Carboplatin with Decitabine Therapy, in Recurrent Platinum Resistant Ovarian Cancer, Alters Circulating miRNAs Concentrations: A Pilot Study.
OBJECTIVE
Plasma miRNAs represent potential minimally invasive biomarkers to monitor and predict outcomes from chemotherapy. The primary goal of the current study-consisting of patients with recurrent, platinum-resistant ovarian cancer-was to identify the changes in circulating miRNA concentrations associated with decitabine followed by carboplatin chemotherapy treatment. A secondary goal was to associate clinical response with changes in circulating miRNA concentration.


METHODS
We measured miRNA concentrations in plasma samples from 14 patients with platinum-resistant, recurrent ovarian cancer enrolled in a phase II clinical trial that were treated with a low dose of the hypomethylating agent (HMA) decitabine for 5 days followed by carboplatin on day 8. The primary endpoint was to determine chemotherapy-associated changes in plasma miRNA concentrations. The secondary endpoint was to correlate miRNA changes with clinical response as measured by progression free survival (PFS).


RESULTS
Seventy-eight miRNA plasma concentrations were measured at baseline (before treatment) and at the end of the first cycle of treatment (day 29). Of these, 10 miRNAs (miR-193a-5p, miR-375, miR-339-3p, miR-340-5p, miR-532-3p, miR-133a-3p, miR-25-3p, miR-10a-5p, miR-616-5p, and miR-148b-5p) displayed fold changes in concentration ranging from -2.9 to 4 (p<0.05), in recurrent platinum resistant ovarian cancer patients, that were associated with response to decitabine followed by carboplatin chemotherapy. Furthermore, lower concentrations of miR-148b-5p after this chemotherapy regimen were associated (P<0.05) with the PFS.


CONCLUSIONS
This is the first report demonstrating altered circulating miRNA concentrations following a combination platinum plus HMA chemotherapy regiment. In addition, circulating miR-148b-5p concentrations were associated with PFS and may represent a novel biomarker of therapeutic response, with this chemotherapy regimen, in women with recurrent, drug-resistant ovarian cancer.
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; VA Roudebush Hospital, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
Eric A
EA
Benson
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana, United States of America.
Todd C
TC
Skaar
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States of America; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
Yunlong
Y
Liu
Departments of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Department of Obstetrics and Gynecology Medical Sciences Program Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana, United States of America.
Kenneth P
KP
Nephew
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; VA Roudebush Hospital, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Department of Obstetrics and Gynecology Medical Sciences Program Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana, United States of America; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
Daniela
D
Matei
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D016190:Carboplatin / Q000008:administration & dosage; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D010865:Pilot Projects; D011379:Prognosis; D015996:Survival Rate; D055815:Young Adult
D014408:Biomarkers, Tumor; D035683:MicroRNAs; D000077209:Decitabine; D016190:Carboplatin; D001374:Azacitidine