Differential platelet levels affect response to taxane-based therapy in ovarian cancer. Clin Cancer Res 2015 Feb 01;21(3):602-10
Date
12/05/2014Pubmed ID
25473001Pubmed Central ID
PMC4315757DOI
10.1158/1078-0432.CCR-14-0870Scopus ID
2-s2.0-84961289449 (requires institutional sign-in at Scopus site) 74 CitationsAbstract
PURPOSE: We hypothesized that platelet levels during therapy could serve as a biomarker for response to therapy and that manipulation of platelet levels could impact responsiveness to chemotherapy.
EXPERIMENTAL DESIGN: The medical records of patients with recurrent or progressive ovarian cancer were retrospectively queried for changes in platelet and CA-125 levels during primary therapy. In vitro coculture experiments and in vivo orthotopic models of human ovarian cancer in mice were used to test the effect of modulating platelet levels on tumor growth and responsiveness to docetaxel.
RESULTS: Thrombocytosis at the diagnosis of ovarian cancer was correlated with decreased interval to progression (P = 0.05) and median overall survival (P = 0.007). Mean platelet levels corrected during primary therapy and rose at recurrence. Contrary to treatment-responsive patients, in a cohort of patients refractory to primary therapy, platelet levels did not normalize during therapy. In A2780, HeyA8, and SKOV3-ip1 ovarian cancer cell lines, platelet coculture protected against apoptosis (P < 0.05). In orthotopic models of human ovarian cancer, platelet depletion resulted in 70% reduced mean tumor weight (P < 0.05). Compared with mice treated with docetaxel, mice treated with both docetaxel and platelet-depleting antibody had a 62% decrease in mean tumor weight (P = 0.04). Platelet transfusion increased mean aggregate tumor weight 2.4-fold (P < 0.05), blocked the effect of docetaxel on tumor growth (P = 0.55) and decreased tumor cell apoptosis. Pretransfusion aspirinization of the platelets blocked the growth-promoting effects of transfusion.
CONCLUSIONS: Platelet-driven effects of chemotherapy response may explain clinical observations.
Author List
Bottsford-Miller J, Choi HJ, Dalton HJ, Stone RL, Cho MS, Haemmerle M, Nick AM, Pradeep S, Zand B, Previs RA, Pecot CV, Crane EK, Hu W, Lutgendorf SK, Afshar-Kharghan V, Sood AKAuthor
Sunila Pradeep PhD Associate Professor in the Obstetrics and Gynecology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Aged, 80 and over
Animals
Antineoplastic Combined Chemotherapy Protocols
Biomarkers
Bridged-Ring Compounds
Cell Line, Tumor
Disease Models, Animal
Disease Progression
Drug Resistance, Neoplasm
Female
Humans
Middle Aged
Neoplasm Recurrence, Local
Ovarian Neoplasms
Platelet Count
Retrospective Studies
Taxoids
Thrombosis
Treatment Outcome
Tumor Burden
Xenograft Model Antitumor Assays