Résumé
Backgroud: Clinicians need new predictive biomarkers of response to therapy hormonal in patients with hormone receptor-positive (HR+) breast cancer (BC). Tumor-associated miRNAs are interesting new markers. Several data indicate the extensive alterations in miRNAs regulation upon estrogen pathway and suggest the utility of considering miRNAs expression in the understanding of hormonal therapy efficacy.
Methods: We have conducted a bicentric, prospective clinical trial in patients who must received an anti-estrogen (Tamoxifen) or an aromatase inhibitor (+/- LHRH agonist) in first line for a HR+ metastatic BC. Plasma of patients were collected before the first administration of hormonal therapy (T=0) and after 1 (T=1), 3, 6 months and therafter in case of objective response or/and progression disease. After extraction from plasma expression i) of 372 miRNAs was analyzed on microRNA Ready-to-Use PCR, Human panel I, V3 from Exiqonand ii) of a selection of candidate miRNAs described in the litterature to be associated with estrogen pathway and hormonotherapy response in tissues were analyzed using the BioMark™ 96.96 Dynamic Array (Fluidigm Corporation) with Exiqon primers. The primary end point of our study, was the feasibility of detection of circulating miRNAs as biomarkers in plasma of patients. Key secondary end points were to compare i) the concentration of determinated miRNAs according patients, under therapy hormonam and according the efficacy or not ii) the profile of miRNAs between patients at T=0 + T=1 month and in the same patient under treatment.
Results : From March 2012 to January 2014, 39 patients were enrolled (5 under tamoxifen and 34 under aromatase inhibitor). At first concentration of circulating miRNAs in pools of patient plasmas from T=0 and T=1 was compared by RTqPCR. miRNAs with a significative fold change ratio together with several miRNAs from the litterature were then further analyzed for individual patient plasmas at T=0 and T=1. Several miRNAs and notably miRNAs previously described in breast tumors to be associated with estrogen pathway and hormonotherapy response are well-detected in plasma and, some of them show difference between T=0 and T=1. After univariate and multivariate analysis, the plasma miRNAs significantly associated with a therapy response will be next examined at 3 and 6 months.
Conclusion : This pilot study provides that tumor-associated circulating miRNAs could be measured in the plasma of patients and that alterations in miRNAs concentration upon hormonal therapy could be observed. More results will be presented at the SABCS meeting.
Citation Format: Florence Dalenc, Monia Ouali, Thomas Filleron, Laurence Gladieff, Henri Roché, Jean-Louis Lacaze, William Jacot, Anna Durigova, Anne Pradines, Pauline Bringer, Magali Farella, Gilles Favre. Circulating miRNAs as surrogate markers for hormonosensibility in patients with hormone receptor-positive metastatic breast cancer? A pilot study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-07-08.