-2507