Presentation on theme: "Embrace the change with confidence LONG-TERM"— Presentation transcript:
1 Embrace the changewith confidenceLONG-TERMendometrial and breast safety of a specific and standardised SOYA ISOFLAVONES extract(PHYTO SOYA®)INFOGYN 2010 – Tarbes – Pr. Palacios S.
2 IntroductionMany women have chosen to not take HRT either because they have contraindication or because they wish to use a more natural treatment.Consequently, a number of women take phyto estrogens either advised by their doctor or also by themselves because phyto estrogens can be sold as a dietary supplement.Many clinical studies have studied the efficacy of phyto estrogens but questions of their safety on endometrium and on breast are raised.
3 E R a E R b Human Estrogen Receptors A and B AF-1DNALigand /AF-2A/BCDEF1180263302552595ERaN--C1144227255504530ERbN--C(18)(97)(30)(59)(18) Different tissue / cell distributions Different affinity for ligands Different gene activations
4 Human Estrogen Receptors A and B Pearce, S. T.; Jordan, V. C. The biological role of estrogen receptors alpha and beta in cancer. Crit Rev Oncol Hematol 2004, 50, 3-22.
5 Phytoestrogen/RE/uterus Dominant in the uterusERERETFPXWeak response to E2Inactivation REGreater increase inresponse to E2Inactivation RE Isoflavones: competition at receptor levelSelective partial agonist: absence of E Selective partial antagonist: presence of E(Messina MJ 1994)
7 Effects of phyto estrogens on endometrium and breast
8 RationaleBreast density (BD) is one of the strongest predictors of breast cancer BC risk.Women with BD > 50% are at three- to five-fold greater risk of breast cancer than women with < 25% dense areaAbout 30% of PM women have high BD, a frequency that is greater than the frequency of most recognized risk factors (for example, a family history of breast cancer occurs in only 10% of women)
9 Rationale A decrease of BD can be induced by several factors: increasing age, menopause, elevated BMI, pregnancy at an early age. An increase is induced by some types of HRT, but SERM can decrease it and reduce the BC risk.
10 Breast density is associated with breast cancer risk Boyd N.F. et al., NEJM 356: , 2007
11 Breast density is associated with breast cancer risk Epidemiologic studies have clearly shown an association between breast density and higher risk to develop breast cancer.The mechanisms by which density confers this increased risk remain unclear.
12 Clinical trials on endometrial effect of phyto estrogens AuthorsIsoflavonesQuantityTreatment period & number of subjectsMethodologyExamsResultsBalk (2002)100 mg/j6 months27 patientsDouble blindvrs placeboBiopsyNo histological modificationDi Carlo (2003)36 mg/j12 months70 patientsopenUltrasoundNo increase of the thicknessPenotti (2002)72 mg/j66 patientsHan (2002)4 months80 patientsScambia (2000)50 mg/j3 months39 patientsUnfer* (2004)150 mg/j5 years379 patientsIncrease of the impact of hyperplasies
13 1. Methodology2. Results of endometrial SAFETY3. Results of breast SAFETY4. Tolerance5. Conclusion
14 1. Study objectiveEvaluate the effects of administration of 70 mg of SOYA ISOFLAVONES (PHYTO SOYA®) on the endometrium and breasts2. Study designInternational, multicentre, non-comparative study, open for a duration of 3 years34 centres in 4 countries:- France, 30 centres: Pr MARES- Spain, 2 centres: Pr PALACIOS- Belgium, 1 centre: Dr PORNEL- Australia, 1 centre: Pr EDEN
15 - Specific, standardised ISOFLAVONE extract 3. Treatment- Specific, standardised ISOFLAVONE extract- Extract composition:50% Daidzein,30% Glycitein,20% Genistein- 2 capsules of PHYTO SOYA®taken in the morning and at night,mg of ISOFLAVONES per gel cap(70 mg per day),- 3 years of treatment.
16 INCLUSION CRITERIA Women ages 45-65 Intact uterus No normal period for at least 2 yearsStatus of menopause confirmed by hormone levels (>30 IU/l) and estradiol levels (<35 ng/l).BMI < 30 kg/m2"Wash-out" period:3 months: hormone therapy, tibolone, raloxifene…2 months: isoflavones1 months: local hormonal treatment
17 INCLUSION CRITERIA Undiagnosed vaginal bleeding Polyps Hyperplasia CancerBiopsy of endometrium:Thickness >4mmSubmucosal fibroidsSevere endometriosisHyperplasia or cancerTransvaginal ultrasound:ACR3: benign anomalies to monitorACR4: indeterminate or suspicious anomaliesACR5: anomalies suggesting the presence of cancerMammography:
18 317 patients finished year 1 192 usable biopsies (smlTT) DISTRIBUTION OF WOMEN THROUGHOUT THE STUDY499 selectedpatients395 admitted patients317 patients finished year 1235 patients admitted for the extension phase197 available biopsies (mlTT)6 final visits (biopsies) were performed in time305 evaluable patients301 usable biopsies3 with no tissue1 with insufficient tissue (endometrial thickness >5 mm)193 evaluable patients1 simple hyperplasia192 usable biopsies (smlTT)78 premature exits35 premature exitsPhase IPhase II
19 DEMOGRAPHIC AND CLINICAL CHARACTERISTICS Number of women:235Age:55.90± 3.93 yearsAverage age of menopause:49.40± 3.31 yearsDuration of menopause:6.49± 3.92 yearsBody mass index (kg/m2):24.58± 3,22
22 ENDOMETRIAL THICKNESS Average endometrial thickness at inclusion: 2.20 mmAverage endometrial thickness at the end of treatment (3 years): 2.17 mmNo significant change from a statistical point of view in terms of endometrial thickness was observed between admission and end of treatment.Endometrial thickness of 8.3 mm was recorded for one patient 24 months after the start of treatment.The patient's histology revealed simple hyperplasia without atypical cytology.
23 Assessment of Breast Safety in women treated during 3-year with Phyto Soya®
24 ACR BI-RADS classification for breast density Type 1 :< 25 %breast is almostentirely fatType 2 : %there are scatteredfibroglandular densitiesType 4 > 75 %breast is extremely denseType 3 : 50 – 75%Breast is heterogenously dense
25 MAMMOGRAPHY RESULTSMammographiesAdmission(Samplepopulationof safety ofthe extension)PopulationmITTsmITTNumbers235191189Missing4342ACR1: number of normal mammographies111(47,2%)81(42,4 %)(42,9%)ACR2: number of mammographies with benign anomalies122(51,9%)108(56,5%)106(56,1 %)ACR3: number of mammographies with anomalies that are likely benign2(0,9 %)(1,0%)(1,1%)ACR4: number of mammographies with indeterminate or suspicious anomaliesACR5: number of mammographies with anomalies suggesting the presence of cancerACR: American College of Radiology
26 MAMMOGRAPHYRESULTSResults of mammographies were similar to those observed during admission visit.No patients were classified as ACR4 or ACR5.There were no patients or populations whose category changed from ACR1, 2 or 3 to ACR4 or 5.No significant change from a statistical point of view in terms of ACR classification was observed between admission and end of treatment.
27 OVERALL TOLERANCEThe only adverse recurring product-related side effects were gastrointestinal problems observed in 4.3% of women.Overall safety after 3 years was observed as "EXCELLENT” or "GOOD" by 99.1% of examiners and by 99.0% of patients from the mITT sample.
28 STUDY CONCLUSION ENDOMETRIUM BREAST These statistics fulfil the conditions for safety evaluations of the endometrium specified in the new European regulatory guidelines, which require a frequency of hyperplasia/cancer of the endometrium ≤ 2% 1 year after treatment.BREASTThe results of this study support the hypothesis that states that this specific extract of isoflavones does not increase breast density 3 years after treatment.
29 STUDY CONCLUSIONThis study was carried out with PHYTO SOYA® specific and standardised extract of SOYA ISOFLAVONES:50% daidzein30% glycitein20% genisteinThis clinical study therefore should not be extrapolated to other SOYA ISOFLAVONE extracts