Differential platelet levels affect response to taxane-based therapy in ovarian cancer.

Abstract

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.

• Authors: Justin Bottsford-Miller, Hyun-Jin Choi, Heather J Dalton, Rebecca L Stone, Min Soon Cho, Monika Haemmerle, Alpa M Nick, Sunila Pradeep, Behrouz Zand, Rebecca A Previs, Chad V Pecot, Erin King Crane, Wei Hu, Susan K Lutgendorf, Vahid Afshar-Kharghan, Anil K Sood
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 3 Pg. 602-10 (Feb 01 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25473001 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Biomarkers
• Bridged-Ring Compounds
• Taxoids
• taxane

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers
• Bridged-Ring Compounds (administration & dosage)
• Cell Line, Tumor
• Disease Models, Animal
• Disease Progression
• Drug Resistance, Neoplasm
• Female
• Humans
• Middle Aged
• Neoplasm Recurrence, Local
• Ovarian Neoplasms (blood, complications, drug therapy, pathology)
• Platelet Count
• Retrospective Studies
• Taxoids (administration & dosage)
• Thrombosis (etiology)
• Treatment Outcome
• Tumor Burden
• Xenograft Model Antitumor Assays