XXV Riunione MITO Napoli 25 Giugno 2014 MITO2 miRNA microarray profile identifies a strong predictor of disease relapse in ovarian cancer XXV Riunione.

Presentazione sul tema: "XXV Riunione MITO Napoli 25 Giugno 2014 MITO2 miRNA microarray profile identifies a strong predictor of disease relapse in ovarian cancer XXV Riunione."— Transcript della presentazione:

1 XXV Riunione MITO Napoli 25 Giugno 2014 MITO2 miRNA microarray profile identifies a strong predictor of disease relapse in ovarian cancer XXV Riunione MITO Napoli 25 Giugno 2014 MITO2 miRNA microarray profile identifies a strong predictor of disease relapse in ovarian cancer Unit of Molecular Therapies Department of Experimental Oncology and Molecular Medicine

2 2 2 MITO2 miRNA profiling Aim: development of a prognostic model to predict disease early relapse Overall design - training set: 179 cases from MITO2 trial; OC179 - validation set1: 263 cases from INT-CRO series; OC263 - validation set2: 452 cases from TCGA data; OC452 Overall 894 EOC cases were analyzed: “the largest miRNA EOC data set so far available” Three different platforms used for profiling; Re-annotation of all detected miRNAs on miRBase21 385 unique miRNA shared among all studies

3 2 2 Patients’ clinical-pathological characteristics

4 n events median 0.95CI 263 195 16 13-21 PFS time (months) n events median 0.95CI 179 124 22.8 18-29 n events median 0.95CI 452 327 17 15-18 PFS time (months) n events median 0.95CI 263 105 60 46-77 Surv time (months) n events median 0.95 CI 179 77 nyr 63-NA time (months) n events median 0.95CI 452 223 49 45-52 Surv time (months) 2 2 Patients’ clinical-pathological characteristics OC179 OC263 OC452 OS PFS

5 miRNA-based classifier End point: disease recurrance Application of an algorithm that on the basis of time-to-progression and relative expression of the 385 miRNAs, classified MITO2 patients as high or low risk to relapse. After a 10-fold cross validation a model was developed containing 35 unique miRNAs whose expression, although with different relevance, significantly contributed to define the risk of relapse of MITO2 cohort. miRNAs (19) whose expression associated to poor prognosis miRNAs (16) whose expression associated to good prognosis 2 2

6 2 2 OC179 – MITO2 patients’ stratification according to n° events median 0.95Cl HR OD 115 71 34 24-54 SOD 64 53 15 12-18 2.1 PFS time (months) Log-rank P<1.001 n° events median 0.95Cl HR high risk 89 72 18 15-22 1.85 low risk 90 52 38 24-nyr Log-rank P<1.001 the molecular classifierResidual disease

7 TTR time (months) 2 2 Stratification for risk prediction and RD improved prognosis of a patients’ subgroup n° events median 0.95Cl miRLr-OD 64 33 53 34-nyr miRLr-SOD 26 19 15 11-nyr miRHr-OD 51 38 21 15-34 miRHr-SOD 38 34 15 10-21 High risk-OD includes 9 stage I-II patients defined NED at primary surgery Stratification for risk prediction and RD improved prognosis of a patients’ subgroup and identified a subset of patients with favorable clinical prognostic marker and high risk of relapse

8 2 2 Molecular classifier validation on independent datasets neventsmedian0.95CI miR=L122733426-45 miR=H1411221210-13 HR 3.16 neventsmedian0.95CI miR=L1691151917-27 miR=H2832121514-18 HR 1.39

9 TTR neventsmedian0.95CI miRH_OD1881341513-18 miRH_SOD66611512-18 miRL_OD122752118-27 miRL_SOD34311412-19 miRH_ OD71591311-15 miRH_ SOD6962107-12 miRL_ OD90464234-62 miRL_ SOD322718.510-26 TTR time (months) High risk-OD includes 8 stage I-II patients, 7 defined NED at primary surgery High risk-OD includes 14 stage I-II patients, 11 defined NED at primary surgery n° events median 0.95Cl miRLr-OD 90 46 42 34-62 miRLr-SOD 32 27 18 10-26 miRHr-OD 71 59 13 11-15 miRHr-SOD 69 62 10 7-12 OC452 OC263 n° events median 0.95Cl miRLr-OD 122 75 21 18-27 miRLr-SOD 34 31 14 12-19 miRHr-OD 188 134 15 13-18 miRHr-SOD 66 61 10 12-18 2 2 Stratification for risk prediction and RD improved prognosis of a patients’ subgroup and identified a subset of patients with favorable clinical prognostic marker but high risk of relapse

10 PFS time (months) miR_treat 2 2 No interaction with treatment arm miR-Low risk miR-high risk

11 2 2 The miRNA molecular classifier is an independent prognostic marker Covariates: Stage: III-IV vs. I-II Residual disease: >1cm vs. <1cm 35 miRNA model: above threshold cut-off vs. below threshold cut-off The miRNA molecular classifier is an independent prognostic marker also in HGSOC subgroup

12 Punti di forza:  prima meta-analisi di miRNAs su EOC  EOC dataset al momento più numeroso (n=894; OC179 da MITO2; OC263 da INT-CRO; OC452 da TCGA)  meta-analisi su diverse piattaforme  analisi di sottotipi miRNA integrabili con espressione genica (RNAseq) per sviluppo di modelli predittivi di risposta  Emendamento per RNAseq su MITO2 ed emendamento su MITO7 per validazione custom panel miRNA/Genes 2 2 MITO2 miRNA profiling: conclusions P=0.000742 OC179 MITO2

13 Punti critici:  annotazioni diverse tra piattaforme con conseguente riduzione dei miRNA comuni alle piattaforme  continuo aggiornamento miRBASE  necessità di recuperare nuove casistiche indipendenti di validazione: MITO7, MITO16?? 2 2 MITO2 miRNA profiling: conclusions Ringraziamenti:  Sandro Pignata, Danela Califano, Simona Losito, Gennaro Chiappetta, Massimo Di Maio, Franco Perrone.................  Loris De Cecco, Marina Bagnoli, Silvana Canevari, Francesco Raspagliesi, Ketta Lorusso, Maria Luisa Carcangiu  Giuseppe Toffoli, Erika Cecchin  tutto il gruppo MITO

14 MITO2 miRNA profiling: future plans miRNA expression patterns on OC179 identified 4 robust and stable patients’ subtypes with different prognosis Consensus matrix miRNA subtype classifier maintained prognostic relevance in OC263 and TCGA case materials 2 2 Strenght: possible integration with gene expression profile to predict response to therapy P=0.000742 OC179 MITO2