Risk-reducing surgery and hormones

Risk-reducing surgery and hormones Nora Johansen Registrar and PhD student at Department of Obstetrics and Gynecology, Sørlandet Hospital Arendal, Norway

No conflicts of interest to declare

Overview Hereditary ovarian cancer and risk-reducing strategies Risk-reducing salpingo-oophorectomy (RRSO) Hormonal effect of bilateral salpingo-oophorectomy (BSO) Hormone replacement therapy (HRT) after RRSO and the risk of breast cancer Use of HRT after RRSO

Ovarian cancer 5-year survival 48.1% 10%-15% of the epithelial ovarian cancers are due to inherited increased risk Inherited ovarian cancer: HNPCC 5 % Other 5 % BRCA2 20 % BRCA1 70 % HNPCC: Hereditary non-polyposis colon rectal cancer syndrome (Lynch syndrome) Cancer in Norway 2015; Pat et al., Cancer 2005

BRCA function Oncosuppressor genes Repair of double strand breaks in the DNA molecule Mutation in the one of the BRCA genes: Defect in the DNA repair results in an accelerated rate of mutations in the genome A wide variation of mutation types and cancer risk

Cancer risk in women with BRCA mutations BRCA1 50% 80% risk of breast cancer 30% 60% risk of ovarian cancer BRCA2 45% 49% risk of breast cancer 11% 18% risk of ovarian cancer The estimates are cumulative risks until 70-75 years Chen et al., J Clin Oncol 2007; Antoniou et al., Am J Hum Genet 2003; Finch et al., JAMA 2006

Before and after Angelina Jolie BRCA test rates before and after 14 May 2013 Jolie editorial versus control period in 2012. Sunita Desai, and Anupam B Jena, BMJ 2016

Before and after Angelina Jolie BRCA test rates before and after 14 May 2013 Jolie editorial versus control period in 2012. Mastectomy rates before and after May 2013 Jolie editorial versus control period in 2012. Sunita Desai, and Anupam B Jena, BMJ 2016

How to reduce cancer related mortality in women with BRCA mutations Breast cancer Mammography/MRI Bilateral mastectomy 95% risk reduction Lowry et al., Cancer 2012; Evans et al., J Med Genet 2009; Rebbeck et al., J Clin Oncol 2004 Ovarian cancer Screening not effective Risk-reducing salpingooophorectomy 80% risk reduction Bilateral salpingectomy with delayed oophorectomy ongoing studies Oral contraception Gaarenstroom et al., Int J Gynecol Cancer 2006; Mannis et al., JAMA Intern Med 2009; Iodice et al., Eur J Cancer 2010; Rebbeck et al., J Natl Cancer Inst 2009; Domchek et al., JAMA 2010; Marchetti et al., BMC Women s Health 2014; Daly et al., J Med Genet 2009.

Risk-reducing salpingo-oophorectomy (RRSO) Removal of both ovaries and fallopian tubes Most effective method of preventing ovarian cancer 80% risk reduction of ovarian cancer 0% 50% risk reduction of breast cancer Ideal timing: After completed child births, at 35 45 years JMS, Indiana University Medical Center (2012) Kauff et al., J Clin Oncol 2008; Domchek et al., JAMA 2010; Domchek et al., Lancet Oncol 2005; Eisen et al., J Clin Oncol 2005; Heemskerk-Gerritsen et al., J Natl Cancer Inst 2015; Finch et al., J Clin Oncol 2014; Marchetti et al., BMC Women s Health 2014; Rebbeck et al., J Natl Cancer Inst 2009.

Hormonal changes after BSO Premenopausal BSO: 85% reduction in plasma estrogen 50% reduction of free androgen index Postmenopausal BSO: 30% reduction in plasma estrogen 20-50% reduction of free androgen index Estimate of bioavailable testosterone: Free androgen index = Total testosterone x 100 / sex hormone binding globulin Waaseth et al., BMC Women s Health 2008; Kindi et al., Oman Med J 2012; Labrie et al., Menopause 2011

Adverse effects after BSO at young age CVD risk Osteporosis Vasomotor symptoms Impaired sexual function Dementia, cognitive impairement Rivera et al., Menopause 2009 Challberg et al., Br J Cancer 2011 Finch et al., Gynecol Oncol 2011 Finch et al., Gynecol Oncol 2011; Johansen et al., Gynecol Oncol 2016 Rocca et al., Neurology 2007

HRT reduces adverse effects after RRSO Fear of breast cancer is the most common reason for non-use among young HRT eligible women after RRSO Is it safe for women who carry a BRCA mutation to use HRT? Rivera et al., Menopause 2009; Challberg et al., Br J Cancer 2011; Finch et al., Gynecol Oncol 2011; Johansen et al., Gynecol Oncol 2016; Rocca et al., Neurology 2007; Challberg et al., Br J Cancer 2011

Is HRT safe in BRCA carriers? Author Participants Design Risk of breast cancer Armstrong et al. 2004 Studies on impact of RRSO and HRT on five major diseases: breast cancer, ovarian cancer, CHD, osteoporosis, and venous thrombosis. Markov decision analytic model Life expectance increased 3.5-8 years after RRSO. Increase in life expectancy with 15 years of HRT. Rebbeck et al. 2005 462 women with BRCA 1/2 mutation (155 RRSO and 307 no RRSO) with no breast or ovarian cancer diagnosis Prospective RRSO women had 63 % lower risk of BC compared with the non-rrso women. No significant differences between HRT users and non-users. Eisen et al. 2008 236 matched pairs. Postmenopausal BRCA1 carriers (nat. + surg.) Cases: Breast cancer. Controls: No breast cancer Case control study OR for BC 0.58 (0.35, 0.96) (HRT vs no HRT) Gabriel et al. 2009 73 BRCA carriers without breast and ovarian cancer Retrospective cohort study BC in 3/33 (9%) of HRT users and 9/29 (31%) of the HRT nonusers Kotsopoulos et al. 2016 432 matched pairs. Postmenopausal BRCA1 carriers (nat. + surg.). Cases: Breast cancer. Controls: No breast cancer. Case control study OR 0.80 (0.55, 1.16) for BC among HRT ever users compared to HRT never users.

Is HRT safe in BRCA carriers? Author Participants Design Risk of breast cancer Armstrong et al. 2004 Rebbeck et al. 2005 Rebbeck et al. 2005 Eisen et al. 2008 Studies on impact of RRSO and HRT on five major diseases: breast cancer, ovarian cancer, CHD, osteoporosis, and venous thrombosis. 462 women with BRCA 1/2 mutation (155 RRSO and 307 no RRSO) with no breast or ovarian cancer diagnosis 462 women with BRCA 1/2 mutation (155 RRSO and 307 no RRSO) with no breast or ovarian cancer diagnosis 236 matched pairs. Postmenopausal BRCA1 carriers (nat. + surg.) Cases: Breast cancer. Controls: No breast cancer Markov decision analytic model Life expectance increased 3.5-8 years after RRSO. Increase in life expectancy with 15 years of HRT. Prospective RRSO women had 63 % Prospective lower risk of BC compared with the non-rrso women. No significant differences between HRT users and Case control study non-users. RRSO women had 63 % lower risk of BC compared with the non-rrso women (P < 0.001). No significant differences between HRT users and non-users. OR for BC 0.58 (0.35, 0.96) (HRT vs no HRT) Gabriel et al. 2009 73 BRCA carriers without breast and ovarian cancer Retrospective cohort study BC in 3/33 (9%) of HRT users and 9/29 (31%) of the HRT nonusers Kotsopoulos et al. 2016 432 matched pairs. Postmenopausal BRCA1 carriers (nat. + surg.). Cases: Breast cancer. Controls: No breast cancer. Case control study OR 0.80 (0.55, 1.16) for BC among HRT ever users compared to HRT never users.

Is HRT safe in BRCA carriers? Author Participants Design Risk of breast cancer Armstrong et al. 2004 Studies on impact of RRSO and HRT on five major diseases: breast cancer, ovarian cancer, CHD, osteoporosis, and venous thrombosis. Markov decision analytic model Life expectance increased 3.5-8 years after RRSO. Increase in life expectancy with 15 years of HRT. Rebbeck et al. 2005 462 women with BRCA 1/2 mutation (155 RRSO and 307 no RRSO) with no breast or ovarian cancer diagnosis Prospective RRSO women had 63 % lower risk of BC compared with the non-rrso women. No significant differences between HRT users and non-users. Eisen et al. 2008 236 matched pairs. Postmenopausal BRCA1 carriers (nat. + surg.) Cases: Breast cancer. Controls: No breast cancer Case control study OR for BC 0.58 (0.35, 0.96) (HRT vs no HRT) Gabriel et al. 2009 Kotsopoulos et al. 2016 Kotsopoulos et al. 2016 73 BRCA carriers without breast and ovarian cancer 432 matched pairs. Postmenopausal BRCA1 carriers (nat. + surg.). Cases: Breast cancer. Controls: No breast cancer. 432 matched pairs. Postmenopausal BRCA1 carriers (nat. + surg.). Cases: Breast cancer. Controls: No breast cancer. Retrospective cohort Case study control study Case control study BC in 3/33 (9%) of HRT users and 9/29 (31%) of the HRT nonusers OR 0.80 (0.55, 1.16) for BC among HRT ever users compared to HRT OR 0.80 (0.55, 1.16) for BC among HRT never users. compared to HRT never users.

Is HRT safe in BRCA carriers? Author Participants Design Risk of breast cancer Armstrong et al. 2004 Rebbeck et al. 2005 Studies on impact of RRSO and HRT on five major diseases: breast cancer, ovarian cancer, CHD, osteoporosis, and venous thrombosis. Markov decision analytic model Life expectance increased 3.5-8 years after RRSO. Increase in life expectancy with 15 years of HRT. No randomized controlled trials among 462 women with BRCA 1/2 mutation (155 Prospective RRSO and 307 no RRSO) no breast or ovarian women cancer diagnosis with BRCA mutations, RRSO women had 63 % lower risk of BC compared with the non-rrso women. No significant differences between HRT users and non-users. Eisen et al. 236 matched pairs. Postmenopausal BRCA1 Case control study OR for BC 0.58 (0.35, 0.96) (HRT vs 2008 but short-term carriers (nat. + surg.) Cases: HRT Breast cancer. use is considered no HRT) safe. Controls: No breast cancer Gabriel et al. 2009 73 BRCA carriers without breast and ovarian cancer Retrospective cohort study BC in 3/33 (9%) of HRT users and 9/29 (31%) of the HRT nonusers Kotsopoulos et al. 2016 432 matched pairs. Postmenopausal BRCA1 carriers (nat. + surg.). Cases: Breast cancer. Controls: No breast cancer. Case control study OR 0.80 (0.55, 1.16) for BC among ever users compared to never users.

Contraindications to HRT after RRSO in women without breast cancer and 52 years Endometrial pathology Venous thromboembolism Cardiovascular disease Severe hepatic disease Porphyria cutanea tarda The Norwegian Guidelines of Gynecologic Oncology 2016; National Institute for Health and Care Excellence (NICE); Cancer in Norway 2015; Statistics Norway 2016; Setiawan et al., Hepatology 2016; Mykletun et al., Tidssk Nor Laegefor 2014

Contraindications to HRT after RRSO in women without breast cancer and 52 years Endometrial pathology < 0.02% annual risk at 35 54 years Venous thromboembolism Cardiovascular disease Severe hepatic disease Porphyria cutanea tarda The Norwegian Guidelines of Gynecologic Oncology 2016; National Institute for Health and Care Excellence (NICE); Cancer in Norway 2015; Statistics Norway 2016; Setiawan et al., Hepatology 2016; Mykletun et al., Tidssk Nor Laegefor 2014

Contraindications to HRT after RRSO in women without breast cancer and 52 years Endometrial pathology < 0.02% annual risk at 35 54 years Venous thromboembolism 0/116 HRT in our data set Cardiovascular disease 1/116 HRT in our data set Severe hepatic disease Porphyria cutanea tarda The Norwegian Guidelines of Gynecologic Oncology 2016; National Institute for Health and Care Excellence (NICE); Cancer in Norway 2015; Statistics Norway 2016; Setiawan et al., Hepatology 2016; Mykletun et al., Tidssk Nor Laegefor 2014

Contraindications to HRT after RRSO in women without breast cancer and 52 years Endometrial pathology < 0.02% annual risk at 35 54 years Venous thromboembolism 0/116 HRT in our data set Cardiovascular disease 1/116 HRT in our data set Severe hepatic disease 4% in the general population Porphyria cutanea tarda 0.01% in the general population The Norwegian Guidelines of Gynecologic Oncology 2016; National Institute for Health and Care Excellence (NICE); Cancer in Norway 2015; Statistics Norway 2016; Setiawan et al., Hepatology 2016; Mykletun et al., Tidssk Nor Laegefor 2014

Contraindications to HRT after RRSO in women without breast cancer and 52 years Endometrial pathology < 0.02% annual risk at 35 54 years Venous thromboembolism 0/116 HRT in our data set Low prevalence of other contraindications to Cardiovascular disease 1/116 HRT in our data set HRT use Severe hepatic disease 4% in the general population Porphyria cutanea tarda 0.01% in the general population The Norwegian Guidelines of Gynecologic Oncology 2016; National Institute for Health and Care Excellence (NICE); Cancer in Norway 2015; Statistics Norway 2016; Setiawan et al., Hepatology 2016; Mykletun et al., Tidssk Nor Laegefor 2014

HRT after RRSO guidelines from the Nordic countries Based on the British guidelines which recommend HRT until the age of 50 for high risk women After RRSO, 5 years with HRT is considered safe, further treatment should be individually evaluated Women after surgical menopause should use HRT until the age of natural menopause (not specified for BRCA mutation carriers) Guidelines from Finland not found No official guidelines in Iceland, but they recommend HRT until the age of 50 if no breast cancer

How many of the HRT eligible women use systemic HRT after RRSO? HRT eligible is defined as 52 years and without a history of breast cancer 71% Tucker et al., Maturitas 2015; Finch et al., Gynecol Oncol 2011; Madalinska et al., J Clin Oncol 2006

How many of the HRT eligible women use systemic HRT after RRSO? HRT eligible is defined as 52 years and without a history of breast cancer 71% 44% Tucker et al., Maturitas 2015; Finch et al., Gynecol Oncol 2011; Madalinska et al., J Clin Oncol 2006

How many of the HRT eligible women use systemic HRT after RRSO? HRT eligible is defined as 52 years and without a history of breast cancer 71% 44% 59% Tucker et al., Maturitas 2015; Finch et al., Gynecol Oncol 2011; Madalinska et al., J Clin Oncol 2006

Our study Primary aim: To determine the use of systemic HRT after RRSO compared with BSO controls from the general population. Cases: 324 women after RRSO. Controls: 950 women after BSO from the Norwegian Women and Cancer study (NOWAC). Method: Questionnaires.

Results RRSO n = 324 BSO controls n = 950 P Age (median, min-max), years 53.5 (33 79) 56 (48 62) 0.001 Age at menopause (median, min-max), years 48 (31 76) 47 (22 59) < 0.001 n (%) n (%) Education High (> 12 years) 133 (41.4) 330 (37.9) 0.27 Low ( 12 years) 188 (58.6) 541 (62.1) Married, cohabiting, or widow 276 (85.2) 790 (83.5) 0.48 History of breast cancer Yes 80 (24.7) 27 (2.8) < 0.001 No 244 (75.3) 919 (96.7)

Use of systemic HRT among women 52 years without breast cancer in history RRSO n = 116 BSO controls n = 237 HRT systemic n (%) n (%) Odds ratio (CI) Current 60 (51.7) 115 (48.7) 1.13 (0.72, 1.76) 0.60 Past 16 (13.8) 53 (22.4) 0.56 (0.302, 1.02) 0.059 Never 22 (19.0) 66 (27.8) 0.61 (0.35, 1.05) 0.072 Missing 18 ( 15.5) 3 (0.8) 14.3 (4.1, 50) < 0.001 P

Type of HRT regimens among women 52 years without breast cancer % 70 60 50 40 30 20 10 0 * RRSO BSO controls * P value < 0.05 *

Use of systemic HRT among women > 52 years RRSO n = 179 BSO controls n = 706 HRT systemic n (%) n (%) Odds ratio breast cancer (CI) P- value brea st cancer Current 30 (16.8) 271 (38.4) 0.44 (0.286, 0.68) < 0.001 Past 51 (28.5) 309 (43.8) 0.57 (0.389, 0.83) 0.004 Never 76 (42.5) 116 (16.4) 2.66 (1.79, 3.93) < 0.001 Missing 22 (12.3) 10 (1.4) 8.9 (3.94, 20.0) < 0.001

Conclusions from our study Only half of HRT eligible women actually used systemic HRT after RRSO Many women probably have unnecessary symptoms and risk of adverse effects Clinicians should be aware of these findings and prescribe hormones when indicated

Trends of HRT sale in Norway Norwegain Institute of Public Health Systemic treatment 2006 Local treatment

HRT after RRSO Finch et al., Women s Health 2012 Intact breasts and no history of breast cancer BRCA1 HRT may be offered until 52 years Limited data on safety of androgens History of breast cancer Systemic HRT contraindicated Bilateral mastectomy and no history of breast cancer Vaginal estrogen may be considered Consider SSRI for vasomotor symptoms HRT should be offered until 52 years BRCA2 HRT may be considered (limited data on safety) Limited data on safety of androgens Systemic HRT contraindicated Vaginal estrogen may be considered Consider SSRI for vasomotor symptoms HRT should be offered until 52 years Androgens may be considered Androgens may be considered

HRT regimens after RRSO: No uterus Unopposed estrogen Probably no increased risk of breast cancer Lower venous thromboembolic risk with transdermal vs peroral Concomitant hysterectomy at the time of RRSO to be able to give unopposed estrogen? www.hysterectomy.org Chlebowski et al., JAMA 2015; Modammed et al., J Clin Endocrinol Metab 2015

HRT regimens after RRSO: Intact uterus Combination treatment (estrogen + progestin) Estrogen Lower venous thromboembolic risk with transdermal vs peroral Progestins Cyclic may be associated with lower breast cancer risk compared with contiuous Cyclic and continuous provide the same endometrial protection Cyclic: 80-90% will experience monthly bleeding Levonorgestrel intrauterine device (IUD) no increased breast cancer risk Modammed et al., J Clin Endocrinol Metab 2015; Tjønneland et al., Cancer 2004; Bakken et al., int J Cancer 2011; Backman et al., Obstet and Gynecol 2005; Dinger et al., Contraception 2011

HRT regimens after RRSO: Intact uterus Combination treatment (estrogen + progestin) Estrogen Lower venous thromboembolic risk with transdermal vs peroral Progestins Cyclic may be associated with lower breast cancer risk compared with contiuous Cyclic and continuous provide the same endometrial protection Cyclic: 80-90% will experience monthly bleeding Levonorgestrel intrauterine device (IUD) no increased breast cancer risk A good choice seems to be estrogen patch and progestin IUD Modammed et al., J Clin Endocrinol Metab 2015; Tjønneland et al., Cancer 2004; Bakken et al., int J Cancer 2011; Backman et al., Obstet and Gynecol 2005; Dinger et al., Contraception 2011

HRT regimens after RRSO Tibolone vs other HRT Estrogenic, progestogenic, and androgen effects Less effective on vasomotor symptoms Fewer unscheduled bleedings Same long-term safety Better effect on sexual dysfunction than combined transdermal estradiol/progestin in naturally postmenopausal women Formoso et al., Cochrane Database Syst Rev 2016; Nijland et al., J Sex Med 2008;

Androgen substitution to women after RRSO? May be effective in treatment of sexual dysfunction Indicated if hypoactive sexual desire disorder (USA) Measure of T at baseline and after 3-6 weeks Reviewing T levels every 6 months to assess overuse Cessation after 6 months if no effect Short term use considered safe No safety evidence beyond 24 months of use No safety data for BRCA mutation carriers Davis et al., Menopause 2006; Flöter et al., Climacteric 2002; Wierman et al., Endocrinol Metab 2014

Conclusions Premenopausal RRSO may have several adverse effects that are reduced by HRT Recommendations concerning HRT use depend on history of breast cancer, type of BRCA mutation, and mastectomy status In practice, HRT is recommended after RRSO until the age of 50-52 if no history of breast cancer Estrogen patch and progestin IUD is maybe the best choice for women with intact uterus; Androgens can reduce sexual dysfunction

The collaborators Trond M Michelsen Astrid H Liavaag Tom Tanbo Ole-Erik Iversen Lars Mørkrid Anne Dørum Alv A Dahl Serena Tonstad Tonje Braaten Are H Pripp Contact: nora.johansen@sshf.no

Vaginal estrogen after breast cancer Does not seem to increase the risk of breast cancer recurrence Le Ray et al., Breast Cancer res Treat 2012 Serum levels of estrogen not increased above the normal range for menopausal women Waaseth et al., BMC Women s Health 2008 Nevertheless: Non-hormonal treatment should be considered first Oncolog should be consulted The woman should be thoroughly informed for the desicion making The American College of Obsteticians and Gynecologists. Commitee Opinion 2016. The use of Vaginal Estrogen in Women With a history of Estrogen-Dependent breast Cancer

Current recommendations Women without a history of breast cancer should use HRT from risk-reducing salpingo-oophorecomy until the age of 52 53 years The Norwegian Guidelines of Gynecologic Oncology 2016 National Institute for Health and Care Excellence, British recommendations 2013 Australasian Menopausal society 2013 The North American Menopause Society 2012

Uptake of preventive surgery in BRCA carriers 2677 BRCA carriers from 9 countries Median 3.9 years after genetic testing 57% RRSO 18% bilateral mastectomy 9% chemotherapy Norway USA France Canada Holland Preventive bilateral mastectomy Preventive bilateral salpingo-oophorectomy 4.5% 36.3% 25% 22.4% 32.5% 73.5% 71.1% 71% 57.3% 64.2% Metcalfe et al., Int J Cancer 2008