Presentation on theme: "INFOGYN 2010 – Tarbes – Pr. Palacios S. LONG-TERM endometrial and breast safety of a specific and standardised SOYA ISOFLAVONES extract (PHYTO SOYA®) Embrace."— Presentation transcript:
INFOGYN 2010 – Tarbes – Pr. Palacios S. LONG-TERM endometrial and breast safety of a specific and standardised SOYA ISOFLAVONES extract (PHYTO SOYA®) Embrace the change with confidence
Introduction Many 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.
N C ER N C ER AF-1DNALigand /AF-2 A/BCDEF (18)(97)(30)(59)(18) Human Estrogen Receptors A and B Different tissue / cell distributions Different affinity for ligands Different gene activations
Pearce, S. T.; Jordan, V. C. The biological role of estrogen receptors alpha and beta in cancer. Crit Rev Oncol Hematol 2004, 50, Human Estrogen Receptors A and B
Phytoestrogen/RE/uterus ER ERE ER TF ER PP X TF P Inactivation RE Greater increase in response to E2 ER Dominant in the uterus Inactivation RE Weak response to E2 Isoflavones: competition at receptor level Selective partial agonist: absence of E Selective partial antagonist: presence of E (Messina MJ 1994)
Kuiper G et al. Endocrinology 1998
Effects of phyto estrogens on endometrium and breast
Rationale Breast 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 area About 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)
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.
Breast density is associated with breast cancer risk Boyd N.F. et al., NEJM 356: , 2007
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. Breast density is associated with breast cancer risk
Clinical trials on endometrial effect of phyto estrogens Authors Isoflavones Quantity Treatment period & number of subjects MethodologyExamsResults Balk (2002) 100 mg/j 6 months 27 patients Double blind vrs placebo Biopsy No histological modification Di Carlo (2003) 36 mg/j 12 months 70 patients openUltrasound No increase of the thickness Penotti (2002) 72 mg/j 6 months 66 patients Double blind vrs placebo Ultrasound No increase of the thickness Han (2002) 100 mg/j 4 months 80 patients Double blind vrs placebo Ultrasound No increase of the thickness Scambia (2000) 50 mg/j 3 months 39 patients Double blind vrs placebo Ultrasound No increase of the thickness Unfer* (2004) 150 mg/j 5 years 379 patients Double blind vrs placebo Biopsy Increase of the impact of hyperplasies
1. Methodology 2. Results of endometrial SAFETY 3. Results of breast SAFETY 4. Tolerance 5. Conclusion
2. Study design International, multicentre, non-comparative study, open for a duration of 3 years 34 centres in 4 countries: - France, 30 centres: Pr MARES - Spain, 2 centres: Pr PALACIOS - Belgium, 1 centre: Dr PORNEL - Australia, 1 centre: Pr EDEN 1. Study objective Evaluate the effects of administration of 70 mg of SOYA ISOFLAVONES (PHYTO SOYA®) on the endometrium and breasts
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.
Women ages Intact uterus No normal period for at least 2 years Status 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: isoflavones 1 months: local hormonal treatment INCLUSION CRITERIA
Biopsy of endometrium: Polyps Hyperplasia Cancer Transvaginal ultrasound: Thickness >4mm Submucosal fibroids Severe endometriosis Hyperplasia or cancer Mammography: Undiagnosed vaginal bleeding ACR3: benign anomalies to monitor ACR4: indeterminate or suspicious anomalies ACR5: anomalies suggesting the presence of cancer INCLUSION CRITERIA
DISTRIBUTION OF WOMEN THROUGHOUT THE STUDY 499 selected patients 395 admitted patients 317 patients finished year patients admitted for the extension phase 197 available biopsies (mlTT) 6 final visits (biopsies) were performed in time 305 evaluable patients 301 usable biopsies 3 with no tissue 1 with insufficient tissue (endometrial thickness >5 mm) 193 evaluable patients 1 simple hyperplasia 192 usable biopsies (smlTT) 78 premature exits 35 premature exits Phase I Phase II
DEMOGRAPHIC AND CLINICAL CHARACTERISTICS Number of women:235 Age:55.90 ± 3.93 years Average age of menopause:49.40 ± 3.31 years Duration of menopause:6.49 ± 3.92 years Body mass index (kg/m2):24.58± 3,22
Effects of PHYTO SOYA on endometrium
BIOPSY RESULTS Classification Admission (Sample population of safety of the extension) Biopsies analysed during the extension phase) (mITT population) Final visit (smITT population) No tissue 03- Insufficient tissue. Endometrial thickness <5 mm Insufficient tissue. Endometrial thickness <5 mm 01- Atrophic/inactive Proliferative 311 Secretory/menstrual 000 Hyperplasia 010 Cancer 000 Total biopsies
ENDOMETRIAL THICKNESS Average endometrial thickness at inclusion: 2.20 mm Average endometrial thickness at the end of treatment (3 years): 2.17 mm No 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.
Assessment of Breast Safety in women treated during 3-year with Phyto Soya®
ACR BI-RADS classification for breast density Type 1 :< 25 % breast is almost entirely fat Type 2 : % there are scattered fibroglandular densities Type 4 > 75 % breast is extremely dense Type 3 : 50 – 75% Breast is heterogenously dense
MAMMOGRAPHY RESULTS Mammographies Admission (Sample population of safety of the extension) Population mITT Population smITT Numbers Missing ACR1 : number of normal mammographies 111 (47,2%) 81 (42,4 %) 81 (42,9%) ACR2 : number of mammographies with benign anomalies 122 (51,9%) 108 (56,5%) 106 (56,1 %) ACR3 : number of mammographies with anomalies that are likely benign 2 (0,9 %) 2 (1,0%) 2 (1,1%) ACR4 : number of mammographies with indeterminate or suspicious anomalies 000 ACR5 : number of mammographies with anomalies suggesting the presence of cancer 000 ACR: American College of Radiology
MAMMOGRAPHY RESULTS Results of mammographies were similar to those observed during admission visit. No patients were classified as ACR4 or ACR5. whose category changed from ACR1, 2 or 3 to ACR4 or 5. 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.
OVERALL TOLERANCE The 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.
ENDOMETRIUM 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. BREAST The results of this study support the hypothesis that states that this specific extract of isoflavones does not increase breast density 3 years after treatment. STUDY CONCLUSION
This study was carried out with PHYTO SOYA® specific and standardised extract of SOYA ISOFLAVONES: 50% daidzein 30% glycitein 20% genistein This clinical study therefore should not be extrapolated to other SOYA ISOFLAVONE extracts STUDY CONCLUSION
Daily administration of 70 mg of specific and standardised ISOFLAVONE extract from PHYTO SOYA® for 3 years can be considered a safe treatment for both the endometrium and the breast STUDY CONCLUSION