PERSONALIZED MEDICINE APPLIED TO ENDOMETRIAL RECEPTIVITY AND EMBRYO TRANSFER

Transcription

1 PERSONALIZED MEDICINE APPLIED TO ENDOMETRIAL RECEPTIVITY AND EMBRYO TRANSFER Felipe Vilella; PhD. Miguel Servet Researcher at IUIVI/INCLIVA Lab Manager at IVI Foundation Carlos Simon; MD, PhD. Professor Ob/Gyn, University of Valencia. Scientific Director Fundación IVI & IVIOMICS Adjunct Clinical Professor Ob/Gyn. Stanford University, USA

2 Learning objectives To understand what is human endometrial receptivity. To learn about endometrial receptivity array (ERA), the diagnostic technique of the endometrial factor. To discuss a new therapeutic option in IF: personalized Embryo Transfer (pet).

3 PROGRESS IN UNDERSTANDING ENDOMETRIAL RECEPTIVITY Histologic characteristics of secretory endometrium defined WOI associated with loss E & P receptors. Single molecule approach failed Use of DNA microarray to understand ER Non-invasive methods Development of ERA WOI in humans occupies 2-4 day interval Embryo-endometrial synchrony Embryo attachment & invasion occurred after day 19 Ultrasound thickness and pattern to predict ER Deletereous effect of supraphisiological levels of E and P

4 + THE STICKY EMBRYO

5 HUMAN ENDOMETRIUM

6 WINDOW OF IMPLANTATION (WOI) Window of endometrial receptivity Hertig et al., Navot et al. E P P +2 P +3 P +4 P +5 P +6 P +7 P +8 Epithelial PR Progesterone

7 DATING THE ENDOMETRIAL BIOPSY 1 Randomized studies - Interobserver and cycle-to-cycle (60%) variations 2 - Endometrial dating is not related to fertility status 3 Histological dating is not a valid method for the diagnosis of luteal phase deficiency neither guidance throughout clinical management in infertility 1. Noyes, et al Murray, et al Coutifaris, et al. 2004

8 THE AGE OF -OMICS Transcriptome Proteome Metabolome TRANSCRIPTION TRANSDUCTION DNA RNA mrna Protein METABOLITES Transcription regulation Alternative splicing Transduction regulation

9 TRANSCRIPTOMICS

10 JCEM MHR MHR HR JCEM Human Reproduction Update, 2007

11 All the gene information from these studies are available at Garrido-Gómez T, Domínguez F, Ruiz-Alonso M, Simón C. The Analysis of Endometrial receptivity. In: Textbook of Assisted Reproductive Techniques. UK; Informa Healthcare; 2012:

12 Learning objectives To understand what is human endometrial receptivity. To learn about endometrial receptivity array (ERA), the diagnostic technique of the endometrial factor. To discuss a new therapeutic option in IF: personalized Embryo Transfer (pet).

13 ENDOMETRIAL RECEPTIVITY ARRAY (ERA)

14 ENDOMETRIAL RECEPTIVITY ARRAY (ERA) Agilent e-array: Customized microarray (238 genes) Bioinformatic analysis of data obtained by the customized microarray Classification and prediction from gene expression Patented in 2009: PCT/ES 2009/000386

15 Predictor classifies the molecular receptivity status of the endometrium. Pre-Receptive Receptive Post-Receptive

16 ENDOMETRIAL RECEPTIVITY ARRAY (ERA)- TIMING OF BIOPSY NATURAL CYCLE Endometrial biopsy must be taken on the 7 th day after the LH surge (LH+7) (urine or serum preferible). HORMONE REPLACEMENT THERAPY CYCLE Endometrial biopsy must be taken on day P+5, after proper E 2 priming E 2 : 6 mg/day P 4 : 800 mg/day

17 Direito, et al. 2013

18 Direito, et al. 2013

19 ENDOMETRIAL RECEPTIVITY ARRAY (ERA)- ACCURACY In a blinded study ERA classifies better than Noyes criteria Pathologist 1 (P1) Pathologist 2 (P2) P1 vs P2 ERA Kappa value ( ) ( ) ( ) ( ) Good Concordance Very Good Concordance Díaz-Gimeno, et al. Fertil Steril 2013

20 ENDOMETRIAL RECEPTIVITY ARRAY (ERA)- CONSISTENCY ERA test analyzed in the same patient, same day, 3-years apart Code Date First Biopsy Date Second Biopsy Months between First Biopsy Results Second Biopsy Results CON1 09/ / Receptive Receptive (0.908) CON2 09/ / Receptive Receptive (0.908) CON3 05/ / Receptive Receptive (0.908) CON4 05/ / Proliferative Non Receptive (0.864) CON5 01/ / Proliferative Non Receptive (0.864) CON6 07/ / Receptive Receptive (0.908) Díaz-Gimeno, et al. Fertil Steril 2013

21 Learning objectives To understand what is human endometrial receptivity. To learn about endometrial receptivity array (ERA), the diagnostic technique of the endometrial factor. To discuss a new therapeutic option in IF: personalized Embryo Transfer (pet).

22 Ruiz-Alonso, et al. Fertil Steril 2013 PERSONALIZED EMBRYO TRANSFER WITH ERA

23 Ruiz-Alonso, et al. Fertil Steril 2013

24 pet outcome after receptive ERA in patients with RIF (n=37) IR PR 50 Rate (%) Months after ERA test Number of patients Implantation Rate (%) Pregnancy Rate (%) Ruiz-Alonso, Fertil Steril et al. 2013

25 pet outcome after receptive ERA in patients with RIF (n=310) IR PR 50 Rate (%) Months after ERA test Number of patients Implantation Rate (%) Pregnancy Rate (%)

26 FIRST PET OUTCOME AFTER RECEPTIVE ERA IN PATIENTS WITH RIF PROLIFERATIVE PRERECEPTIVE RECEPTIVE POSTRECEPTIVE P+6 P+4 P+5 Receptive Pre-receptive Ruiz-Alonso, et al. Fertil Steril 2013

27 Ruiz-Alonso, et al. Fertil Steril 2013 CLINICAL OUTCOME OF PET WITH ERA

28 CLINICAL OUTCOME OF PET WITH ERA P P +1 P +2 P +3 P +4 P +5 P +6 P +7 P +8 P +9 Epithelial PR Progesterone

29 ERA clinical applicability A case report and pilot study comparing routine embryo transfer versus pet (Ruiz-Alonso et al Hum Reprod 2014 Apr 15).

30 CASE REPORT Previous ART treatments Routine work-up negative 1. IVF with fresh day-3 ET 2. IVF with fresh day-3 ET ART treatments in our center 3. IVF with fresh day-5 ET 4. IVF with differed day -5 ET in natural cycle 5. OD with day-3 ET in HRT cycle (P+2) 6. OD with day-3 ET in natural cycle 7. OD with day-5 ET in HRT cycle (P+5) DIAGNOSTIC INTERVENTION ERA pre-receptive at P+5, being receptive at P+7 8. OD with pet using day-5 blastocysts in HRT cycle after 7 days of progesterone (P+7) Succesful twin pregnancy Ruiz-Alonso, et al. HR, 2014.

31 CLINICAL OUTCOME Ruiz-Alonso, et al. HR, 2014.

32 CLINICAL OUTCOME Ruiz-Alonso, et al. HR, 2014.

33 CLINICAL OUTCOME Ruiz-Alonso, et al. HR, 2014 in press.

34 CLINICAL OUTCOME Ruiz-Alonso, et al. HR, 2014 in press.

35 Fertil Steril Fertil Steril Fertil Steril Fertil Steril Hum Reprod Hum Reprod (in press) What difference 2 days make: personalized embryo transfer (pet) a case report and pilot M. Ruiz-Alonso, N Galindo, A Pellicer and C. study Simón Carlos.simon@i vi.es

36 PERSONALIZED EMBRYO TRANSFER (PET) AS A TREATMENT ET P+3 P+5 P+7 LH+5 LH+7 LH+9

37 3,209 PATIENTS Endometrial biopsy 12% Post-receptive 80% Receptive 20% Non-receptive 88% Pre-receptive 2 nd Endometrial biopsy 88.7% Receptive 10.4% Receptivity between 2 biopsies 0.9% Same result than 1 er biopsy

38 CLINICAL OUTCOME AND EFFICIENCY OF ET ACCORDING ERA DIAGNOSIS Clinical Outcome NR (52) R (205) IR First attempt 13% (12/90) 45% (161/355) IR Total attempts 10% (17/174) 41% (182/441) PR First attempt 23% (12/52) 60% (123/205) PR Total attempts 17% (17/100) 55% (140/253) OPR First attempt 0% (0/12) 74% (91/123) OPR Total attempts 0% (0/100) 74% (103/140) Clinical efficiency Positive (52) Negative (205) True False Sensitivity (TP/TP+FN) 0.33 Specificity (TN/TN+FP) 0.91 PPV (TP/TP+FP) 0.77 NPV (TN/TN+FN) 0.60 P-466 Ruiz-Alonso et al, Clinical efficiency of embryo transfer performed in receptive vs non-receptive endometrium diagnosed by the endometrial receptivity array (ERA) (70 th ASRM Annual Meeting, Honolulu, Hawaii. 2014)

39 CONCLUSIONS The transcriptomic signature of endometrial receptivity (ERA test) reveal that the endometrial factor is responsible for 25% of cases of patients with RIF. The WOI is displaced in 25% of RIF patients, and personalized Embryo Transfer (pet) normalize clinical results. WE ARE WORKING ON THE CLINICAL VALIDATION in ALL PATIENTS as an International Multicenter RCT

40 ClinicalTrials.gov Identifier: NCT

41 ERA RCT SITES

42

43 Thanks to ERA department at Igenomix

44 This work was supported by the EU: FP7-PEOPLE-2012-IAPP grant SARM, No

45 Felipe Vilella; PhD. Miguel Servet Researcher at IUIVI/INCLIVA Lab Manager at IVI Foundation PERSONALIZED MEDICINE APPLIED TO ENDOMETRIAL RECEPTIVITY AND EMBRYO TRANSFER