Molecular Markers To Predict The Sensitivity To Paclitaxel/Platinum In Epithelial Ovarian Cancers

【Background and Purpose】Paclitaxel/platinum is currently the first-line regimen for postoperative patients with epithelial ovarian cancer(EOC),and the complete response rate after 6 cycles of paclitaxel/platinum is about 60%～70%.Predictors to chemosenstivity may be helpful to achieve individualized treatment and to improve clinical outcome.In the present study,we attempted to discover molecular markers to predict response to paclitaxel/platinum in EOCs.【Patients and Methods】Fifty-seven EOCs were selected in the patients treated in Cancer Hospital,Chinese Academy of Medical Scienses from Jan 2001 to Oct 2006. Genomic DNAs were isolated from the tumor specimens obtained during the primary surgeries.Array comparative genomic hybridization(CGH) were carried with genomic DNA from 8 chemosensitive cases and 9 chemoresistant cases to screen candidate genes,copy-number changes(CNCs) of which were significantly different between sensitive and resistant cases.CNCs of the candidate genes were validated by fluorescence in situ hybridization(FISH) or by real-time PCR in other 40 cases.The correlation between CNCs of the candidate genes and time to recurrence(TTR) was analyzed.【Results】Among 57 EOCs,35 were chemosensitive and 22 were chemoresistant. The overall TTR was 9 months.Seventeen candidate genes were identified by Array CGH.Aberrations in 15q25.3,where candidate genes clustered,were detected by FISH(BAC clone RP11-91E10).The median TTR of the cases with(n=18) and without amplification(n=23) in 15q25.3 were 18 and 5 months,respectively (P=0.002).The accuracy of aberrations in 15q25.3 by FISH to predict chemosensivity was 65.9%(27/41).For the validation of the candidate genes by real-time PCR,the results of Array CGH and real-time PCR were consistent in GSTT1,ISG20L1, STARD5 and FREM1,CNCs of which by real-time PCR were individually correlated with TTR(P＜0.05).The accuracy of CNCs of the 4 genes to predict chemosensivity was 62.3%(33/53).Among the "resistant" cases indicated simultaneously by the changes of both 15q25.3 and the 4 genes,those with TTR shorter than 6 months and 10 months were 64.7%(11/17) and 94.1%(16/17),respectively.Among the "sensitive" cases indicated simultaneously by the changes of 15q25.3 and the 4 genes, those with TTR longer than 6 months and 12 months were 100%(7/7) and 85.7% (6/7),respectively.【Conclusions】Aberrations in 15q25.3 by FISH(BAC clone RP11-91E10) and CNCs of GSTT1,ISG20L1,STARD5 and FREM1 by real-time PCR were both correlated with TTR.The "resistant" cases indicated simultaneously by the above markers were likely to be resistant to the first-line chemotherapy of paclitaxel/platinum,and majority of them recurred within 10 months.The "sensitive" cases indicated simultaneously by the above markers were sensitive to paclitaxel/platinum,and most of them showed a relatively good prognosis with TTR longer than 12 months.