178P - Generation of a plasma microRNA (miRNA) signature predicting response to metronomic chemotherapy (MC) for advanced breast cancer (ABC)

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Breast Cancer, Metastatic
Translational Research
Presenter Urban Emmenegger
Citation Annals of Oncology (2014) 25 (suppl_4): iv58-iv84. 10.1093/annonc/mdu326
Authors U. Emmenegger1, B.A. Sousa2, V.C. Hoang3, A. Chow3, M. Clemons4, S. Dent4, N.S. Wong5, R. Kerbel3, M. Trudeau6, J. Slingerland7, A. Eisen6, J.M. Ebos8, K. Chan6, S. Gardner9, K. Pritchard6
  • 1Medical Oncology, Sunnybrook Odette Cancer Center, Sunnybrook HSC, M4N3M5 - Toronto/CA
  • 2Medical Oncology, Champalimaud Cancer Center, Lisbon/PT
  • 3Biological Sciences, Sunnybrook Research Institute, Toronto/CA
  • 4Systemic Therapy, The Ottawa Hospital Regional Cancer Centre, Ottawa/CA
  • 5Medical Oncology, National Cancer Center, 169610 - Singapore/SG
  • 6Medical Oncology, Sunnybrook Odette Cancer Center, Sunnybrook HSC, Toronto/CA
  • 7Medical Oncology, Sylvester Comprehensive Cancer Centre, Miami/US
  • 8Genitourinary Section, Department Of Medicine, Roswell Park Cancer Institute, Buffalo/US
  • 9Dalla Lana School Of Public Health, University of Toronto, Toronto/CA

Abstract

Aim

MC (continuous administration of low doses of conventional chemotherapeutics) is characterized by an excellent therapeutic index. In fact, we recently demonstrated that 24% of patients with ABC receiving daily dalteparin and oral cyclophosphamide, twice-weekly methotrexate, and daily prednisone (dalCMP) achieved clinical benefit with minimal toxicity. While there are no predictive markers of response to MC, circulating miRNAs have a high potential to serve as easy accessible biomarkers. Hence we sought to generate a predictive plasma miRNA signature of response to dalCMP.

Methods

We analyzed pre-treatment plasma samples from top-responders versus patients with dalCMP refractory ABC (n = 6 each) using the nCounter® miRNA expression assay (NanoString Technologies). Candidate miRNAs were validated by qRT-PCR.

Results

Of 800 human miRNAs of miRBase v18.0, we identified 210 miRNAs expressed in all patient samples. Of these, the average expression of 24 miRNAs displayed a > 2-fold change in either direction in responders to dalCMP (mean ± SD time to tumor progression 65.6 ± 13.9 weeks) versus non-responders (3.2 ± 1.0 weeks). Student t-testing followed by Benjamini–Hochberg correction revealed 6 miRNAs significantly upregulated in non-responders: miR-451a, miR-122-5p, miR-142-3p, miR-548ai, miR-150-5p, and miR-342-3p. Using qRT-PCR, we confirmed the differential expression pattern of miR-451a, miR-122-5p, miR-142-3p, and miR-548ai. In contrast to our findings, miR-451a overexpression has been found by others to exert in vitro chemosensitizing properties, whereas miR-122-5p, miR-142-3p and miR-548ai have not been associated with chemosensitivity modulation to date.

Conclusions

We describe the first candidate miRNA signature predicting response to MC (i.e. dalCMP), currently being validated in the original and extension dalCMP study populations (n = 92). This signature may become a helpful tool to select patients with ABC suitable for dalCMP, and to possibly predict response to other MC regimens as well as to MC used for other tumor types.

Disclosure

All authors have declared no conflicts of interest.