Poster Presentation 26th Lorne Cancer Conference 2014

Circulating microRNAs associated with chemotherapy outcome of prostate cancer (#198)

Hui-Ming Lin 1 , Lesley Castillo 1 , Kate Mahon 1 2 , Kate Chiam 1 , Brian Yong Lee 1 , Quoc Nguyen 1 , Michael Boyer 2 , Martin Stockler 2 3 , Nick Pavlakis 4 , Gavin Marx 5 , Girish Mallesara 6 , Howard Gurney 7 , Susan Clark 1 , Alexander Swarbrick 1 , Roger Daly 8 , Lisa Horvath 2
  1. Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Chris O'Brien Lifehouse, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
  3. National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia
  4. Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia
  5. Northen Haematology and Oncology Group, Sydney Adventist Hospital, Wahroonga, NSW, Australia
  6. Calvary Mater Newcastle Hospital, Waratah, NSW, Australia
  7. Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, NSW, Australia
  8. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia

Background: Despite a range of new treatments, docetaxel remains the first-line chemotherapy for castration-resistant prostate cancer (CRPC). Only 50% of patients respond to docetaxel, and response is determined quite late in the treatment schedule after patients have experienced significant toxicity. Early therapeutic response biomarkers are needed to identify non-responders quickly and assist in therapeutic decision-making. This study aims to determine if circulating microRNAs are associated with docetaxel chemotherapy outcome in CRPC patients.
Methods: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma or serum from 97 CRPC patients, collected before (pre-docetaxel) and after the first, second or third cycle of docetaxel chemotherapy (post-docetaxel). Mann-Whitney-U test, Kaplan-Meier analysis, ROC analysis and Cox regression were used to assess the association between microRNA levels and chemotherapy outcomes. Chemotherapy outcomes were defined by serum prostate-specific antigen (PSA) responses (non-responders = stable or progressive disease) and overall survival.
Results: Fourteen microRNAs were associated with PSA response or overall survival (p<0.05). Non-responders and patients with shorter survival generally had high pre-docetaxel levels of miR-200 family members (miR-200a, miR-200b, miR-200c, miR-429), or decreased/unchanged post-docetaxel levels of miR-17 family members (miR-20a, miR-20b) (p<0.05). Pre-docetaxel levels of miR-200a, post-docetaxel change in miR-222, hemoglobin levels and PSA response were independent predictors of overall survival when microRNAs were modeled together with clinicopathological factors (multivariate Cox regression p<0.05).
Conclusions: Circulating microRNAs are potential early predictors of docetaxel chemotherapy outcome and may be useful in stratifying patients into appropriate treatments. Futhermore, these microRNAs may be involved in docetaxel resistance or CRPC progression, and thereby represent potential therapeutic targets.