Gynecological Considerations for Breast Patients #83

Michael L Krychman MDCM MPH FACOG

Executive Director of the Southern California Center for Sexual Health & Survivorship Medicine AASECT Certified Sexual Counselor Associate Professor USC Newport Beach, California USA

Why Focus on Survivorship?

 Rapidly growing population

 Increasing patient and community expectations for good quality of life

 Increased funding of survivorship research – NIH investment in survivorship . $38,000,000 Fiscal 2001 (<$4.25 per survivor) . $46,000,000 Fiscal 2004

What has contributed to this remarkable progress? Earlier detection

New and more effective therapies often including multimodal and multi-agent combinations

More effective adjuvant and/or maintenance therapies

Better supportive care

Growing attention to long-term surveillance Survivors Needs Lance Armstrong Foundation LIVESTRONG™ Poll n=1020

 Secondary Health Problems – 53% - secondary health problems . 54% - deal with chronic pain . 33% - infertility  Non-Medical Support – 49% - non-medical cancer needs were unmet – 53% - practical and emotional consequences of cancer are often harder than medical issues  Emotional Support – 70%- dealt with depression – 78% - did not seek professional services  Relationships – 58%- dealt with loss of sexual desire and/or sexual function

Cancer Survivorship is an International Agenda

 CDC Report 2004  NCI – Enhance surveillance; identify on- – Office of Cancer Survivorship going health concerns – Comprehensive Cancer Center – Educate survivors and general requirements public about value of long-term follow up care  President’s Cancer Panel – Establish clinical practice guidelines 2004 for survivorship – Public education campaign – Establish multidisciplinary teams of – Survivor care and standards health care providers for survivors for communication  Lance Armstrong Foundation – Psychosocial care – Funding source – Insurance coverage – Centers of Excellence

Why do Patients Need Long-Term Follow-Up?

 Chronic side effects of chemotherapy

 Late effects of – radiation therapy –surgery

 Risk of secondary

 Other long-term health issues Survivorship and QOL Concerns

 Cancer Screening – Ovarian cancer screening – Colon screening  General Health Maintenance –Pap smears –Bone health – Cardiovascular concerns  Reproductive Health Concerns – Pregnancy – Fertility – Sexuality  Life Management –Diet –Exercise – Sleep management – Stress management – Time management

Breast Cancer-Related Complaints

 Anatomical sequelae from surgical intervention

 Sequelae from adjunctive therapy –Chemotherapy – Radiation changes

 Maintenance therapies –Hormonal manipulation – Immune modulators – Cytostatic medications

Effect of Treatment: Other Surgeries  Cosmetic – cosmesis may not always be satisfactory – Nipples?

 Prophylactic – Bilateral Salpingo-oophorectomy adversely affects sexual functioning Van Oostrom et al (2003) Early loss of estrogen has serious medical concerns - Prophylactic mastectomy Fear of bilaterality Fear of another primary Major Concerns for Gynecology Survivorship

. Menopausal Hot Flashes . Genital Syndrome of . Sexual Complaints . Fertility

. Other: . Cognitive and Sleep Disturbances . Musculoskeletal Changes . Bone

Menopausal Road blocks

Premenopausal women

 Literature suggests that the adaptation after BC diagnosis is more difficult for younger women

 Standardized measures of depression and QOL for younger women show greater changes in mood and poorer emotional functioning

 Reproductive health effects of adjuvant therapy that specifically affect younger women – infertility – early menopause Hot Flashes

 Hot Flashes/Flushes: – sudden, transient sensations of warmth to intense heat with a range of physiologic and emotional responses (flushing, perspiration, palpitations, anxiety, embarrassment, irritation, disruption of activities especially sleep) maybe associated with a chill

 Frequency not necessarily related to reported severity  evaluation of hot flashes should include frequency and patients’ subjective experience

 10-15% of women have frequent debilitating hot flashes lasting 1-5 minutes

1. Couzi et al. 1995

 Highest frequency – in first 2 years of menopause – decline thereafter – Some persist for 10 years

 Study of women across nations (SWAN) study – ethnicity may play role

 Surgical menopause is more severe

 Severe hot flashes in 59% of BC patients – severity associated with younger age at diagnosis and with use1

Treatment Pearls

 Medications – Anti-hypertensives – SSRI –Venlafaxine – Paroxitine ( FDA approved)

 HT Alternatives – Nutritional counseling –Exercise – Environmental changes – Rhythmic breathing –Menopausal . PJ/ Chillow/ Sheets – Supplements – Integrative medicine . Acupuncture . Maitake . Yoga  ATAC (Arimidex tamoxifen alone or in combination)  BIG (Breast International Group)  ITA (Italian Tamoxifen Anastrazole Trial)  IES (Intergroup Exemestane Study)  MA-17

Other ongoing trials – AI have surpassed tamoxifen in treatment for recurrent – Same maybe for early breast disease

– Support AI use for Breast Cancer patients

Will need good treatments for FSD, atrophic vaginitis, bone health and menopausal hot flashes

Introduction  25% of new cases present before the menopause and 15% before the age of 45. Younger age is associated with decreased social and emotional function

 Up to 90% BC survivors are suffering in silence. 20 years from diagnosis 29% report sexual problems attributable to having had BC1

 FSD leads to changes in . Compliance, Marital discord and Poor overall health

 Sexuality is ignored and unaddressed

 Few studies have rigorously addressed sexual dysfunction most are retrospective studies

1. Kornblith et al. Cancer 15;98(4):679-89.

Urogenital and Vaginal Changes

 Dryness  Urgency  Vaginal irritation   Malodorous discharge Frequency  Sensitive vulva  Urinary stress incontinence  Thinning of vaginal rugae  Increased risk for UTI  Fecal incontinence maybe caused by decreased estrogen levels and neuromuscular dysfunction – The anorectum has NAMS Menopause Practice a abundant estrogen Clinicians Guide receptors  Breast cancer survivors can possibly use minimally absorbed local vaginal estrogen products like – vaginal estrogen ring – vaginal estradiol tablets

With very little systemic escape

 Consider following estradiol levels, tailor the treatment regime.

Cellular Shift Changes

Premenopausal Post menopausal

Superficial 15% Superficial 1% Intermediate 80% Intermediate 60% Parabasal 5% Parabasal 39%

Breast Cancer and Sexual Function

50% to 90% of breast cancer survivors complain of some form of FSD – “Yes I am thankful to be alive, but I am dead down there” – “Breast cancer treatment contributed to the deterioration of my excellent marriage” – “They never told me I would feel like this…..”

 Most common FSD: vaginal dryness with painful intercourse

 Changes in self-esteem are very troublesome

 Prophylactic surgeries adversely affects sexual functioning

 Topical estrogen may not be associated with increased risk of breast cancer recurrence Dew JE et al. Climacteric. 2003;6:45-52. AV Before & After Local Estrogen Therapy

Vaginal biopsy specimen Vaginal biopsy specimen showing atrophic changes from the same patient after Pandit L et al. Am J Med Sci. 1997;314:228-231. local estrogen therapy Images courtesy of Lila Nachtigall, MD. 22

Goals of Treatment

 Relieve symptoms

 Reverse anatomical changes

 Improve sexual function and quality of life

Lubricants Moisturizers Hormonal Options: Estrogens

 Systemic Hormonal  Vaginal Hormonal –Cream –Tablets . Estrace® (micronized 17- Estradiol) –Patches . Premarin® (conjugated equine estrogens) –Gels/Lotions . Estrasorb –Ring . Estrogel® . Estring® (micronized 17- Estradiol) . Femring (systemic) –Creams? –Tablet . Vagifem® ( 17B estradiol )

Minimally Absorbed Local Vaginal Topical Estrogens

Composition Dosing Vaginal Cream 17 B Estradiol cream Initial 2-4 g 1-2 wk Maintenance: 1g/d(0.1mg active ingredient /g)

Conjugated estrogens 0.5-2.0 g/d ( 0.625 mg active ingredient/g)

(Formally conjugated equine estrogens) Vaginal Ring Device contains 2mg 17 Beta Estradiol Releases 7.5 microgram per day for 90 d Vaginal tablet Initial dose: 1 tab q/day for 14day Estradiol hemihydrate Maintenance 1 tab BIW (Tablet 10.3 mcg of estradiol hemihydrate, equivalent to 10mcg of estradiol)

North American Menopause Society. Menopause. 2007;14:357-369. Cirigliano M. J Womens Health (Larchmt). 2007;16:600–631.

Simon JA, et al. Obstet Gynecol. 2008;112:1053-1060. Simon JA, et al. Obstet Gynecol. 2010; 116 (4): 1-8

Effects of Local Estrogen

 Improve sensory perception  Increase central and peripheral nerve transmission  Increase lubrication  Reduce pH  Increase peripheral blood flow  Augment capacity to develop muscle tension  Increase vibratory sensation  Increase vaginal vault relaxation  Increase vaginal vault size  Increase tissue elasticity

 Increase vaginal collagen content

– Sarrel PM. Sexuality in the middle years. Obstet Gynecol Clin North Am. 1987; 14: 49-52. Gescheider GA, Verillo RT, McCann JT, et al. Effects of the menstrual cycle on vibrotactile sensitivity. Percept Psychophys 1984; 36: 586-592. Kow L, Pfaff D. Effects of oestrogen treatment o the size of receptive field and response threshold of the pudendal nerve in the female rat. Neuroendocrinology 1973; 13: 299-313. Lara LA, et al. J Sex Med. 2009;6:30-39. NIH State-of-the-Science Conference Statement on management of menopause- Surveys

 Pfizer – ReVeal ( Revealing Vaginal Effects at Mid Life) –Healthy Women  NovoNordisk –VIVA ( Vaginal Health Insight, Views and Attitudes) – CLOSER Study  Shionogi – REVIVE (REal Women’s VIews of Treatment Options for Menopausal Vulvar/Vaginal ChangEs)

Many Users Claim Vaginal Estrogen Interrupts Routine and Requires Privacy

On average, 81% takes ensure they 1 min, have privacy before applying 50 secs vaginal estrogen to apply therapy

25% 68% 21% 11% 61% apply in early at night apply in apply in morning bedroom the bathroom evening

29 B15c, B15d, B19, B20, B20B, B21, B22; C15, C16 Base: Ever treated VVA with topical estrogen (n=858); Have partner and use topical estrogen (n=305), Partner is aware (n=295)

Dislikes with Current VVA Therapies

OTC Rx

K-Y Vagisil Astroglide K-Y Silk E Replens Estrace Premarin Vagifem Vagina not Vagina not Not enough relief Safety for long It's expensive It's messy (48%) It's messy (40%) It's messy (39%) restored to natural restored to natural VVA symp (37%) term use (41%) (40%) (43%) (43%) Vagina not Vagina not Vagina not Vagina not Safety for long Concern hormone Not enough relief restored to natural restored to natural restored to natural It's messy (40%) restored to natural term use (38%) exposure (38%) VVA symp (38%) (40%) (32%) (35%) (37%) Can’t be sexually Can’t be sexually Vagina not Administering it is Not enough relief Concern breast Safety for long spontaneous spontaneous It's messy (36%) restored to natural annoying (27%) VVA symp (39%) cancer (36%) term use (34%) (25%) (27%) (36%) Can’t be sexually Vagina not Not enough relief Not enough relief Not enough relief It's expensive Concern hormone It's expensive spontaneous restored to natural VVA symp (24%) VVA symp (23%) VVA symp (25%) (33%) exposure (32%) (36%) (24%) (29%) Administering it is Inconvenient to Administering it is Inconvenient to Vaginal discharge Risk of side effects Administering it is Concern hormone annoying (21%) take (21%) annoying (21%) take (18%) (26%) (27%) annoying (29%) exposure (29%)

Inconvenient to Vaginal discharge Inconvenient to Administering it is Administering it is It's expensive Concern breast It's messy (28%) take (17%) (17%) take (18%) annoying (18%) annoying (23%) (25%) cancer (26%) Can’t be sexually It's not discrete It's not discrete It's not discrete Takes long time to Not enough relief Risk of side effects Risk of side effects spontaneous (13%) (12%) (12%) work (22%) VVA symp (24%) (24%) (25%) (16%) Can’t be sexually It's not an oral pill Safety for long Safety for long Vaginal discharge Concern breast Dosing schedule spontaneous It's messy (23%) (8%) term use (15%) term use (5%) (8%) cancer (23%) difficult (17%) (22%) It's expensive It's not an oral pill Don't like touching It's not an oral pill It's not an oral pill Administering it is Inconvenient to It's not an oral pill (5%) (15%) body (5%) (7%) (13%) annoying (19%) take (23%) (14%)

Takes long time to Takes long time to It's not an oral pill Interrupts daily Safety for long Inconvenient to Vaginal discharge Takes long time to work (4%) work (10%) (5%) life (5%) term use (12%) take (18%) (19%) work (13%)

B11a. What do you dislike about the treatment(s) you are currently taking for your vaginal/vulvar symptoms? 30 Base: Currently treating VVA Putting WHI Risks Into Perspective

EPT EPT ET ET

Relative Absolute Risk Relative Risk Absolute Risk Risk (number per (number per Event 10,000 women) 10,000 women) CHD 1.29 7 more 0.91 5 less

Stroke 1.41 8 more 1.39 12 more

VTE 2.11 18 more 1.33 7 more Breast 1.26 8 more 0.77 7 less cancer

Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-333. Women’s Health Initiative Steering Committee. JAMA. 2004;291:1701-1712.

Comparative Risk of Breast Cancer in RCT of Hormone Therapy and Statin Therapy Placebo: Therapy Relative Risk Additional cases Therapy/Study No of Breast No Of Breast per 10,000 Cancer Cancer women per year of therapy EPT WHI‐ EPT 150 199 1.20 8 HERS 25 32 1.3 12

Statin Therapy PROSPER 11 18 1.65 15 AFCAPS/TexCAPS 9 13 1.44 15 4S ( 10yr Follow 5 7 1.44 5 up) CARE 1 12 12.17 77 LIPID 10 10 1.0 0 ALLHAT‐LLT 37 34 0.93 ‐2 HPS 51 38 0.75 ‐10

ET WHI‐ET 161 129 0.82 ‐8

17 B Estradiol WEST 5 5 1.0 ‐2

 Hodis; Cleveland Clinic Journal of medicine: 17;S4 3-12

VVA and Sexual Function

 Cross-sectional, population-based study of 1,480 sexually active, postmenopausal women

 57% had vulvovaginal atrophy

 55% had female sexual dysfunction

 Women with sexual dysfunction ~4X more likely to also have vulvovaginal atrophy

 Conclusion: Reducing symptoms of one condition may also relieve symptoms of the other

– Levine KB, et al. Menopause. 2008;15(4 pt 1):661-666. Is Local Really Local?

 Kendall et. al. cautions that vaginal estradiol is contraindicated in postmenopausal women on adjuvant aromatase inhibitors1.

 Labrie et. al. demonstrate that even small doses of vaginal preparations

– Vagifem 25 μg; Premarin Vaginal Cream result in significant systemic absorption through estrogen naive vaginas(2).

 Naessen et al showed that 7.5 μg/24h could improve the lipid profile and bone density without affecting the endometrium3-5.

 1Kendall A, et. al. Ann Oncol 2006;17:584-587. 2Labrie F, et. al. Menopause 2009;16:30-36. 3-5Naessen T, et. al. J Clin Endocrinol

Metab 2001;86:2757-2762.; Am J Obstet Gynecol 1997;177:115-119.; Am J Obstet Gynecol 2002;186:944-947.

Kendall M., Dowsett et al: Caution: Vaginal estradiol appears to be contraindicated in postmenopausal women on adjunctive aromatase inhibitors

Annals of Oncology: 1/27/2006 UK study of 7 women on AI. Serum E2, FSH, LH measured at baseline the 2, 4 7-10 and 12 weeks later. Specific assay for postmenopausal LOW levels Serum levels rose from baseline of <5pmol/l consistent with AI therapy to a mean of 72 pmol/l at 2 weeks, by week 4 this had decreased to <35 pmol/l in the majority of women Conclusion: Vagifem significantly raises systemic estradiol levels at least in the short term. This may reverse the estradiol suppression achieved by AI in women with Breast Cancer and is contraindicated. Current Overview of the Management of Urological Atrophy in Women with Breast Cancer

Pruthi S, Simon JA, Early AP. Breast J. 2011 Jul-Aug;17(4):403-8. doi: 10.1111/j.1524-4741.2011.01089.x. Epub 2011 Jun 6

Local Estrogen Therapy and Risk of Breast Cancer Recurrence among Hormone Treated Patients: A Nested Case Control Study LeRay I., Dell’aniello S. et al Breast Cancer Res Treat 2012;135:603

 Design – Impact of vaginal estrogen on recurrence risk was evaluated among 917 women with BC recurrence (cases) who were compared to women with BC in remission (controls) – Matched for age and initial endocrine treatment – Rate of vaginal estrogen use was low (<3%) – Most frequent local estrogen: cream and tablets

 Results –Rate of concomitant vaginal estrogen use with endocrine therapy was similar with cases and controls ( 2.1% versus 2.8% respectively) suggesting that concomitant use is not associated with an increased risk of recurrence ( (RR 0.97)

– The rate of sequential se of vaginal estrogen following completion of endocrine therapy was also similar ( 0.25 in cases and controls) suggesting there was no in risk in the risk of recurrence

Dew et al: Conclusions

 Cohort: N=1472 – HRT: 342 (23%) – Local vaginal estrogens: 69 (4.7%) . Tablets, cream  Diagnosis to treatment: 5.25 years ( 0-20 years)  Median time of use: 1 year Median follow-up: 5.5 years  Deaths: 11.5% entire population – 6% in local vaginal estrogen users

 Study was underpowered for definitive data outcomes  Topical vaginal estrogen usage appears not to increase risk of recurrent breast cancer

Dew et al. 2003. Climacteric. 2003;6:45-52. 39 Important New Studies

 Goldfarb et al (SABC 2012) n=26 – BC Stage 1-3 on AI; 10mcg 17B-estradiol – Median change in estradiol from baseline to wk 12 was 0.2 with a range from -3.0 to 14.6 – Only 5/26 (19%) had sporatic elevation in E2 outside menopausal range – Clinical significance of the systemic E2 absorption is unknown and warrants further study – Impression: . Elevations in E2 are rare and brief, data does not support the routine monitoring of E2 levels . Improvements in sexual function is not associated with an elevation of E2 levels

 Melisko et al ( SABC 2012) N=29 – Vaginal Testosterone 1% 0.5g qd (15) Vs. Estring 2mg (14) in BC pt on AI – Preliminary Data . Both effective to tx vaginal dryness . Neither have met criteria for stoping . Modest and mostly transient elevations of E2 have occurred, more often and only persistent in the Test arm . Accrual continues

 Wills et al ( J of Onc Pract 2012 8:(3): 144-148) N=24 – Postmenopausal women with ER(+) BC or at high risk for BC who were taking an AI or a SERM. (Estring VS 25mcg-17B estradiol tablets) on VE for 90 days – VE Ring: E2 levels pre insertion and 12 weeks post insertion were significantly greater than controls (p<0.001) – VE Tablets: E2 levels pre insertion were NOT significantly different than controls (p=0.48) and post insertion levels were 76 pmol/L higher than pre insertion – Preinsertion levels for pt on VE tablets were not elevated compared with those of controls suggesting that E2 elevations with this preparation may not be continuously sustained

Low Dose Vaginal Estrogen Treatment

 Breast cancer survivors may possibly use minimally absorbed local vaginal estrogens products like the ring (Estring ®) and tablets (Vagifem ®) and Conjugated Equine Estrogen (Premarin Vaginal Cream) ® Estradiol cream (estrace ®) – with very little systemic escape. OFF LABEL!  Kendal et al (2006): increased E2 level in BC patients on Vagifem ®  Surgical oncologists, medical oncologists, gynecologists and patients will often disagree about safety  NAMS and OBGYN advocate personalized and individualized plans  Formulate management plan – Monitor estradiol levels – Evaluate abnormal bleeding – Try alternatives first? – Know your personal comfort zone 42 In Development for Menopausal VVA

Drug Name Drug Category Pharma Sponsor Current Development Synthetic CE- A Cream Estrogen Teva Inc., NDA Bijuiva Ospemifene Tablets SERM Quatrx Inc., APPROVED!!! (Osphena) Shionogi Pharmaceuticals BZA/CEE Tablets STEAR Pfizer APROVED !!! TSEC Pharmaceuticals DHEA Vaginal Ovules Androgenic Precursor Endoceutics Inc Phase III (Prasterone) Bayer

Lasofoxifene SERM Ligand Pharmaceuticals NDA Status Unclear (Fablyn) Pfizer Inc EMEA- Approved

Seala SERM BioNovo Phase I-II

Tamoxifen SERM Pear Tree Pharmaceuticals Phase I-II (vaginal inserts) BZA/CEE- Bazedoxifene+ conjugated equine estrogen SERM: Selective modulator STEAR: Selective tissue estrogenic activity regulator TSEC: Tissue Selective Estrogen Complex

Topical Testosterone for Breast Cancer Patients with Vaginal Atrophy Related to Aromatase Inhibitors: A Phase I/II Study. Witherby S, Johnson J, Demers L, Mount S, Littenberg B, Maclean CD, Wood M, Muss H.

Providence, Rhode Island, USA;

Abstract Purpose. Controversy exists about whether vaginal estrogens interfere with the efficacy of aromatase inhibitors (AIs) in breast cancer patients. With the greater incidence of vaginal atrophy in patients on AIs, a safe and effective nonestrogen therapy is necessary. We hypothesized that vaginal testosterone cream could safely treat vaginal atrophy in women on AIs.

Methods. Twenty-one postmenopausal breast cancer patients on AIs with symptoms of vaginal atrophy were treated with testosterone cream applied to the vaginal epithelium daily for 28 days. Ten women received a dose of 300 μ g, 10 received 150 μ g, and one was not evaluable. Estradiol levels, testosterone levels, symptoms of vaginal atrophy, and gynecologic examinations with pH and vaginal cytology were compared before and after therapy.

Results. Estradiol levels remained suppressed after treatment to <8 pg/mL. Mean total symptom scores improved from 2.0 to 0.7 after treatment (p < .001) and remained improved 1 month thereafter (p = .003). Dyspareunia (p = .0014) and vaginal dryness (p <.001) improved. The median vaginal pH decreased from 5.5 to 5.0 (p = .028). The median maturation index rose from 20% to 40% (p < .001). Although improvement in total symptom score was similar for both doses (-1.3 for 300 μ g, -0.8 for 150 μ g; p = .37), only the 300-μ g dose was associated with improved pH and maturation values.

Conclusions. A 4-week course of vaginal testosterone was associated with improved signs and symptoms of vaginal atrophy related to AI therapy without increasing estradiol or testosterone levels. Longer-term trials are warranted

Intravaginal DHEA (Vaginorm/Prasterone ®)  Labrie et al – Journal of Steroid Biochemistry and Molecular Biology 111 (2008) 178-194  Treatment – One ovule of DHEA 0.0%, 0.5%, 1.0% or 1.8% – 7 days vaginal PH was significantly decreased – Serum Estradiol and Testosterone remained within normal postmenopausal values at all DHEA values – DHEA permits rapid effects for local beneficial effects against vaginal atrophy, without changes in estradiol thus avoiding the increased risk of breast cancer associated with the current intravaginal or systemic estrogenic formulations

Labrie et al. Menopause vol 16 no 5 907-922 Ospemifene (Osphena)

 First and Only oral non estrogen for the treatment of moderate to severe dyspareunia a symtptom of VVA due to menopause  2010 RCT Stage III: SERM ospemifene – Quatrix Inc/ Shionogi Inc  827 women randomized either 30, 60 mg or placebo for 12 weeks  60 mg was shown to be effective, well tolerated for vaginal dryness and dyspareunia  No proliferative effect on endometrium  Side effect: 8 % hot flashes – 0.7% severe in 60mg group – one participant (0.4%) in the 60 mg group discontinued because of hot flashes. – Bachman et al. Menopause: 17:3:: 480-486  Interesting: Ospemifene and 4-hydroxyospemifene effectively prevent and treat breast cancer in Mtag.TG Transgenic Mouse. – Burich et al Menopause 19:1: 96-103

Tissue Selective Estrogen Complex-

 TSEC ( AKA STEAR) pair a selective estrogen receptor modulator (SERM) with 1 or more estrogens to provide clinical results based on their blend of tissue selective activities. APRROVED AS DUOVIV ® STAY TUNED!!!

 The ideal TSEC maintains the positive benefits of estrogens on vasomotor symptoms, vulvar/vaginal atrophy (VVA) and bone without stimulatory effects on the uterus and breast

 The first TSEC in clinical development pairs Bazedoxifene (BZA) a SERM with a unique endometrial profile with conjugated estrogens.

– Goldfischer et al 2008 ISSWSH 2008

Neogyn ® Vulvar Soothing Cream

 Cutaneous Lysate of cultured fetal fibroblasts

 More than 100 cytokines, growth factors, inflammatory interleukins IL-1RA, IL-4 and IL-10.

 In clinical studies improvement in symptoms of atrophy as well as for vulvar pain disorders (vulvodynia,lichen sclerosus)

 Don’t forget the VUVLA Treatment Tools

 Lifestyle modification  Moisiturizers/lubricants  Diet/exercise  Behavioral techniques  Modify medications  Mindfulness  Structured sexual tasks  Therapy  Vibrators/dilators  Relaxation exercises  Sexual  Acupuncture enhancers/accessories

49

Pharmacological Agents

 Hormones  Tibolone –Estradiol  Bremelanotide – Testosterone  Lybrydo/Lybridos  PD5 inhibitors  Femprox  Local Treatment  Flibanserin for atrophy  BZA/CEE  Osphefene  Estriol 50

Treatment Paradigm

Alternative Medicine Structured Behavior Sexual Modification Tasks

Treat Sexual Systemic Device Illnesses

Sexual Treatment Pharmacology Evaluate medications

Patient And Consultations Partner Education Psycho Pain therapy management

51 A Tale of Recovery

Flibanserin

Novel, non‐hormonal therapy that works on key sexual pathways in the brain Over 10,000 women studied in trials to date Once daily pill taken at bedtime Demonstrated efficacy on measurements of desire, distress and satisfying sexual events (SSEs) Well tolerated safety profile. Most common side effects – dizziness, nausea, fatigue and somnolence Flibanserin acquired by Sprout Pharmaceuticals from Boehringer Ingelheim Re‐submission to FDA with 14 new trials and a validation study scheduled for 2013

Flibanserin: Structure Mechanism of ACTION

. Serotonin may have a role in HSDD by acting as a sexual satiety signal. . Serotonergic agents (e.g. SSRIs) inhibit desire, arousal, and orgasm. . Flibanserin is a 5‐HT1A receptor agonist which could have pro‐sexual effects. . Stimulating the serotonin 5‐HT2A receptor has been associated with decreased sexual behavior (male rodents). . Flibanserin is a 5‐HT2A antagonist which might have pro‐sexual effects.

Borsini F, Evans K, Jason K, et. al. Pharmacology of flibanserin. CNS Drug Rev. 2002;8(2):117-42. FLIBANSERIN’S MECHANISM OF ACTION

- Flibanserin - - - Testosterone 5-HT - X σ receptors Progesterone + ++ +/- + Melanocortins Estrogen + + + Desire Dopamine (DA) + - X - - + Flibanserin 5-HT - - - -- ++ X Prolactin Subjective Norepinephrine (NE) Excitement

++ Oxytocin Orgasm Adapted from Clayton A, Hamilton D. Psychiatr Clin N Am. 2010;33:323-338.

Pivotal Study Endpoints

Primary Endpoints Change from baseline to the final visit period in the monthly frequency of Satisfying Sexual Events (SSEs) Desire score as measured by eDiary (511.71 and .75) or FSFI‐d (511.147 and .130) Secondary Endpoints Female Sexual Function Index (FSFI) desire items (511.71 and .75) Female Sexual Distress Scale‐ Revised total score and Item 13 (FSDS item 13) Other Endpoints Female Sexual Function Index (FSFI) total score Patient Global Impression (PGI) of improvement Patient benefit evaluation responder endpoint eDiary Distress eDiary Desire day

CHANGE FROM BASELINE FOR SATISFYING SEXUAL EVENTS (SSE) – STUDY 511.147

** ** ** ** **

*

* p= 0.033; ** p < 0.0001 for difference between placebo and flibanserin M. Katz, L. DeRogatis, R. Ackerman, P. et. al. Efficacy of flibanserin in women with Hypoactive Sexual Desire Disorder: results from the BEGONIA trial. J Sex Med (in press). CHANGE FROM BASELINE FOR FSFI‐ DESIRE DOMAIN (FSFI‐d) – STUDY 511.147

** ** ** *

* p = 0.0002; ** p < 0.0001 difference between placebo and flibanserin M. Katz, L. DeRogatis, R. Ackerman, P. et. al. Efficacy of flibanserin in women with Hypoactive Sexual Desire Disorder: results from the BEGONIA trial. J Sex Med (in press).

Consistent Efficacy: 4 different US Phase III Clinical Trials*

RATE OF FIRST ONSET OF MOST COMMON SIDE EFFECTS –ALL TRIALS*

16

14

12

10

8 Placebo Flibanserin 100 mg qhs 6

% of subjects % of 4

2

0 Week 1 Week 2 Week 3 Week 4 *Somnolence, fatigue, or sedation in phase III placebo controlled trials (%) 60 Data on file Sprout Pharmaceuticals. Flibanserin Summary & Conclusions

Consistently demonstrated safety and efficacy Large scale trials in more than 10,000 women Fourteen new trials and one validation study Only compound for FSD in Phase III clinical study To be re‐submitted to FDA in 2013

Femprox

 RCT Stage III trial of topical alprostadil 0.4% cream with a skin penetration enhancer (DDAIP) an ester of N, N dimethylalanine and dodecanol  900 mg dose showed statistically significant and clinically relevant improvements in primary and secondary efficacy outcomes – Primary endpoint: arousal success (yes to #3 of Female Sexual encounter profile ) – Secondary endpoints: FSFI and Global Assessment Questionaire and Sexual Distress Scale. –Goldstein et al J Sex Med 2012 9: supl 1 22

Lybrido and Lybridos

 Lybrido combines testosterone  Lybridos combines with a phosphodiesterase testosterone with a 5HT(1A) inhibitor (PDE5 inhibitor) agonist (buspirone).  Lybrido is designed for women  Designed for women with with HSDD and low motivation, HSDD who have sexual relatively insensitive system for inhibition. sexual cues.  Testosterone increases sexual  Testosterone is believed to motivation and buspirone improve desire, whereas the counters the sexual inhibition. PDE5 inhibitor works to  Administration of Lybridos is increase genital sensitivity. sublingual and the timeframe  Administered sublingually, the for the pharmacological effects time of peak concentration of of the buspirone coincide with the PDE5 inhibitor coincides the behavioral window for with the 4-hour delay in testosterone administration.3,4 behavioral effect of the testosterone. Bremelanotide

 Melanocortin receptor 4 agonist (MCR4 agonist) for treatment of HSDD and/or FSAD.  Was initially delivered as a nasal spray and Phase II - adverse effects on BP. Results:  The drug reformulated in a lower 1.25 and 1.75 mg SC was dose for SQ injection. effective in decreasing distress, increasing arousal and desire  Phase IIb study is completed in and increasing the number of premenopausal women with SSE with robust dose response HSDD and or FSAD and consistency of effect across all key endpoints.

1.Stephen B. Levine, MD;1 Candace Brown, MSN, PharmD;2 Eileen Palace, PhD;3 Steven Fischkoff, MD;4 Christine Schnorrbusch, Phase 2B., Bremelanotide Study in Pre and Post Menopausal Women with Female Sexual Arousal Disorder BS4. Poster Presentation. ACOG Annual Meeting. Annual Clinical Meeting. New Orleans LA. Poster 56. May 2008.

Do you have any questions concerning infertility and parenthood after cancer? Many of your cancer patients are at risk for infertility due to treatment……..

A patient seen in General Gynecology recently said….. I was never given any information concerning infertility and sexuality at any point in my treatment, I think this is malpractice. Parenthood Options after Cancer

 1)Natural Conception

 2) Assisted Conception

 Donor eggs

 Donor sperm

 Donor embryos

 Third Party Reproduction – Surrogacy . Gestational versus Traditional - Adoption - Infant - National and International - Cancer friendly agencies - Embryo

 Child free living

 Oocyte Cryopreservation – No longer considered experiment – Improved outcomes with vitrification . Rapid freezing with liquid nitrogen and the oocyte is solidified into a glass like structure . No evidence of increased neonatal risks . Implantation Rates 17%-41% . Clinical Pregnancy Rates 36-65% – Cobo et al 2010; Rienzi 2010  Embryo Cryopreservation – Often considered gold standard – Mature oocytes harvested – ASRM and SART Guidelines  Invitro Oocyte Maturation – Experimental – Attractive to those who need urgent chemotherapy – Lower implant rates, clinical pregnancy rates and live birth rates versus IVF

 Ovarian Tissue Cryopreservation – Prepubscent girls ( 6000 cancers girls aged: – Orthotopic reimplantation in the pelvic cavity – Heterotopic reimplantation outside – > 24 live births orthotopic /505 naturally conceived

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 Surgical Techniques – Ovarian shielding – Ovarian transposition . Variable success – 16-90% reduction . Rodriguez et al 2012

 Fertility Sparing Surgery – Simple Oophorectomy for Borderline – Radical trachelectomy . 212 case study, 66% achieved pregnancy, of those who were pregnancy, 45% reached full term, 255 delivered between 28-36 weeks, and 5% delivered before 28 weeks – Speiser et al 2011

 Early Stage Endometrial Cancer – 45 studies – 391 participants – Complex atypical hyperplasia or Grade 1 adenocarcinoma treated with progestin – CAH response (66%)- repro outcome 41.2% – Grade 1 response (48%)-repro outcome 34.8% – 117 live births . Gunderson et al 2012

 Medical Suppression – GNRH agonists prior to chemo – Debatable efficacy

72 Embryo Freezing Ovarian Suppression Embryo Freezing

Egg (Oocyte) Freezing Ovarian Shielding Egg (Oocyte) Freezing

Ovarian Tissue Freezing Ovarian Tissue Freezing

Ovarian Transposition Donor Embryos

Radical Trachelectomy Donor Eggs

Surrogacy

Adoption

Natural Conception

Using Frozen Embryos

Using Frozen Eggs

Using Frozen Ovarian Tissue

Cycle of Cancer

• Early Diagnosis • Preservation of • Less Aggressive hormones Treatment • Limited organ • Same Outcome Destruction

Cancer Sexuality Survivorship

Pregnancy Fertility

• Pregnancy after • Preservation of Diagnosis gonadal function •Pregnancy if feasible During Diagnosis

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Attention to Issues! There are Needs to be Addressed! Of 635 Japanese breast surgeons, 32% were consulted about sexual issues.1 “ ’ Although majority recognized importance of patients sexuality-related concerns, they did ” not necessarily think that surgeons had a professional responsibility to deal with them. ’ •Of 35 specialists in gynecologic/women s cancers, 20% reported they had the time to discuss sexual issues with their patients.2 “ With little time for sensitive discussions on sexuality, fertility and intimacy issues, and perceived lack of support once a problem has been identified, it is understandable why ” physicians do not routinely discuss such issues with their patients.

1. Takahasmi, et al. JCO 2006; 24:5763-68. 2. Wiggins, et al. J Psychosoc Onc 2007; 25:61-70. The Business of Survivorship Medicine Healing is an Art

Medicine is Science

Healthcare is Business

Preceptorships and consultations are available for you and your institution

Components of Cancer Care

Medical Patient Clinical Training Education Excellence and Research And Education Support

Conclusions . ASK… You cannot treat a problem if you do not know that one exists… Menopausal issue, Sexuality and other quality of life concerns are paramount.

. Know your own personal comfort zone and level of expertise

. Get help, get trained and get formalized

. Refer when appropriate Thank you for your kind attention

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