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

 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 & 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

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

 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

 70% of breast cancer expresses estrogen receptors alpha (ERα) and progesterone receptors (PR) and thus susceptible to adjuvant endocrine therapy (Jordan 2008, Moor 2004)  So drugs, treatments or surgical intervention that block hormonal effect, or lower there levels can be used for such types of breast cancer, as several meta analyses confirmed efficacy of endocrine therapy in improving outcome in such HR +ve patients, so consensus is widely accepted about anti-hormone therapy in breast cancer. Hormones and cancer breast

Agents & Techniques Selective estrogen receptor modulator ( SERM ) Tamoxifen. 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.

Brain Estrogen Target Tissues Bone Uterus Liver Heart Breast

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

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

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

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

 The first SERM to be investigated extensively for its anticancer properties is Tamoxifen.  Tamoxifen blocks the action of estrogen in breast tissue by binding to the estrogen receptors of breast cells, thereby preventing estrogen molecules from binding to these receptors. But unlike what occurs when estrogen binds to its receptor, tamoxifen binds but does not change the receptor’s shape, so co activators are unable to bind. As a result, the genes that stimulate cell proliferation cannot be activated.  S0 by this way, tamoxifen blocks the ability of estrogen to stimulate the proliferation of breast cells.  Tamoxifen and cancer body, low incidence compared to placebo and limited to age over 55.

Aromatase Inhibitors Anastrozole ( 1 mg / day ). Letrezole ( 2,5 mg / day ). Exemestane ( 25 mg / day ). Decrease estrogen level. Up regulation of estrogen receptors.

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 ( قمع ) of estrogen receptor transcription activity ( mRNA formation ) as well as ( gluco., mineralocorticoids and androgens transcription ) is dep. on PRA expression, A receptors regulates inhibition of steroid action wherever expressed.

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.

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. 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) 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)

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.

 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

 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

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.

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 ± drugs, PCO, or surgery.

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..

© 2011 Society for EndocrinologySummary