INFOGYN 2010 – Tarbes – Pr. Palacios S.

LONG-TERMendometrial and breast safety of a specific and

standardised SOYA ISOFLAVONES extract

(PHYTO SOYA®)

Embrace the changewith 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.

1 144 227255N-

504 530-CER

1 180 263302N-

552595-CER

AF-1 DNA Ligand / AF-2A/B C D E F

(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, 3-22.

Human Estrogen Receptors A and B

Phytoestrogen/RE/uterus

ERERERE

ERTF

ERERP P

X

TFP

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 356:227-236, 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

estrogensAuthors

Isoflavones

Quantity

Treatment period &

number of subjects

Methodology

Exams Results

Balk (2002)

100 mg/j6 months

27 patients

Double blind

vrs placeboBiopsy

No histological modification

Di Carlo (2003)

36 mg/j12 months70 patients

openUltrasoun

dNo increase of the

thickness

Penotti (2002)

72 mg/j6 months

66 patients

Double blind

vrs placebo

Ultrasound

No increase of the thickness

Han (2002)

100 mg/j4 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/j5 years

379 patients

Double blind

vrs placeboBiopsy

Increase of the impact of

hyperplasies

1. Methodology

2. Results of endometrial SAFETY

3. Results of breast SAFETY

4. Tolerance

5. Conclusion

2. 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

1. Study objectiveEvaluate 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,

- 17.5 mg of ISOFLAVONES per gel cap (70 mg per day),

- 3 years of treatment.

Women ages 45-65Intact 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

INCLUSION

CRITERIA

Biopsy of endometrium: PolypsHyperplasiaCancer

Transvaginal ultrasound:

Thickness >4mmSubmucosal fibroidsSevere endometriosisHyperplasia or cancer

Mammography:

Undiagnosed vaginal bleeding

ACR3: benign anomalies to monitorACR4: indeterminate or suspicious anomaliesACR5: anomalies suggesting the presence of cancer

INCLUSION

CRITERIA

DISTRIBUTION OF WOMEN THROUGHOUT THE STUDY

499 selectedpatients

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 tissue1 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)

Biopsiesanalysed duringthe extension

phase)(mITT population)

Final visit(smITT population)

No tissue 0 3 -Insufficient tissue. Endometrial thickness <5 mm

19 25 24

Insufficient tissue.Endometrial thickness <5 mm

0 1 -

Atrophic/inactive 213 167 167Proliferative 3 1 1Secretory/menstrual 0 0 0Hyperplasia 0 1 0Cancer 0 0 0

Total biopsies 235 197 192

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 : 25 - 50 %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 235 191 189

Missing 0 43 42

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

0 0 0

ACR5: number of mammographies with anomalies suggesting the presence of cancer

0 0 0

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.

• There were no patients or populations whose category whose category changed from ACR1, 2 or 3 to ACR4 or 5.changed from ACR1, 2 or 3 to ACR4 or 5.

No significant change from a statistical point of No significant change from a statistical point of view in terms of ACR classification was observed view in terms of ACR classification was observed

between admission and between admission and end of treatment.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.

• ENDOMETRIUMENDOMETRIUM

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.

• BREASTBREAST

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

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

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

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