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. 2020 Jul 7;12(7):1820.
doi: 10.3390/cancers12071820.

Prospective Assessment of Systemic MicroRNAs as Markers of Response to Neoadjuvant Chemotherapy in Breast Cancer

Andrew McGuire  1 , Maire-Caitlin Casey  1 , Ronan M Waldron  1 , Helen Heneghan  1 , Olga Kalinina  2 , Emma Holian  2 , Ailbhe McDermott  1 , Aoife J Lowery  1 , John Newell  2 , Róisín M Dwyer  1 , Nicola Miller  1 , Maccon Keane  3 , James A L Brown  1   4   5 , Michael J Kerin  1   6
Affiliations

Prospective Assessment of Systemic MicroRNAs as Markers of Response to Neoadjuvant Chemotherapy in Breast Cancer

Andrew McGuire et al. Cancers (Basel). .

Abstract

Neoadjuvant chemotherapy (NACT) is used in locally advanced breast cancer to reduce tumour burden prior to surgical resection. However, only a subset of NACT treated patients will respond to treatment or achieve a pathologic complete response (pCR). This multicenter, prospective study (CTRIAL-IE (ICORG) 10-11 study) evaluated circulating microRNA as novel non-invasive prognostic biomarkers of NACT response in breast cancer. Selected circulating microRNAs (Let-7a, miR-21, miR-145, miR-155, miR-195) were quantified from patients undergoing standard of care NACT treatment (n = 114) from whole blood at collected at diagnosis, and the association with NACT response and clinicopathological features evaluated. NACT responders had significantly lower levels of miR-21 (p = 0.036) and miR-195 (p = 0.017), compared to non-responders. Evaluating all breast cancer cases miR-21 was found to be an independent predictor of response (OR 0.538, 95% CI 0.308-0.943, p < 0.05). Luminal cancer NACT responders were found to have significantly decreased levels of miR-145 (p = 0.033) and miR-21 (p = 0.048), compared to non-responders. This study demonstrates the prognostic ability of miR-21, miR-195 and miR-145 as circulating biomarkers stratifying breast cancer patients by NACT response, identifying patients that will derive the maximum benefit from chemotherapy.

Keywords: biomarker; breast; chemotherapy; microRNA; neoadjuvant; prognostic.

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Conflict of interest statement

M. Kerin, H. Heneghan and N. Miller: circulating miR-195 as a biomarker patent. All miRNA were measured on blinded samples and the unblinded analysis was performed by independent study statisticians. All other authors declare no potential conflicts of interest.

Figures

Figure 1
Figure 1
Levels of indicated miRNAs in the specified breast cancer subtypes. No significant association between the target miRNA level and any breast cancer subtype was found. Luminal, n = 57; Luminal B Her2, n = 20; Her2+, n = 14; Triple negative, n = 23.
Figure 2
Figure 2
Relationship between the target miRNAs levels and tumour bed response to NACT in responders compared to non-responders. Responders n = 51, Non-responders n = 58. p < 0.05 considered significant.
Figure 3
Figure 3
Univariate analysis of miRNA-21 and miRNA-195 level as an independent predictor of response. (A) For miRNA-21 every unit increase miRNA-21, the odds ratio of being a non-responder relative to a responder is 1.86 (1/0.538) times higher. (B) miRNA-195—with every unit increase in miRNA-195, the odds ratio of being a non-responder relative to a responder is 1.78 (1/0.561) times higher. Observations = n (indicated for each).
Figure 4
Figure 4
Variation in levels of each target miRNA by response to NACT was assessed in the four breast cancer subtypes. (A) miRNA-21 patients with low levels had a higher response rate in Luminal cancers. (B) miRNA-145 patients with low levels had a higher response rate in Luminal cancers. Luminal (responders n = 15, non-responders n = 41), Luminal B Her2 (responders n = 12, non-responders n = 7), Her2+ (non-luminal) (responders n = 10, non-responders n = 3), Triple negative (responders n = 14, non-responders n = 9). p < 0.05 considered significant.
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