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

• Published in: Clinical cancer research Vol. 21; no. 3; pp. 602 - 610
• Main Authors: Bottsford-Miller, Justin, Choi, Hyun-Jin, Dalton, Heather J, Stone, Rebecca L, Cho, Min Soon, Haemmerle, Monika, Nick, Alpa M, Pradeep, Sunila, Zand, Behrouz, Previs, Rebecca A, Pecot, Chad V, Crane, Erin King, Hu, Wei, Lutgendorf, Susan K, Afshar-Kharghan, Vahid, Sood, Anil K
• Format: Journal Article
• Language: English
• Published: United States 01.02.2015
• Subjects: 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; Ovarian Neoplasms - complications; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - pathology; Platelet Count; Retrospective Studies; Taxoids - administration & dosage; Thrombosis - etiology; Treatment Outcome; Tumor Burden; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-14-0870

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. 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. 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. Platelet-driven effects of chemotherapy response may explain clinical observations.