BSO, HRT, and ERT Jubilee Brown, MD Professor & Associate Director, Gynecologic Oncology Levine Cancer Institute at the Carolinas HealthCare System Charlotte, North Carolina No relevant financial disclosures
Objectives To review the WHI data on MI, CVA, DVT, breast CA, and osteoporosis risk with ERT and HRT separately, in short and long term Describe actual risks of BSO on heart disease, CVA, osteoporosis stratified by age and use of ERT Review data surrounding estrogen after breast cancer Timeline 2002: Initial results released from WHI: suggested negative impact on breast cancer 2007: Updated results released - more balanced outcomes 2013: Parker study released: suggested ovaries should be retained
Impact of HRT-related decisions Among 500,000 women with vasomotor symptoms, patients who were untreated had 1.5 million more doctor visits = $340M = $27.7 M lost wages Patients with untreated vasomotor symptoms: 83% more doctor visits for any reason = $1346 / pt / year Women s Health Initiative (WHI) Study Review this trial with regard to effects on MI, CVA, osteoporosis, breast cancer, DVT, and all cause mortality Evaluate ESTROGEN effects (ERT) versus combined ESTROGEN-PROGESTERONE effects (HRT) - they are different Discuss short- and long-term effects Describe effect of age
-Grimes, Obstet Gynecol 2002 -Grimes, Obstet Gynecol 2002
-Grimes, Obstet Gynecol 2002 Effects on MI / Cardiovascular disease Estrogen + Progesterone (n=16,608) Outcome HR CI Adjusted CI CV Disease 1.29 1.02-1.63 0.85-1.97 Death from CV disease 1.18 0.70-1.97 0.47-2.98 Nonfatal MI 1.32 1.02-1.72 0.82-1.23 FU time 62 months -Grimes, Obstet Gynecol 2002
Update: Overall CV Events Compared ERT to HRT Trial HR CI Excess Risk per 10,000 person-yrs Combined Trials (ERT+HRT) 1.07 0.92-1.23 3.1 Estrogen only 0.95 0.78-1.16-2.9 Estrogen + Progesterone 1.23 0.99-1.53 7.8 -Rossauw, JAMA 2007 Update: Overall CV Events Compared ERT to HRT Trial HR CI Excess Risk per 10,000 person-yrs Combined Trials (ERT+HRT) 1.07 0.92-1.23 3.1 Estrogen only 0.95 0.78-1.16-2.9 Estrogen + Progesterone 1.23 0.99-1.53 7.8 -Rossauw, JAMA 2007
Age HR CI 50-59 0.86 0.44-1.65 60-69 1.20 0.70-2.04 70-79 5.08 2.08-12.40 Protective in women 50-59 Increased risk in women 70-79 -Rossauw, JAMA 2007 Bottom Line - Cardiovascular Disease Study criticism: unhealthy population may overestimate risk: 36% HTN, 49% smoked, 34% obese Improvement in Coronary Heart Disease in women 50-59 (women up to 10 years after menopause) Increased risk in women 70-79 (women further out from menopause Estrogen does not appear to be harmful - progesterone is the bad actor
-Grimes, Obstet Gynecol 2002 Effects on CVA Estrogen + Progesterone (n=16,608) Outcome HR CI Adjusted CI Stroke 1.41 1.07-1.85 0.86-2.31 Fatal 1.20 0.58-2.50 0.32-4.49 Nonfatal Stroke 1.50 1.08-2.08 0.83-2.70 FU time 62 months -Grimes, Obstet Gynecol 2002
Update: Stroke Compared ERT to HRT Trial HR CI Excess Risk per 10,000 person-yrs Combined Trials (ERT+HRT) 1.32 1.12-1.56 9.3 Estrogen only 1.33 1.05-1.68 10.9 Estrogen + Progesterone 1.31 1.03-1.68 7.8 -Rossauw, JAMA 2007 Bottom Line - Stroke Risk is increased across the board, independent of age, time since menopause, or presence of progesterone
Effects on Venous TED (DVT/PE) Estrogen + Progesterone (n=16,608) Outcome HR CI Adjusted CI Venous TED 2.11 1.58-2.82 1.26-3.55 DVT 2.07 1.49-2.87 1.14-3.74 PE 2.13 1.39-3.25 0.99-4.56 FU time 62 months -Grimes, Obstet Gynecol 2002 Bottom Line - Thromboembolic Disease Appears to be some risk, but the trial ended too early to be definitive for level of risk May be an early harm effect of HRT in first 2 years after use How I counsel patients: risk is 20-30/100,000 women, whereas risk of TED in pregnancy is 60/100,000 women!
-Grimes, Obstet Gynecol 2002 Effects on Breast Cancer Risk Estrogen + Progesterone (n=16,608) -Grimes, Obstet Gynecol 2002
July 2002: 26% increase in risk of breast cancer in treated women Actual meaning: <1 additional case of breast CA per 1000 women taking menopausal HRT above the baseline risk of 3-4 per 1000 per year - not statistically significant How I counsel patients: risk is 20-30/100,000 women, whereas risk of TED in pregnancy is 60/100,000 women! That statement yielded a 27-80% decrease in the use of ERT / HRT
Women using HRT had fewer metastases and better prognosis tumors ERT did NOT show a significant increase in breast CA incidence - only HRT...even in the 2002 report The ESTROGEN-ONLY arm data released in 2004 showed a technically not significant reduction in breast CA after 7 years of ERT No increase in breast CA in the women with no prior HRT use (this was not announced)
Effects on Fractures Estrogen + Progesterone (n=16,608) Outcome HR CI Hip 0.66 0.45-0.98 Vertebral 0.66 0.44-0.98 Other 0.77 0.69-0.86 Total 0.76 0.69-0.85 FU time 62 months -Grimes, Obstet Gynecol 2002 Bottom Line - Osteoporosis ERT-only trial: 35-39% reductions in fracture with improvement in bone mineral density Fractures decreased for ERT and HRT
How do we put this together? How do we put this together?
Global Index (by age and treatment) Risk profile improved with estrogen only Protective ages 50-59, neutral age 60-69, increased risk ages 70-79 How do we put this together?
Conclusions - 2007 There were no significant increases in risk due to hormone therapy for any outcome at ages 50-59 years There was a reduction in total mortality in the age group of 50-59 years...10 fewer deaths per 10 000 person years in the treated group. This compared with 16 additional deaths at ages 70-79 years. -Rossauw, JAMA 2007 Bottom Line Cardiovascular disease and MI: may be improved in women close to menopause, especially on ERT DVT/PE: probably increased risk Breast cancer: NO increased risk with ERT alone Osteoporosis / Fracture risk: improved with ERT or HRT Global index improved and lower mortality, especially in women age 50-59 on estrogen-alone therapy -Rossauw, JAMA 2007
Take Home Message ERT and HRT are relatively safe for women under age 70 ERT is safer than HRT - very safe profile But use ERT with caution in women 70 or over Informed consent is important -Rossauw, JAMA 2007 BSO What are the current data surrounding removal of ovaries and Fallopian tubes? When we counsel our patients, what are the real risks? -Rossauw, JAMA 2007
BSO Hysterectomy is the 2nd most common surgery for women in the US It is common practice to remove ovaries at that time in women in mid-40 s and up - reduces ovarian cancer risk, prevents future surgery, assumes ERT given Patients at risk for hereditary cancers should have ovaries removed -Rossauw, JAMA 2007 Causes of Hereditary Susceptibility to Ovarian Cancer Sporadic BRCA1 (~70-75%) Hereditary (~10%) Other single genes (<5%) HNPCC (~2%) BRCA2 (~20%)
Hereditary Breast Ovarian Syndrome 90% 68% 46% Risk General Population HBOC 45% 23% 0% Ovarian Breast Schorge et al Gynecol Oncol 2010 Lynch Syndrome (HNPCC) 80% 60% 40% General Population HNPCC women HNPCC men 20% 12% Risk 0% Ovarian Uterine Colon Schorge et al Gynecol Oncol 2010
Occult cancers in risk reducing salpingooophorectomy samples from BRCA mutation carriers 1-Ovulation causes genotoxic stress 2-DNA damage occurs in FT 3 - TIN occurs when there is a DNA repair deficiency (BRCA+) Levanon K, JCO 26:5284, 2008
BRCA1/2 Rate of unsuspected neoplasia at RRSO is 4.4-7.9% Hazard ratio for breast or BRCA-related gyn cancer = 0.25 (95% CI, 0.08-0.74) - a 75% reduction in risk!!! Connor Gynecol Oncol 2014; Finch JAMA 2006; Powell Int J Gynecol Cancer 2011; Kauff NEJM 2002 BRCA1/2 Decreases breast CA up to 50% Decreases ovarian CA risk by 85-95% Improves overall mortality Connor Gynecol Oncol 2014; Finch JAMA 2006; Powell Int J Gynecol Cancer 2011; Kauff NEJM 2002
BRCA1/2 What about ERT or HRT after RRSO? Important to discuss menopausal side effects before surgery and have a plan in place RRSO with short term HRT was still associated with a profound reduction in breast cancer risk in carriers of BRCA1 and BRCA2 mutations HR = 0.37 (95% CI, 0.14 to 0.96) -Rebbeck TR, et al. J Clin Oncol 2005 What about in benign wildtype patients who have oophorectomy? -Rossauw, JAMA 2007
122, 700 RN s enrolled in NHS in 1976 29,380 women had a hysterectomy for benign disease 16, 345 women (55.6%) had BSO 13, 035 (44.4%) kept ovaries - ovarian conservation To consider what diseases and conditions women died from in the years after their surgery over 28 years of follow up
Ovarian cancer risk reduction: largest benefit to high risk women 44 of 13,305 women (0.9%) who kept ovaries got ovarian cancer (4 vs 44 women) BSO reduced but did not eliminate risk of ovarian cancer Breast CA risk reduction (HR 0.6 if <45 y) - 25% less breast CA
Long-term health risk - heart disease, stroke, and lung cancer are more common in this group in the NHS study All cause mortality, CV disease, stroke, cognitive function, neurologic disease, depression, anxiety, sexual dysfunction, osteoporosis CHD: HR 1.26 for women <45 yo with both ovaries removed Not a healthy population: 1/3 smokers Risk of CV disease and stroke in this population does not take into account the use of ERT post-hysterectomy MUCH higher risk among never-users of ERT: CV disease HR 1.98 and stroke HR 2.19 in never-users of ERT <45 yo ESTROGEN USE MATTERS! ERT after BSO reduces risk!
Bottom Line on Risk of BSO For women under 50 years old at time of hysterectomy, BSO was associated with increased mortality after oophorectomy - Only in never users of ERT - NOT in past or current users of ERT - Study confounded by an unhealthy population with CV risk factors - 1/3 were smokers and there was a high risk of lung cancer in this populationrisk of CV disease and stroke in this population does not take into account the use of ERT post-hysterectomy ESTROGEN USE MATTERS! ERT after BSO reduces risk! Are there other confirmatory studies? NHS: younger women who did not take ERT were at the highest risk - OR 1.4 (95% CI 1.01-1.96) - Increase in mortality from lung CA - Increased risk for CAD Mayo Cohort Study confirmed this - HR 1.67 (95% CI 1.16-2.4) - Risk higher if <45 yo and no ERT WHS: no difference in any age group
My interpretation: Faulty take-home message. Should be that ERT is important after BSO. 2013 Update on NHS 30,117 patients underwent hysterectomy +/- BSO BSO associated with a lower risk of death from ovarian or breast cancer BSO NOT associated with lower overall or cause-specific mortality Women <50 yo at time of BSO who were never-users of ERT had a higher mortality (HR 1.41) - also had an increase in CHD and lung cancer These risks were NOT seen in women who were past or current users of ERT (HR 1.05)
2013 Update on NHS My take-home: NO increased risk to BSO even in women <50 years old as long as ERT is prescribed post-operatively How to proceed? Evaluate indication for oophorectomy Evaluate menopausal status (post-menopausal patients may be risk-neutral) Counsel appropriately Consider that BSO followed by ERT does not appear to confer risk and does protect against breast and ovarian cancer
What about in patients with a history of breast cancer? Long term results of breast cancer outcomes are favorable Median FU 11.8 years ERT use (median = 5.9 y) was associated with a lower incidence of invasive breast CA: HR 0.77, 95% CI 0.62-0.95 Consider that BSO followed by ERT does not appear to confer risk and does protect against breast and ovarian cancer Lower mortality in ERT arm: HR 0.37, 95% CI 0.13-0.91
Breast Cancer Incidence Lower Incidence Anderson, Lancet Oncol 2012 Breast Cancer Mortality Lower Incidence Anderson, Lancet Oncol 2012
All Cause Mortality after Breast Cancer Lower Mortality Anderson, Lancet Oncol 2012 26 of 219 HRT patients and 7 of 215 non-hrt patients had a new breast cancer event so the trial was stopped early
Favorable results: 288 patients with breast cancer received HRT Median FU 10 years No difference in new breast cancer events, mortality, or new primary malignancies More patients had contralateral breast CA in the HRT group (Eur J Cancer, 2013) Since estrogen thought to increase breast cancer recurrence, suggest that ERT is contraindicated in women with breast CA EXCEPT some symptomatic women with BRCA mutations who have ER- breast cancers, preferably post mastectomy
My Plan Evaluate Counsel risk pre-operatively Consider pre-operative genetic testing/ counseling ERT for post-bso patients at least until age 59 Thank you!