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 Peña, Miguel Izquierdo, Jens Huober, José Baselga, Martine Piccart, Filippo G. De Braud, Giovanni Apolone, Paolo Verderio, Maria Grazia Daidone

Research output: Contribution to journalArticle

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 (n=183) and testing (n=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.

Original languageEnglish
Pages (from-to)3887-3895
Number of pages9
JournalClinical Cancer Research
Volume25
Issue number13
DOIs
Publication statusPublished - Jan 1 2019

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Neoadjuvant Therapy
MicroRNAs
Breast Neoplasms
Disease-Free Survival
Therapeutics
ROC Curve
Area Under Curve
Logistic Models
Confidence Intervals
Proportional Hazards Models
Estrogen Receptors
Research Design
Biomarkers
Trastuzumab

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Plasma miRNA levels for predicting therapeutic response to neoadjuvant treatment in HER2-positive breast cancer : Results from the NeoALTTO trial. / Di Cosimo, Serena; Appierto, Valentina; Pizzamiglio, Sara; Tiberio, Paola; Iorio, Marilena V.; Hilbers, Florentine; De Azambuja, Evandro; De La Peña, Lorena; Izquierdo, Miguel; Huober, Jens; Baselga, José; Piccart, Martine; De Braud, Filippo G.; Apolone, Giovanni; Verderio, Paolo; Daidone, Maria Grazia.

In: Clinical Cancer Research, Vol. 25, No. 13, 01.01.2019, p. 3887-3895.

Research output: Contribution to journalArticle

Di Cosimo, S, Appierto, V, Pizzamiglio, S, Tiberio, P, Iorio, MV, Hilbers, F, De Azambuja, E, De La Peña, L, Izquierdo, M, Huober, J, Baselga, J, Piccart, M, De Braud, FG, Apolone, G, Verderio, P & Daidone, MG 2019, 'Plasma miRNA levels for predicting therapeutic response to neoadjuvant treatment in HER2-positive breast cancer: Results from the NeoALTTO trial', Clinical Cancer Research, vol. 25, no. 13, pp. 3887-3895. https://doi.org/10.1158/1078-0432.CCR-18-2507
Di Cosimo, Serena ; Appierto, Valentina ; Pizzamiglio, Sara ; Tiberio, Paola ; Iorio, Marilena V. ; Hilbers, Florentine ; De Azambuja, Evandro ; De La Peña, Lorena ; Izquierdo, Miguel ; Huober, Jens ; Baselga, José ; Piccart, Martine ; De Braud, Filippo G. ; Apolone, Giovanni ; Verderio, Paolo ; Daidone, Maria Grazia. / Plasma miRNA levels for predicting therapeutic response to neoadjuvant treatment in HER2-positive breast cancer : Results from the NeoALTTO trial. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 13. pp. 3887-3895.
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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 (n=183) and testing (n=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.",
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T1 - Plasma miRNA levels for predicting therapeutic response to neoadjuvant treatment in HER2-positive breast cancer

T2 - Results from the NeoALTTO trial

AU - Di Cosimo, Serena

AU - Appierto, Valentina

AU - Pizzamiglio, Sara

AU - Tiberio, Paola

AU - Iorio, Marilena V.

AU - Hilbers, Florentine

AU - De Azambuja, Evandro

AU - De La Peña, Lorena

AU - Izquierdo, Miguel

AU - Huober, Jens

AU - Baselga, José

AU - Piccart, Martine

AU - De Braud, Filippo G.

AU - Apolone, Giovanni

AU - Verderio, Paolo

AU - Daidone, Maria Grazia

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 (n=183) and testing (n=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.

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