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INFOGYN 2010 – Tarbes – Pr. Palacios S.

Embrace the change with confidence. LONG-TERM endometrial and breast safety of a specific and standardised SOYA ISOFLAVONES extract (PHYTO SOYA®) . INFOGYN 2010 – Tarbes – Pr. Palacios S. Introduction.

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INFOGYN 2010 – Tarbes – Pr. Palacios S.

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  1. Embrace the change with confidence LONG-TERM endometrial and breast safety of a specific and standardised SOYA ISOFLAVONES extract (PHYTO SOYA®) INFOGYN 2010 – Tarbes – Pr. Palacios S.

  2. 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.

  3. Human Estrogen Receptors A and B AF-1 DNA Ligand / AF-2 A/B C D E F 1 180 263 302 552 595 a E R N- -C 1 144 227 255 504 530 b E R -C N- (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. ER ER ERE X ER TF P P ER ER P TF Phytoestrogen/RE/uterus ER Dominant in the uterus Weak response to E2 Inactivation RE Greater increase in response to E2 Inactivation RE  Isoflavones: competition at receptor level Selective partial agonist: absence of E Selective partial antagonist: presence of E (Messina MJ 1994)

  6. Kuiper G et al. Endocrinology 1998

  7. Effects of phyto estrogens on endometrium and breast

  8. 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)

  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 356:227-236, 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

  13. 1. Methodology 2. Results of endometrial SAFETY 3. Results of breast SAFETY 4. Tolerance 5. Conclusion

  14. 1. Study objective Evaluate the effects of administration of 70 mg of SOYA ISOFLAVONES (PHYTO SOYA®) on the endometrium and breasts 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

  15. 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, • - 17.5 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 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

  17. INCLUSION CRITERIA Undiagnosed vaginal bleeding Polyps Hyperplasia Cancer Biopsy of endometrium: Thickness >4mm Submucosal fibroids Severe endometriosis Hyperplasia or cancer Transvaginal ultrasound: ACR3: benign anomalies to monitor ACR4: indeterminate or suspicious anomalies ACR5: anomalies suggesting the presence of cancer Mammography:

  18. 499 selected patients Phase I 395 admitted patients 6 final visits (biopsies) were performed in time 78 premature exits 305 evaluable patients 317 patients finished year 1 301 usable biopsies Phase II 235 patients admitted for the extension phase 3 with no tissue 1 with insufficient tissue (endometrial thickness >5 mm) 35 premature exits 197 available biopsies (mlTT) 193 evaluable patients 192 usable biopsies (smlTT) 1 simple hyperplasia DISTRIBUTION OF WOMEN THROUGHOUT THE STUDY

  19. DEMOGRAPHIC AND CLINICAL CHARACTERISTICS

  20. Effects of PHYTO SOYA on endometrium

  21. BIOPSY RESULTS

  22. 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.

  23. Assessment of Breast Safety in women treated during 3-year with Phyto Soya®

  24. ACR BI-RADS classification for breast density Type 2 : 25 - 50 % there are scattered fibroglandular densities Type 1 :< 25 % breast is almost entirely fat Type 4 > 75 % breast is extremely dense Type 3 : 50 – 75% Breast is heterogenously dense

  25. MAMMOGRAPHY RESULTS ACR: American College of Radiology

  26. MAMMOGRAPHY RESULTS • Results 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 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.

  28. STUDY CONCLUSION • 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.

  29. 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

  30. Menopause. 2007 Nov-Dec;14(6):1006-11.

  31. Climacteric. 2010 Aug;13(4):368-75.

  32. STUDY CONCLUSION Daily administration of 70 mg of specific and standardised ISOFLAVONE extract from PHYTO SOYA® for 3 years can be considered asafe treatment for both the endometrium and the breast

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