1 Nedaplatin And Paclitaxel Compared With Carboplatin And Paclitaxel For Patients With Platinum-Sensitive Recurrent Ovarian Cancer 2 Copy Number Variations Of Neurotrophic Tyrosine Receptor Kinase 3 (NTRK3) May Predict Prognosis Of Ovarian Cancer

PART Ⅰ Nedaplatin and Paclitaxel Compared with Carboplatin and Paclitaxel for Patients with Platinum-Sensitive Recurrent Ovarian Cancer[Background and Objectives]For patients with platinum-sensitive recurrent ovarian cancer,chemotherapy is an important part of treatment protocols.Many large international researches indicated that CP(carboplatin plus paclitaxel)and CD(carboplatin plus pegylated liposomal doxorubicin)were common combined chemotherapeutic protocols for platinum-sensitive ovarian cancer.Our study was designed to evaluate the efficacy and safety of nedaplatin plus paclitaxel(NP)compared with carboplatin plus paclitaxel(CP)in platinum-sensitive recurrent ovarian cancer.[Materials and Methods]Patients with histologically proven epithelial ovarian,fallopian tube,or primary peritoneal cancer with recurrent interval ≥ 6 months after finishing platinum-based therapies between January 1,2009 and December 31,2014 were investigated.Patients received an intravenous infusion of NP(nedaplatin 80 mg/m2 plus paclitaxel 175 mg/m2)or CP(carboplatin at an area under the curve of 5 plus paclitaxel 175 mg/m2)protocols every 3 weeks for at least 6-8 cycles or until disease progression.The total cycles were no more than 8 cycles.Primary end point was progression-free survival(PFS);secondary end points were toxicity and overall survival(OS)[Results]PFS was the main end-point of the analysis.After a median follow-up of 63.5 months and 375 PFS events,NP arm showed a non-significant increase in PFS compared with CP arm,with an HR of 0.847(P=0.109).The median PFS was 11.0 months and 9.5 months for NP arm and CP arm,respectively.Compared with CP arm,there was no OS benefit in NP arm(P=0.765).The median OS was 74 months in the CP arm versus 73 months in the NP group.According to treatment-free interval(6 to 12 months v>12 months),we performed subgroup analysis and the results indicated that the PFS of NP protocol(10.0 months)was superior than CP regimen when treatment-free interval was between 6 and 12 months(8.0 months,P=0.048),while no significance existed between two group when treatment-free interval was>12 months(PFS,12 months in both groups,P=0.543).Cox regression model evaluated the impact of age,number of previous lines of chemotherapy,recurrent interval,operation at relapse,residual status of debulking,tumor differentiation,pathological classification,ECOG score,therapy protocols and cycles of regimen on PFS.ECOG score,recurrent interval,operation at relapse,therapy protocols and cycles of regimen maintained significance in the multivariate Cox regression model.[Conclusions]Compared to the CP,NP protocol did not improve 5-year overall survival in platinum-sensitive recurrent ovarian cancer,but it had better tolerance.NP obtained significant benefit in progression-free survival when the recurrent interval was between 6 and 12 months,although the efficacy of two protocols were similar when the recurrent interval≥12 months.PART Ⅱ Copy Number Variations of Neurotrophic Tyrosine Receptor Kinase 3(NTRK3)may Predict Prognosis of Ovarian Cancer[Background and Objectives]Ovarian cancer is one of the most deadly gynecological cancers,representing the fifth leading cause of death from cancer among women.Lacking effective early detection methods and typical clinical symptoms,the proportion of advanced ovarian cancer is close to 70%at the time of diagnosis.The responsive rate of first-line chemotherapy in ovarian cancer is 70%,however,70%of all patients will experience recurrence within 2 years.After one or repeated recurrence,most of patients will be in relentless trajectory to eventual drug resistance,which is the crucial factor to determine the survival prognosis of ovarian cancer.In our study,array CGH was adopted to detect the copy number variations between platinum-resistant group and platinum-sensitive group,finally concentrating on the evaluation of the correlation between copy number variations(CNVs)of neurotrophic tyrosine receptor kinase 3(NTRK3)and the prognosis of ovarian cancer,which might associate with platinum resistance in ovarian cancer patients.[Materials and Methods]Array comparative genomic hybridization(Array CGH)was used to test gene backgrounds between platinum-sensitive and platinum-resistant relapsed populations and CNVs of NTRK3 were indicated by cluster analysis.Fluorescence in situ hybridization(FISH)was adopted in 52 cases for further verification with satisfied results among 41 cases,which confirmed the results of array CGH.Spearman’s rank correlation analysis and x test were used to evaluate the accuracy of CNVs of NTRK3 which predicted platinum-sensitive or platinum-resistant recurrence.[Results]The CNVs of NTRK3 among 17 cases by array CGH were further confirmed by FISH,and the results of 14 cases checked by FISH conformed to the standard.The CNVs of 11 cases were coincident in both array CGH and FISH examination.Concordance rate of both tests was 78.6%and there was no statistical difference between array CGH and FISH.Among 41 cases with satisfied FISH results,the median time to recurrence(TTR)of patients with amplified and nonamplified NTRK3 were respectively 18 and 5 months(P<0.01).The cut-off value of TTR to differentiate platinum-sensitive or platinum-resistant recurrence was 6 months in accordance with NCCN(National Comprehensive Cancer Network)clinical practice standard.According to the above standard,15 cases with NTRK3 amplification were platinum-sensitive and 12 cases without NTRK3 amplification were platinum-resistant recurrences,which demonstrated that the accuracy of NTRK3 amplification/nonamplification to predict recurrent types was 65.9%(27/41).[Conclusion]CNVs of NTRK3 were associated with platinum-sensitive and platinum-resistant recurrences.Amplification of NTRK3 perfectly predicted platinum-sensitive recurrence of ovarian cancer.