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. E R a E R b Human Estrogen Receptors A and B
AF-1
DNA
Ligand /
AF-2
A/B C D E F 1
180
263
302
552
595 E R a N- -C 1
144
227
255
504
530 E R b N- -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 uterus ER
ERE TF P X
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: , 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
Authors
Isoflavones
Quantity
Treatment period & number of subjects
Methodology
Exams
Results
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
open
Ultrasound
No increase of the thickness
Penotti (2002)
72 mg/j
66 patients
Han (2002)
4 months
80 patients
Scambia (2000)
50 mg/j
3 months
39 patients
Unfer* (2004)
150 mg/j
5 years
379 patients
Increase of the impact of hyperplasies

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. - 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 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. 317 patients finished year 1 192 usable biopsies (smlTT)
DISTRIBUTION OF WOMEN THROUGHOUT THE STUDY
499 selected
patients
395 admitted patients
317 patients finished year 1
235 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

19. 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

20. Effects of PHYTO SOYA on endometrium

21. BIOPSY RESULTS Total biopsies 235 197 192 3 - 19 25 24 1 213 167
Classification
Admission
(Sample
population
of safety of
the extension)
Biopsies
analysed during
the extension
phase)
(mITT population)
Final visit
(smITT population)
No tissue 3 -
Insufficient tissue.
Endometrial thickness <5 mm 19 25 24 1
Atrophic/inactive
213
167
Proliferative
Secretory/menstrual
Hyperplasia
Cancer
Total biopsies
235
197
192

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 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

25. MAMMOGRAPHY RESULTS
Mammographies
Admission
(Sample
population
of safety of
the extension)
Population
mITT
smITT
Numbers
235
191
189
Missing 43 42
ACR1: number of normal mammographies
111
(47,2%) 81
(42,4 %)
(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 %)
(1,0%)
(1,1%)
ACR4: number of mammographies with indeterminate or suspicious anomalies
ACR5: number of mammographies with anomalies suggesting the presence of cancer
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 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.
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 Aug;13(4):

32. 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