Clinical validation of chemotherapy predictors developed on global microRNA expression in the NCI60 cell line panel tested in ovarian cancer.
OBJECTIVE
Ovarian cancer is the leading cause of death among gynecologic malignancies. This is partly due to a non-durable response to chemotherapy. Prediction of resistance to chemotherapy could be a key role in more personalized treatment. In the current study we aimed to examine if microRNA based predictors could predict resistance to chemotherapy in ovarian cancer, and to investigate if the predictors could be prognostic factors for progression free and overall survival.


METHODS
Predictors of chemotherapy-resistance were developed based on correlation between miRNA expression and differences in measured growth inhibition in a variety of human cancer cell lines in the presence of Carboplatin, Paclitaxel and Docetaxel. These predictors were then, retrospectively, blindly validated in a cohort of 170 epithelial ovarian cancer patients treated with Carboplatin and Paclitaxel or Docetaxel as first line treatment.


RESULTS
In a multivariate cox proportional analysis the predictors of chemotherapy-resistance were not able to predict time to progression after end of chemotherapy (hazard ratio: 0.64, 95% CI: 0.36-1.12, P = 0.117). However, in a multivariate logistic analysis, where time to progression was considered as either more or less than 6 months, the predictors match clinical observed chemotherapy-resistance (odds ratio: 0.19, 95% CI: 0.05-0.73, P = 0.015). Neither univariate nor multivariate, time-dependent, cox analysis for progression free survival (PFS) or overall survival (OS) in all 170 patients showed to match predicted resistance to chemotherapy (PFS: hazard ratio: 0.69, 95% CI: 0.40-1.19, P = 0.183, OS: hazard ratio: 0.76, 95% CI: 0.42-1.40, P = 0.386).


CONCLUSIONS
In the current study, microRNA based predictors of chemotherapy-resistance did not demonstrate any convincing correlation to clinical observed chemotherapy-resistance, progression free survival, or overall survival, in patients with epithelial ovarian cancer. However the predictors did reflect relapse more or less than 6 months.
Department of Pathology, Molecular unit, Danish CancerBiobank, Herlev University Hospital, Herlev, Denmark.|Department of Gynecology, The Juliane Marie Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Kira Philipsen
KP
Prahm
Department of Gynecology, The Juliane Marie Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Claus
C
Høgdall
Department of Pathology, Molecular unit, Danish CancerBiobank, Herlev University Hospital, Herlev, Denmark.|Department of Gynecology, The Juliane Marie Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Mona Aarenstrup
MA
Karlsen
Department of Pathology, Molecular unit, Danish CancerBiobank, Herlev University Hospital, Herlev, Denmark.
Ib Jarle
IJ
Christensen
Department of Pathology, Molecular unit, Danish CancerBiobank, Herlev University Hospital, Herlev, Denmark.
Guy Wayne
GW
Novotny
Medical Prognosis Institute, Hørsholm, Denmark.
Steen
S
Knudsen
Medical Prognosis Institute, Hørsholm, Denmark.
Anker
A
Hansen
Medical Prognosis Institute, Hørsholm, Denmark.
Peter Buhl
PB
Jensen
Medical Prognosis Institute, Hørsholm, Denmark.
Thomas
T
Jensen
Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Mansoor Raza
MR
Mirza
Department of Gynecology, The Juliane Marie Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Anne Weng
AW
Ekmann-Gade
Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Lotte
L
Nedergaard
Department of Pathology, Molecular unit, Danish CancerBiobank, Herlev University Hospital, Herlev, Denmark.
Estrid
E
Høgdall
D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D016190:Carboplatin / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000627:therapeutic use; D011379:Prognosis; D043823:Taxoids / Q000627:therapeutic use
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D035683:MicroRNAs; D043823:Taxoids; D000077143:Docetaxel; D016190:Carboplatin; D017239:Paclitaxel