Transcript Diapositive 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.
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.
Human Estrogen
Receptors A and B
AF-1
A/B
ERa
ERb
1
N-
DNA
C D
Ligand /AF-2
E
180 263302
1
N-
552595
-C
144 227255
(18)
(97) (30)
F
(59)
504 530
-C
(18)
 Different tissue / cell distributions
 Different affinity for ligands
 Different gene activations
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.
Phytoestrogen/RE/uterus
ERER
ERE
ER X
TF
P
P
ERER
ERa
Dominant in the uterus
Inactivation REa
Weak response to E2
Inactivation RE b
Greater increase in
response to E2
P
TF
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 356:227-236, 2007
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.
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
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
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
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.
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
INCLUSION
CRITERIA
Undiagnosed vaginal bleeding
Biopsy of endometrium:
Polyps
Hyperplasia
Cancer
Transvaginal ultrasound:
Thickness >4mm
Submucosal fibroids
Severe endometriosis
Hyperplasia or cancer
Mammography:
ACR3: benign anomalies to monitor
ACR4: indeterminate or suspicious anomalies
ACR5: anomalies suggesting the presence
of cancer
DISTRIBUTION OF WOMEN
THROUGHOUT THE STUDY
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)
235 patients
admitted for
the extension
phase
197 available
biopsies (mlTT)
1 simple
hyperplasia
Phase I
395 admitted
patients
317 patients
finished year
1
193
evaluable
patients
192 usable
biopsies
(smlTT)
499 selected
patients
78 premature
exits
Phase II
35 premature
exits
DEMOGRAPHIC AND
CLINICAL CHARACTERISTICS
Number of women:
235
55.90
± 3.93
years
49.40
± 3.31
years
Duration of menopause:
6.49
± 3.92
years
Body mass index (kg/m2):
24.58
± 3,22
Age:
Average age of menopause:
Effects of
PHYTO SOYA on
endometrium
BIOPSY RESULTS
Admission
Classification
(Sample
population
of safety of
the extension)
Biopsies
analysed during
the extension
phase)
Final visit
(smITT population)
(mITT population)
0
3
-
19
25
24
0
1
-
213
167
167
Proliferative
3
1
1
Secretory/menstrual
0
0
0
Hyperplasia
0
1
0
Cancer
0
0
0
235
197
192
No tissue
Insufficient tissue.
Endometrial thickness <5 mm
Insufficient tissue.
Endometrial thickness <5 mm
Atrophic/inactive
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 %
Type 2 : 25 - 50 %
Type 3 : 50 –
75%
Type 4 > 75 %
breast is almost
entirely fat
Breast is heterogenously
dense
there are scattered
fibroglandular densities
breast is extremely dense
MAMMOGRAPHY RESULTS
Admission
Mammographies
(Sample
population
of safety of
the extension)
Population
mITT
Population
smITT
235
191
189
0
43
42
Numbers
Missing
ACR1: number of normal
mammographies
ACR2: number of
mammographies with benign
anomalies
ACR3: number of
mammographies with anomalies
that are likely benign
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
111
(47,2%)
81
(42,4 %)
81
(42,9%)
122
(51,9%)
108
(56,5%)
106
(56,1 %)
2
(0,9 %)
2
(1,0%)
2
(1,1%)
0
0
0
0
0
0
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.
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.
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.
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
Menopause. 2007 Nov-Dec;14(6):1006-11.
Climacteric. 2010 Aug;13(4):368-75.
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