Circulating microRNAs are associated with docetaxel chemotherapy outcome in castration-resistant prostate cancer.
BACKGROUND
Docetaxel is the first-line chemotherapy for castration-resistant prostate cancer (CRPC). However, response rates are ∼50% and determined quite late in the treatment schedule, thus non-responders are subjected to unnecessary toxicity. The potential of circulating microRNAs as early biomarkers of docetaxel response in CRPC patients was investigated in this study.


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/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients.


RESULTS
Fourteen microRNAs were associated with serum prostate-specific antigen (PSA) response or overall survival, according to Mann-Whitney U or log-rank tests. Non-responders to docetaxel and patients with shorter survival generally had high pre-docetaxel levels of miR-200 family members or decreased/unchanged post-docetaxel levels of miR-17 family members. Multivariate Cox regression with bootstrapping validation showed that pre-docetaxel miR-200b levels, post-docetaxel change in miR-20a levels, pre-docetaxel haemoglobin levels and visceral metastasis were independent predictors of overall survival when modelled together.


CONCLUSIONS
Our study suggests that circulating microRNAs are potential early predictors of docetaxel chemotherapy outcome, and warrant further investigation in clinical trials.
Cancer Research Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
H-M
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Lin
Cancer Research Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
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Castillo
1] Cancer Research Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia [2] Sydney Medical School, University of Sydney, Camperdown, New South Wales 2006, Australia.
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Mahon
Cancer Research Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
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Chiam
Cancer Research Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
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Lee
1] Cancer Research Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia [2] Pharmacogenomic Research for Individualised Medicine (PRIMe) consortium, New South Wales, Australia.
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Nguyen
1] Sydney Medical School, University of Sydney, Camperdown, New South Wales 2006, Australia [2] Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, New South Wales 2050, Australia [3] Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia.
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Boyer
1] Sydney Medical School, University of Sydney, Camperdown, New South Wales 2006, Australia [2] Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, New South Wales 2050, Australia [3] Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia [4] Medical Oncology, Concord Repatriation General Hospital, Concord, New South Wales 2139, Australia.
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Stockler
1] Sydney Medical School, University of Sydney, Camperdown, New South Wales 2006, Australia [2] Medical Oncology, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia.
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Pavlakis
1] Sydney Medical School, University of Sydney, Camperdown, New South Wales 2006, Australia [2] Northern Haematology and Oncology Group, Sydney Adventist Hospital, Wahroonga, New South Wales 2076, Australia.
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Marx
1] Pharmacogenomic Research for Individualised Medicine (PRIMe) consortium, New South Wales, Australia [2] Calvary Mater Newcastle Hospital, Waratah, New South Wales 2298, Australia.
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Mallesara
1] Sydney Medical School, University of Sydney, Camperdown, New South Wales 2006, Australia [2] Pharmacogenomic Research for Individualised Medicine (PRIMe) consortium, New South Wales, Australia [3] Westmead Hospital, Westmead, New South Wales 2145, Australia.
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Gurney
1] Cancer Research Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia [2] St Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Sydney, New South Wales, Australia.
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Clark
1] Cancer Research Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia [2] St Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Sydney, New South Wales, Australia.
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Swarbrick
Signalling Network Laboratory, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
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Daly
1] Cancer Research Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia [2] Sydney Medical School, University of Sydney, Camperdown, New South Wales 2006, Australia [3] Pharmacogenomic Research for Individualised Medicine (PRIMe) consortium, New South Wales, Australia [4] Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, New South Wales 2050, Australia [5] Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia.
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Horvath
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000556:secondary / Q000601:surgery; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D045744:Cell Line, Tumor / Q000187:drug effects; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D008875:Middle Aged; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012334:RNA, Neoplasm / Q000097:blood*; D012372:ROC Curve; D012307:Risk Factors; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; C524941:MIRN17 microRNA, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D012334:RNA, Neoplasm; D043823:Taxoids; D000077143:Docetaxel; D017430:Prostate-Specific Antigen