BACKGROUND: Sequential treatment with azacitidine can induce re-expression of epigenetically silenced genes through genomic DNA hypomethylation and reverse carboplatin resistance of epithelial ovarian cancer cells. A phase 1b-2a clinical trial of this sequential combination of azacitidine and carboplatin was initiated in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer. METHODS: Patients with pathologically confirmed intermediate-grade or high-grade epithelial ovarian cancer who developed disease progression within 6 months (resistant disease, n = 18 patients) or during a platinum-based therapy (refractory disease, n = 12 patients) were eligible. All patients had measurable disease. RESULTS: Thirty patients received a total of 163 cycles of treatment. This regimen produced 1 complete response, 3 partial responses (overall response rate [ORR], 13.8%), and 10 cases of stable disease among 29 evaluable patients. For those patients who achieved clinical benefits, the median duration of the treatment was 7.5 months. The median progression-free survival (PFS) and overall survival (OS) for all patients were 3.7 months and 14 months, respectively. Patients with platinum-resistant disease achieved an ORR of 22%, with a median PFS of 5.6 months and a median OS of 23 months. The predominant toxicities were fatigue and myelosuppression. Correlative studies indicated that DR4 methylation in peripheral blood leukocytes was decreased during treatment in 3 of 4 objective responders (75%), but in only 5 of 13 nonresponders (38%). CONCLUSIONS: To the authors' knowledge, the results of the current study provide the first clinical evidence that a hypomethylating agent may partially reverse platinum resistance in patients with ovarian cancer. Further clinical evaluation of hypomethylating agents in combination with carboplatin is warranted.
BACKGROUND: Sequential treatment with azacitidine can induce re-expression of epigenetically silenced genes through genomic DNA hypomethylation and reverse carboplatin resistance of epithelial ovarian cancer cells. A phase 1b-2a clinical trial of this sequential combination of azacitidine and carboplatin was initiated in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer. METHODS:Patients with pathologically confirmed intermediate-grade or high-grade epithelial ovarian cancer who developed disease progression within 6 months (resistant disease, n = 18 patients) or during a platinum-based therapy (refractory disease, n = 12 patients) were eligible. All patients had measurable disease. RESULTS: Thirty patients received a total of 163 cycles of treatment. This regimen produced 1 complete response, 3 partial responses (overall response rate [ORR], 13.8%), and 10 cases of stable disease among 29 evaluable patients. For those patients who achieved clinical benefits, the median duration of the treatment was 7.5 months. The median progression-free survival (PFS) and overall survival (OS) for all patients were 3.7 months and 14 months, respectively. Patients with platinum-resistant disease achieved an ORR of 22%, with a median PFS of 5.6 months and a median OS of 23 months. The predominant toxicities were fatigue and myelosuppression. Correlative studies indicated that DR4 methylation in peripheral blood leukocytes was decreased during treatment in 3 of 4 objective responders (75%), but in only 5 of 13 nonresponders (38%). CONCLUSIONS: To the authors' knowledge, the results of the current study provide the first clinical evidence that a hypomethylating agent may partially reverse platinum resistance in patients with ovarian cancer. Further clinical evaluation of hypomethylating agents in combination with carboplatin is warranted.
Authors: Huidong Shi; Susan H Wei; Yu-Wei Leu; Farahnaz Rahmatpanah; Joseph C Liu; Pearlly S Yan; Kenneth P Nephew; Tim Hui-Ming Huang Journal: Cancer Res Date: 2003-05-01 Impact factor: 12.701
Authors: Julia Willner; Kaitlyn Wurz; Kimberly H Allison; Vijaya Galic; Rochelle L Garcia; Barbara A Goff; Elizabeth M Swisher Journal: Hum Pathol Date: 2007-01-29 Impact factor: 3.466
Authors: H T See; R S Freedman; A P Kudelka; T W Burke; D M Gershenson; S Tangjitgamol; J J Kavanagh Journal: Int J Gynecol Cancer Date: 2005 Mar-Apr Impact factor: 3.437
Authors: Peter Horak; Dietmar Pils; Griet Haller; Ingrid Pribill; Max Roessler; Sandra Tomek; Reinhard Horvat; Robert Zeillinger; Christoph Zielinski; Michael Krainer Journal: Mol Cancer Res Date: 2005-06 Impact factor: 5.852
Authors: Roger M Lyons; Thomas M Cosgriff; Sanjiv S Modi; Robert H Gersh; John D Hainsworth; Allen L Cohn; Heidi J McIntyre; Indra J Fernando; Jay T Backstrom; C L Beach Journal: J Clin Oncol Date: 2009-03-02 Impact factor: 44.544
Authors: Laura Menendez; DeEtte Walker; Lilya V Matyunina; Erin B Dickerson; Nathan J Bowen; Nalini Polavarapu; Benedict B Benigno; John F McDonald Journal: Mol Cancer Date: 2007-01-25 Impact factor: 27.401
Authors: George S Watts; Bernard W Futscher; Nicholas Holtan; Koen Degeest; Frederick E Domann; Stephen L Rose Journal: BMC Med Genomics Date: 2008-09-30 Impact factor: 3.063
Authors: Min-Yu Chen; Warren S-L Liao; Zhen Lu; William G Bornmann; Violeta Hennessey; Michele N Washington; Gary L Rosner; Yinhua Yu; Ahmed Ashour Ahmed; Robert C Bast Journal: Cancer Date: 2011-10-01 Impact factor: 6.860
Authors: Jia Yu; Bo Qin; Ann M Moyer; Somaira Nowsheen; Tongzheng Liu; Sisi Qin; Yongxian Zhuang; Duan Liu; Shijia W Lu; Krishna R Kalari; Daniel W Visscher; John A Copland; Sarah A McLaughlin; Alvaro Moreno-Aspitia; Donald W Northfelt; Richard J Gray; Zhenkun Lou; Vera J Suman; Richard Weinshilboum; Judy C Boughey; Matthew P Goetz; Liewei Wang Journal: J Clin Invest Date: 2018-04-30 Impact factor: 14.808
Authors: Fang Fang; Joanne Munck; Jessica Tang; Pietro Taverna; Yinu Wang; David F B Miller; Jay Pilrose; Gavin Choy; Mohammad Azab; Katherine S Pawelczak; Pamela VanderVere-Carozza; Michael Wagner; John Lyons; Daniela Matei; John J Turchi; Kenneth P Nephew Journal: Clin Cancer Res Date: 2014-10-14 Impact factor: 12.531