discussing hormone therapy in hormone receptors positive breast cancer, gynecologic approach

1. Adjuvant Endocrine Therapy
In Breast Cancer
Gynecologic View
Dr. Mamdouh Sabry
MD. Ain Shams, Ph.D. France
Consultant Ob. & Gyn.
EL Mataria Teaching Hospital, Nasser Institute
Cairo, Egypt

2. WHY???
• Because we work as a team interested in
keeping better life of cancer patients,
organ transplanted patients and critically ill
patient, with special concern regarding
fertility, sexuality and trying to make for
these patients a state of EQUILIBRIUM
between healthy condition and body
performance.

3.  Breast cancer is the most frequently
diagnosed malignancy and leading cause of
cancer death in women world wide.
 It is the commonest invasive malignancy in
women at rep. age. (Jemal et al. 2010 & 2011)
 30% of patients are premenopausal and 10%
aged (35 – 45) years old. (Bines et al. 1996)
 Hormone receptors-positive ( ER and/or PR )
represent 75% of all cases

4.  Surgery.
 Chemotherapy.
 Radiotherapy.
 Endocrine therapy (non surgical, surgical)
 Biological TTTs → monoclonal antibody carried
and directed to cancer cells.
Treatment plan

5.  Bulk of evidence points to estrogens as the major
etiological factor ?. (Santen et al. 2009)
 Recent papers and studies have also implicated
progesterone receptors in breast carcinogenesis.
(Horwitz 2008, Lange et al. 2008)
 This is also confirmed by other studies.
(Beral 2003, Chlebowoski et al. 2003, 2010)
Hormones and cancer breast

6.  70% of breast cancer expresses estrogen receptors alpha
(ERα) and progesterone receptors (PR) and thus
susceptible to adjuvant endocrine therapy (Jordan 2008,
Moor 2004) , many meta analyses confirmed that.
 So drugs, treatments or surgical intervention that block
hormonal effect, or lower their levels can be used for
such types of breast cancer,
 But choice of drugs in Age rep. period is different from
those at menopause, and differentiation of amenorrhea
from menopause is mandatory .
Hormones and cancer breast

7. Agents & Techniques
• Selective estrogen receptor modulator
( SERM ) Tamoxifen, ( ERDR ) Flavestrant.
• Aromatase inhibitors, that inhibits peripheral
conversion of androgen to estrogen.
• Ovarian suppression via ( GnRH ) or
ablation via surgery or radiation.
• Selective progesterone modulators and anti-
progestins.

8. Brain
Estrogen Target Tissues
Bone
Uterus
Liver
Heart
Breast

9. Estrogen and Cancer
Uterus
Increases cancer risk
Beneficial effects Harmful effects
Breast
Programs milk production
Liver and heart
Controls cholesterol
Uterus
Prepares for fetus
Bone
Preserves strength
Breast
Increases cancer risk

10. Estrogen Receptors
Estrogen target cell
(e.g., breast, uterine
lining, liver, etc.)
Estrogen
receptor
Tamoxifen
Estrogen
Non-target cell
(contains no
estrogen receptor)

12. Estrogen prod, continue
• Aromatase enzyme is responsible for
Estrogens production.
• Postmenopausal women ovarian aromatase
is about 10% of premenopausal level,
meanwhile breast stromal and epithelial cells
contain measurable amount of aromatase.
• So the small amount of estrogen produced
by breast tissue may promote cancer growth

13. SERM & ERDR
• Tamoxifen.
• Toremifen, analogue to tamoxifen, with
similar profile almost.
• Fluvestrant, ERDR, pure ER antagonist
with 50 times affinity more than tamoxifen
to ER, and similar safety profile.
• Arzoxifene HCl.

14. SERMs
SERM
Uterine
receptor
activated
Estrogen receptor
in uterine cell
Uterine cell proliferation
Breast receptor
not activated
Estrogen
receptor in
breast cell
No breast cell
proliferation

15. Tamoxifen and Cancer
Estrogen
molecule binds
to estrogen
receptor
Tamoxifen
receptor
cannot bind to
cooactivators
Tamoxifen
receptor does
not acquire
changed
shape
Tamoxifen
molecule binds
to estrogen
receptor
Estrogen
receptor binds
to cooactivators
Estrogen
receptor
acquires
changed shape

16.  Tamoxifen is the first SERM investigated for its
anticancer properties.
 Tamoxifen blocks the action of estrogen in breast
tissue by binding to its receptors.
 Tamoxifen binds but without changing receptor’s
shape, so co-activators are unable to bind. As a
result, the genes that stimulate cell proliferation
cannot be activated.
 So , tamoxifen blocks the ability of estrogen to
stimulate the proliferation of breast cells.
 Tam. and cancer body, low incidence compared to
placebo and limited to age over 55, ( weak agonist )

17. Aromatase Inhibitors
• Anastrozole ( 1 mg / day ) .
• Letrezole ( 2,5 mg / day ) .
• Exemestane ( 25 mg / day ), steroidal
androgen derivative and may give
androgenic side effects.
• All AI Decrease estrogen level.
• Up regulation of estrogen receptors.

20. Progesterone Receptors
• Two isoforms, ( PRA ) , ( PRB ) receptors.
• PR are expressed in most tissues and body organs
• PRB is the positive regulator of progesterone
response gene and PRA inhibits its B activity in
most cells of action.
• The repression of estrogen receptor transcription
activity ( mRNA formation ) as well as ( gluco.,
mineralocorticoids and androgens transcription
and translation ) is dep. on PRA expression, A
receptors regulates inhibition of steroid action
wherever expressed.

21. Progesterone receptors (cont.)
• PRA inhibits estrogen receptors only in
cells with critical factor.
• Progesterone shares with estrogen and
(all steroid probably) the ability to exert
activity at the cell membrane
independently of progesterone receptors.
• For example, progesterone or its
metabolite can prevent ut. contractions by
binding to exogenous G protein receptor in
cell membrane inhibiting its function.

22. Progesterone Receptors and Antiprogestins
 The clinical and experimental data reviewed
strongly suggest that antiprogestins have a
potential to be used with TAM in a subgroup of
breast cancer patients.
 Looking for potential biomarkers to be used in
immunohistochemistry associated with high
expression of PR-A Genes that are up regulated
can be used for progesterone or anti-progestins
treatment of cancer . (Claudia Lanari et al.2012)

23. Progesterone Receptors and Antiprogestin
Selective modulators of PRS (SPRM).
 Type 1 → onapristone, others, → antagonist.
 Type 2 → mifepristone (MFP, RU – 486) → agonist
 Type 3 → lonoprisan → pure antagonist.
 Progesterone A Receptors ( PgA ) action in
progress.

24.  In endocrine responsive early breast cancer
adjuvant chemotherapy (CT) is added before
endocrine therapy if pts. ≤ 50 years of age. It
prolongs survival. (Goldhirsh et al. 2011, NCCN.
Breast cancer guidelines 2011) .
 As a consequence of (CT) , a remarkable
percentage of patients develop transient
amenorrhea, CIA ( chemotherapy induced
amenorrhea ) or menopause, CIM (chemotherapy
induced menopause).
 As a consequence, correct diagnosis of
menopause is crucial to establish choice of
endocrine therapy.
Menopause

25.  Antral follicle count, ovarian volume and stromal
blood flow → Ultrasound → conflicting results, but
still most reliable U.S predictor.
 Estradiol ≤ 20 pg/ml
 LH →↑ slowly and not reliable
 AMH → slowly progressive and linear decline, less
than one
 Inhibins → not affected by tamoxifen, more precise,
not yet popular.
Tools available to judge menopause
 FSH day 3  ≥ 20 IU/1 → peri-menopause
 ≥ 30 IU/1 → poor pregnancy outcome
 ≥ 40 IU/1 → late menopause

26. Menopause Criteria
 According to national cancer comprehensive network
(NCCN – breast cancer guideline 2011) and others;
 Bilateral oophorectomy.
 Age ≥ 60 years.
 Age ≤ 60 years. + amenorrhea for ≥ 12 months in
absence of CT, tamoxifen, or ovarian suppression +
FSH and E2 in post menopausal range.
 Amenorrhea on tamoxifen, FSH, E2 postmenopausal
level
 Age of natural menopause ranges (40 – 60) with a mean
51 years. (Devos et al. 2010)
 Laparoscopic oophorectomy X surgery X RT.

27. Conclusion
●Adjuvant ET for all patients with hormone receptor-
positive breast cancer (Grade 1A) 5 years.
-Premenopause;-With high-risk BC, suppress ovaries
plus exemestane rather than tamoxifen (Grade 2B).
-If not a high-risk tamoxifen as single-
agent therapy (Grade 2B).
- AIs not used in women with intact
ovarian function as a single agent
-Post menopause;- AIs better than Tam. (Grade
2A).? Side effects?, used alternatively sometimes.
-Pregnancy……

28. Prevention
 As tamoxifen or raloxifen shown to ↓ risk of
breast cancer in specific patients, So, are they
helpful in prevention of cancer in high risk
women !?
 Using tamoxifen in blocking estrogen action in
the breast of healthy women → may decrease
female chances to develop future cancer.
 According to national cancer institute study in
1992 TAM is effective in lowering rate of breast
cancer in susceptible groups!?!?
 Others ± Gene therapy, drugs, PCO, or surgery.

29. CRITICAL ACTIONS
1. Bleeding: Premenopause; Tamoxifen < shedding,
GnRH < shedding or atrophic endometrium .
Postmenopause; Atrophic, shedding, stop AI that up
regulated ER . Quantity and quality of bleeding.
2. Endometrial thickness: Symptomatic, asymptomatic
age and drug use is considered. Bl P. and thyroid ?
3. Pregnancy: During, recurrence or accidental during
treatment. May or may not continue ……
4. Lactation: Yes and No . Suppression??? .
5. Contraception: Individualization , no hormones.
6. Future fertility and sexuality: Ova, embryo banking..

30. © 2011 Society for Endocrinology
Summary