Evaluating the Role of Circulating MicroRNAs to Aid Therapeutic Decision Making for Neoadjuvant Chemotherapy in Breast Cancer: A Prospective, Multicenter Clinical Trial

Matthew G Davey, Maire Caitlin Casey, Andrew McGuire, Ronan M Waldron, Maxwell Paganga, Emma Holian, John Newell, Helen M Heneghan, Ailbhe M McDermott, Maccon M Keane, Aoife J Lowery, Nicola Miller, Michael J Kerin, Matthew G Davey, Maire Caitlin Casey, Andrew McGuire, Ronan M Waldron, Maxwell Paganga, Emma Holian, John Newell, Helen M Heneghan, Ailbhe M McDermott, Maccon M Keane, Aoife J Lowery, Nicola Miller, Michael J Kerin

Abstract

Objective: To evaluate whether circulating micro ribonucleic acids (miRNAs) predict response to neoadjuvant chemotherapy (NAC) and inform decision-making in breast cancer patients.

Introduction: Deciphering response to NAC remains a challenge. Those unlikely to respond may benefit from NAC de-escalation before completion, while "responders" should complete treatment. Establishing biomarkers which identify response to NAC is imperative to personalize treatment strategies. miRNAs are small noncoding RNA molecules which modulate genetic expression. miRNAs are believed to inform response to NAC.

Methods: This prospective, multicenter trial (NCT01722851) recruited 120 patients treated with NAC across 8 Irish treatment sites. Predetermined miRNAs were quantified from patient whole bloods using relative quantification polymerase chain reactiond. Venous sampling was performed at diagnosis and midway during NAC. Trends in miRNA expression between timepoints were correlated with treatment response. Data analysis was performed using R 3.2.3.

Results: A total of 120 patients were included (median age: 55 years). Overall, 49.2% had luminal breast cancers (59/120), 17.5% luminal B (L/HER2) (21/120), 12.5% human epidermal growth factor receptor-2 positive (HER2+) (15/120), and 20.8% triple negative disease (25/120). In total, 46.7% of patients responded to NAC (56/125) and 26.7% achieved a pathological complete response (pCR) (32/120). For patients with L/HER2, increased Let-7a predicted response to NAC ( P =0.049), while decreased miR-145 predicted response to NAC in HER2+ ( P =0.033). For patients with luminal breast cancers, reduced Let-7a predicted achieving a pCR ( P =0.037) and reduced miR-145 predicted achieving a pCR to NAC in HER2+ ( P =0.027).

Conclusions: This study illustrates the potential value of circulatory miRNA measurement in predicting response to NAC. Further interrogation of these findings may see miRNAs personalize therapeutic decision-making for patients undergoing NAC for early breast cancer.

Conflict of interest statement

The authors report no conflicts of interest.

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.

Figures

FIGURE 1
FIGURE 1
Scheme of timepoints at which venous sampling occurred during this study: Timepoint 1 (T1) which involved venous sampling at breast cancer diagnosis (and before standard-of-care with neoadjuvant chemotherapy), and Timepoint 2 (T2) at the halfway point during neoadjuvant chemotherapy).
FIGURE 2
FIGURE 2
The difference in miRNA expression profiles between Timepoint 2 minus Timepoint 1 and the correlation with response to neoadjuvant chemotherapy for each of the breast cancer molecular subtypes.
FIGURE 3
FIGURE 3
The difference in miRNA expression profiles between Timepoint 2 minus Timepoint 1 and the correlation with pathological complete response to neoadjuvant chemotherapy for each of the breast cancer molecular subtypes.

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