About ESTEEM

Karen Sermon, coordinator of ESTEEM

ESTEEM is the first randomised trial of 23 chromosome testing of polar bodies using array CGH. The study is performed in women aged between 36 and 41 years and has two primary aims:

  1. to estimate the likelihood of having no euploid embryos in future ART cycles
  2. to improve live birth rates in women of advanced maternal age. 

At the onset it was estimated that 560 cycles needed to be randomized into either the treatment or the no-treatment, control group. The study is now in its last six months of recruitment, and it is to be hoped that by next ESHRE meeting in Geneva we will be able to present significant results.
No fewer than eight European IVF centres from six countries participate in the study (box 1 participant list) and is sponsored by Illumina (formerly Bluegnome) who provide the arrays and other materials for the analysis of the first and second polar bodies using array-CGH.

 

ESTEEM - A brief history

ESHRE PGS TASK FORCE
In 2007, ESHRE’s executive committee agreed that the answer to the question “Does PGS work?” was and important one, and they decided to promote studies designed to answer this question. The PGS Task Force was set up just for that and would be coordinated by Joep Geraedts (box 2 member list). At that moment, it became clear that cleavage stage biopsy and FISH were not reasonable approaches to PGS. It was then that the idea of a proof of principle study developed, using then state-of-the-art technology for genetic analysis, array-CGH, and polar body biopsy. This was preferred because at that time, there were strict legal restrictions on embryo biopsy both in Germany and Italy, both participants in the pilot and the ESTEEM study itself.
The PGS Task Force agreed to carry out a pilot study of PGS - analysing one of each pair of 23 chromosomes in polar bodies - in collaboration with BlueGnome, now Illumina. If the pilot study was positive, the project would be extended to an international randomised trial, ESHRE’s first sponsored study since 1994. 
The first phase began in September 2009 in two centres chosen for their expertise in polar body biopsy: the University of Bonn (M. Montag), Germany and SISMER, Bologna, Italy (C. Magli). The data from the study were independently analysed by Dr. Sjoerd Repping, from the Academic Medical Centre in Amsterdam. The pilot resulted in two reports, one on the clinical side (Geraedts et al., 2011)(http://humrep.oxfordjournals.org/content/26/11/3173) and one on the genetic side (Magli et al., 2011) (http://humrep.oxfordjournals.org/content/26/11/3181)

MISSION ACCOMPLISHED FOR THE TASK FORCE – UP TO ESTEEM
Following completion of the pilot study, the PGS Task Force was disbanded and its responsibilities passed on to the PGS trial study group. The positive outcome of that study was behind the design of ESTEEM, a randomised clinical trial to test chromosome analysis in polar bodies in women of advanced maternal age.
The ESTEEM study was started with eight centres (box 1), and Joep Geraedts at the helm as coordinator. He was assisted by Veerle Goossens, scientific officer of ESHRE, and Patrick Bossuyt, epidemiologist at the Amsterdam Medical Centre. For the project management, the Centre for Clinical Trials Maastricht (CTCM) was taken on board, and originally Liesbeth Knaepen was assigned as project manager. Currently, that task is filled by Kristel Diepvens. The centre at Brno left the project early on, and was recently replaced by the centre at Lübeck.

 

ESTEEM – present and future

Since May 2015, I have taken over as coordinator of ESTEEM, but not of course without a capable steering committee with complementary expertise: Joep Geraedts accepted to remain as the longterm memory of the project, and we are still skillfully assisted by Veerle Goossens. Patrick Bossuyt also remains bringing his important expertise in randomized controlled trials.
The recruitment of patients is still ongoing, and will be continued until the end of 2016. Illumina continue to sponsor the project, not only by providing materials for the cycles themselves, but also with a generous incentive for the participating centres who enroll patients.
Early 2017, the code will be broken and the data will be analysed. We foresee to present the first results at the ESHRE meeting in Geneva, and to publish during 2017 at least two papers detailing the results on the biological and on the clinical side. 
ESTEEM will be the largest RCT on PGS today (Lee et al., 2015)(Sermon et al., 2016), and I expect that it will bring novel insights both into the early genetics of the human embryo, but most of all significant facts about the clinical value of PGS. 

Geraedts J, Montag M, Magli MC, Repping S, Handyside A, Staessen C, Harper J, Schmutzler A, Collins J, Goossens V, et al. Polar body array CGH for prediction of the status of the corresponding oocyte. Part I: clinical results. Hum Reprod [Internet] 2011;26:3173–3180.
Lee E, Illingworth P, Wilton L, Chambers GM. The clinical effectiveness of preimplantation genetic diagnosis for aneuploidy in all 24 chromosomes (PGD-A): systematic review. Hum Reprod [Internet] 2015;30:473–483.
Magli MC, Montag M, Köster M, Muzi L, Geraedts J, Collins J, Goossens V, Handyside AH, Harper J, Repping S, et al. Polar body array CGH for prediction of the status of the corresponding oocyte. Part II: technical aspects. Hum Reprod [Internet] 2011;26:3181–3185.
Sermon K, Capalbo A, Cohen J, Coonen E, Rycke M De, Vos A De, Delhanty J, Fiorentino F, Gleicher N, Griesinger G, et al. The why, the how and the when of PGS 2.0: current practices and expert opinions of fertility specialists, molecular biologists, and embryologists. Mol Hum Reprod [Internet] 2016;0:gaw034.