9/30/2013

TREATMENTS FOR THERAPUTIC AGENTS: VVA/ ARE THEY SAFE? • Systemic HT/ET Steven R. Goldstein, M.D. Professor of Obstetrics & Gynecology • LlETLocal ET New York University School of Medicine Director of Gynecologic Ultrasound • Ospemifene Co-Director of Bone Densitometry New York University Medical Center

I will NOT discuss Local Estrogen Therapy systemic HT/ET (it would take the entire lecture)

Boxed Warning (Class Labeling for all Estrogens regardless of dose or route of administration)

LET’S START WITH z Estrogens increase the risk of THE LABELLING… endometrial cancer z Should not be used for prevention of (AND REMEMBER cardiovascular disease or dementia z Ï Risk of stroke and DVT WE ARE TALKING z E+P in WHI ÏRisk of MI, stroke, ABOUT LOCAL E2) invasive breast cancer, PE and DVT

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Boxed Warning (Class Labeling Contraindications (Estrogen for all Estrogens regardless of Class Labeling regardless of dose or route of administration) dose or route of administration)

z Undiagnosed abnormal genital bleeding z Ï risk of “developing probable dementia in PM women >65 y/o” in z Known, suspected, or history of breast WHIMS sub study (Women’s Health cancer Initiative Memory Study) z Known or suspected estrogen- dependent neoplasia z Restates “lowest effective doses z Active deep vein thrombosis, and shortest-duration consistent pulmonary embolism or a history of with treatment goals and risks for these conditions individual women”

Contraindications (Estrogen Concerning Breast Class Labeling regardless of dose or route of administration) Cancer… z Active arterial thromboembolic z ALL estrogen containing products’ disease (for example stroke, and package inserts clearly state that myocardial infarction), or a history of these products are “contraindicated in these conditions women with estrogen dependent z Known liver dysfunction or disease neoplasias including breast cancer” z Known or suspected pregnancy z Thus ALL such use (remember we are on LOCAL Rx) would be “off label” and against FDA recommendations.

DVT, Dementia, MI, Stroke SYSTEMIC ABSORPTION

z Absorption of vaginal estrogen depends z As already mentioned ALL primarily upon the estrogen dose (e.g. Estrogen products contain these Estring® vs. FemRing®) warnings. z Severity of vaginal may have an effect on systemic absorption z Obviously these (as well as breast z Some studies report systemic absorption is cancer)when discussing LOCAL highest in the first days or weeks of therapy and then decreases with ongoing treatment 1,2 use should depend on level of 1. Ganz, PA , Rowland JH, Desmond K, et al. Life after breast cancer: understanding women’s health-related quality of life and sexual functioning. J Clin Oncol 1998;16:501-14 systemic absorption (if any) AND, 2. Cella D, Fallowfield L, Barker P, Cuzick J, Locher G, Howell A, ATAC Trialists 9 Group, Quality of life of postmenopausal women in the ATAC (“Arimidex,” Tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for early breast cancer: is it safe? European if present, its clinical relevance. J Cancer 2005:41:2673-81

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ESTRADIOL PREPARATIONS Adapted from Pruthi,S. et al, The Breast Journal,2011,17:403-408 SYSTEMIC ABSORPTION

z Another study using highly sensitive E2 measurements did not support this findi ng3 z One hypothesis is that the thin atrophic vaginal epithlium allows initial higher absorption which diminishes as epithelium thickens with treatment.

3. Ponzone, R, Biglia N, Jacomuzzi MF, et al. Vaginal oestrogen therapy after breast cancer: is it safe? European J Cancer 2005;41;2673-81

PROBLEMS WITH SUCH DATA SO WHAT ABOUT CEE CREAM? z Each set of information is collected in a different study on different individuals. zApproved for TWO z Each study has different sample sizes , indications each with estrogen- measurement techniques, schedules, and reference ranges. DIFFERENT dosing z Does not include CEE (Conjugated Equine Estrogen) because CEE contains several estrogenic compounds that are NOT typically measured in assays for estradiol.

SO WHAT ABOUT CEE CREAM? SO WHAT ABOUT CEE CREAM? z For “atrophic and z For “moderate to severe Kraurosis Vulvae” dyspareunia, a symptom of VVA z 21 days of 0.5 gm intravaginally due to menopause”. daily and then 7 days off. z 0.5 gm. intravaginally twice “Adjust dose (0.5-2.0 gm) based weekly OR cyclical regimen of on individual response” 21 days on and 7 days off.

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What Do the Data show: BREAST PAIN:A SURROGATE CEE Cream FOR CLINICAL ABSORPTION? z Each gram of cream contains 0.625 z CEE Cream (0.5gm) 21/7 5.6% mg CEE z Placebo 21/7 1.4% z 24 weeks of 2gm/day resulted in 47% of women having Estradiol levels ABOVE a menopausal range. z CEE Cream (0.5gm) 2x/wk 2.9% z ¼ gm of CEE cream T.I.W for 6 months showed no significant increase in z Placebo 2x/wk 0% plasma levels of E2 in 20 women.

TAKE HOME What Do the Data Show: MESSAGE:ABSORPTION Breast Cancer Recurrence

z A prospective cohort study of z Appears to be less with tablets 1472 women with breast cancer and local ring than creams . ildd69ttdfincluded 69 treated for an z Little good data to truly rely on average of one year with local (different dosing, assays, E2 (range 0.1-5 years) with no Ï study populations, etc.) risk of recurrence

Nilsson K, Heimer G. Low-dose estradiol in the treatment of urogenital estrogen deficiency – a pharmacologic and pharmacodynamic study. Maturitas 1992;15:121-7

What Do the Data Show: What Do the Data Show: Breast Cancer Risk Aromatase Inhibitors z AIs, by blocking estrogen synthesis, result z In a prospective observational in circulating E2 levels < 1 pg/ml study of 18,314 women, local z Limited data with estrogen coadiittidministration vaginal estrogen therapy was z One study (25-ug E2 tablets) resulted in not associated with an increases from baseline (0.82 pg/ml) to day increased risk of breast cancer. 14 (19.6 pg/ml) but by day 28 all levels were < 10pg/ml

Bachmann G, Lobo RA, Gut R, Nachtigall L, Notelovitz M. Efficacy of low- dose estradiol vaginal tablets in the treatment of ; a Simon J, Nachitgall L, Ulrich L, et al. Endometrial safety of ultra- randomized controlled trial. Obstet Gynecol 2008;111:67-76 low dose estradiol vaginal tablets. Obstet Gynecol 2010;116:876-

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TAKE HOME NAMS 2013 Position MESSAGE:BREAST Statement Recommendation z No good level I evidence FOR z “For women with a history of or AGAINST safety of local E2 breast or endometrial cancer, in women WITH or WITHOUT a management depends upon a history of breast cancer but woman’s preference, need, CLEARLY less absorption understanding of potential than systemic E2 risks, and consultation with her oncologist”

ENDOMETRIAL SAFETY ENDOMETRIAL SAFETY z A primary concern of use of any z Although available evidence estrogen therapy in women with suggests that low doses of an intact is the risk of locally administered vaginal and estrogen are generally safe in even occasionally carcinoma the , the data are associated with unopposed limited. estrogen.

ENDOMETRIAL SAFETY (SINCE ENDOMETRIAL SAFETY COCHRANE REVIEW)

z 10-ugr E2 tablet in 336 PM women with a zCochran review reported 2% uterus had no Ï in EM proliferation or incidence of hyperplasia with hyperplasia. 1 z Another study of 10-ugr E2 tablet (n-205) the vaginal ring and a 4% reported a single case of Stage II EM incidence with CEE cream. carcinoma considered unlikely to have developed in response to the relatively Col NF, Kim JA, Chlebowski RT. Menopausal hormone replacement 2 therapy after breast cancer: a meta-analysis and critical appraisal of short course of study drug exposure. the evidence. Breast Cancer Res 2005;7:R535-40 1 Ulrich L Climacteric 2010, 13(3):228-237 2 Simon J., et al, Obstet Gynecol2008,112(5):1053-1060

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TAKE HOME TAKE HOME MESSAGE:ENDOMETRIUM MESSAGE:ENDOMETRIUM z Progestogen is generally not z IF a woman is at high risk for endometrial cancer, OR is using a higher indicated when low -dose dfilETdose of vaginal ET OR is usi ng vagilinal vaginal estrogen is ET for more than 1 year, transvaginal administered for symptomatic ultrasound or intermittent progestogen therapy may be considered. There are VVA. Endometrial safety data insufficient data to recommend routine are not available for use annual endometrial surveillance in greater than one year. asymptomatic women using vaginal ET.

BUT KEEP IN TAKE HOME MIND…ACOG PRACTICE MESSAGE:ENDOMETRIUM BULLETIN 7/2012 z Spotting or bleeding in any “Blind EM biopsy is only an pppostmenopausal woman who has an intact uterus (local E2 therapy endpoint when it reveals or not) requires a thorough cancer or atypical complex evaluation, which may include hyperplasia.” transvaginal ultrasound and/or endometrial biopsy. (Maybe I can talk on that NEXT year?)

WHAT ABOUT… OSPEMIFENE VTE

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WHAT THE LABELLING SAYS: WHAT THE DATA SHOW:

z Incidence of VTE in the clinical • “Contraindications: Active trials was 1. 45/1000 women- deep vein thrombosis (DVT), years with Ospemifene vs. pulmonary embolism (PE), or 1.04/1000 women-years with a history of these conditions” Placebo

WHAT IS THE TAKE HOME MESSAGE? z VTE risk in the background population is about 1/1000 women/year. z With systitemic EtEstrogen, TifTamoxifen, Breast Cancer Raloxifene (and I believe Ospemifene) it increases to 2.5/1000 women/year. These are all” estrogens” in the venous system. I do not believe Ospemifene is any less thrombogenic.

WHAT THE LABELLING SAYS: WHAT THE DATA SHOW:

z In all the Ospemifene trials there were z “Osphena™ has not been 2 cases of invasive breast cancer (one adequately studied with breast placebo, one Ospemifene) cancer therefore it should not z Abundant data point to an be used in women with known antiestrogen effect in preclinical or suspected breast cancer or models of breast cancer. (MCF-7 and with a history of breast other cell lines of estrogen dependent breast cancer) cancer.”

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WHAT IS THE TAKE HOME WHAT IS THE TAKE HOME MESSAGE? MESSAGE? z All SERMs have antiestrogenic effects in preclinical models of breast cancer. Thus, z In my opinion, the patient with an Ospemifene will certainly have a positive old history of breast cancer who SERM like effect on breast tissue. However has finished her Tamoxifen or the magnitude of that effect with this dosage Aromatase Inhibitor, now with a is totally unknown and unstudied. Thus new partner who has dyspareunia substitution of Ospemifene for other SERMs from VVA is EXACTLY the kind of studied and approved for their effect on patient who would benefit MOST breast would be ill advised. from Ospemifene

WHAT THE LABELLING SAYS:

z “In the endometrium, UTERINE Osphena™ has estrogenic agonistic effects. There is an EFFECTS increased risk of endometrial cancer in a woman who uses unopposed estrogen.”

WHAT THE DATA SHOW: (THE SINGLE CASE OF SIMPLE WHAT THE DATA SHOW: HYPERPLASIA) z 54 year old woman, menopausal at 49. z In all women treated with 2 years of HT. On Ospemifene 4 Ospemifene for 52 weeks months. Episode of staining. Bx showed active proliferation. Study drug there were no cases of stopped. No treatment given. Plan to endometrial cancer. follow up at 3 months. At 88 days, bled again. Bx showed simple hyperplasia ō z There was one case of simple atypia. Treated with a single course of endometrial hyperplasia progestin. D&C revealed benign polyp without atypia and inactive EM.

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WHAT THE LABELLING SAYS: WHAT THE DATA SHOW: z “The incidence of any type of zAt 52 weeks the incidence proliferative endometrium of simple hyperplasia with (weakly proliferative plus ospemifene was 0.3% and active plus disordered) was 86.1 per 1000 in Osphena vs. active proliferation was 13.3 per 1000 placebo.” 1.0%.

zActive proliferation is HISTOLOGY characterized by abundant 101 mitotic activity and glandular progression.

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zInactive/atrophic EM is characterized by simple tubular glands which lack mitotic activity and fibrotic stroma with increased collagen fibers

z“Weakly proliferative” is a misnomer which is confusing to clinicians and apparently to the FDA as well.

zHistologically it appears as inactive endometrium with rare mitotic figures and no glandular progression.

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z“Weakly” proliferative is much closer to FURTHERMORE inactive/atrophic EM and should be considered a variant of those and not combined with active

THE UTERINE SAFETY STUDY WITH RALOXIFENE

STUDY DESIGN Treatment Arms – Placebo (n=109) z 12 Month prospective, double blind, randomized – Rlx 60mg/day (n=101) z 415 women, 2-8 years postmenopausal rangiiing in age f rom 47 -60 – Rlx 150mg/day (n=105) Treatment Arms: – Conjugated Equine Estrogen – Placebo (n=109) 0.625 mg/day (n=100) – Rlx 60mg/day (n=101) – Rlx 150mg/day (n=105) – Conjugated Equine Estrogen 0.625 mg/day (n=100)

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HISTOLOGY RESULTS YOU DECIDE…`

At Endpoint z Is ospemifene more like raloxifene in the endometrium ERT Placebo RLX 60 RLX 150 (1% active proliferation, 0.3 Hyperplasia 23% 2% 0% 0% simple hyperplasia vs. 3% Proliferation 39% 2% 3% 0% active proliferation, 0% hyperplasia for raloxifene, at one year)

YOU DECIDE…

zMore like unopposed OR estrogen (39% active proliferation, 23% hyperplasia, at one year or less if they bled)

…but to call Ospemifene I acknowledge that ospemifene does not have the weight of a “estrogenic” in the uterus study like the MORE Trial (3955 (causing The Medical Letter women treated for 3 years with to recommend progestogen), Raloxifene who showed a 20% in my opinion, is unfair to non significant reduction in EM patients and clinicians as cancer)… well.

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WHAT IS NOT In the 52 week trial the incidence of any vaginal IN THE LABEL bleeding (which in clinical practice mandates evaluation) (THAT SHOULD was 1.4% (5 pts.) 4 had inactive BE…) EM, 1 had active proliferation

z Thus in clinical practice you can expect that 1 in 70 patients placed zThus, in my opinion, on Ospemifi ne w ill experi ence absent bleeding , in bleeding ospemifene patients no z And of those who bleed 4/5 will periodic surveillance nor have inactive, atrophic EM and 1/5 ot those will have active progestin therapy is proliferation. warranted.

IN SUMMARY IN SUMMARY z Local estrogens are labeled for increasing VTE although data suggesting that are few z VVA is a serious medical z Local estrogens have minimal effect on concern with important medical EM, and although long term data is and quality of life issues. lacking, routine use of progestogen is unnecessary z Safety is a huge concern z Local estrogens are minimally absorbed especially when a condition systemically (if at all) and are likely safe in like VVA is not “life patients with an old history of breast cancer although Level 1 Evidence is threatening”. lacking

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IN SUMMARY IN SUMMARY z Ospemifene is a SERM that is used z Although Ospemifene is labelled as systemically estrogenic in the EM, studies place it much more like Raloxifene in the z Ospemifene is estrogenic in the uterus than it is like estrogen in the venous system uterus z Ospemifene ,in preclinical use, is z The incidence of an antiestrogen in breast. The with Ospemifene is 1.4% but 4/5 of MAGNITUDE of that effect in those are inactive EM while only 1/5 women is unknown of those are actively proliferative

THANK YOU FOR YOUR ATTENTION!

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