The role of Hysterectomy on BRCA mutation carriers
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Hysterectomy may reduce the risk of uterine cancer for BRCA mutation carriers taking tamoxifen, by allowing estrogen-only hormone therapy and eliminating the uterine cancer risk from tamoxifen. However, the risks of hysterectomy, such as surgical complications, need to be weighed against the uncertain increased uterine cancer risk from tamoxifen. Studies have found both increased and similar uterine cancer rates in BRCA carriers taking tamoxifen compared to the general population. The decision to perform hysterectomy should be individualized based on risk factors and treatment options.
The role of Hysterectomy on BRCA mutation carriers
- 1. THE ROLE OF HYSTERECTOMY ON BRCA 1/2 MUTATION CARRIERS ON PREVENTING UTERINE CANCER VALENTINA METSAVAHT CARÁ OBSERVER – THE WILLIAM J. HARRINGTON PROGRAM GYO MAY/2015
- 3. WHY TALK ABOUT BRCA 1 and BRCA 2 MUTATIONS? ◼BRCA1 and BRCA2 are tumor suppressing genes – germline mutations are the main genes responsible for Hereditary Breast and Ovarian Cancer syndrome (HBOC) - 80% of the cases. ◼Autosomal dominant pattern of inheritance, prevalence of 1:400 to 1:800, increased in Ashkenazi Jewish descent (1:40!!), and Icelanders (1:166).
- 4. ◼BRCA 1 → Discovered in 1990, cloned in 1994, over 1600 mutations identified so far. Located on the long arm of chromosome 17. More commonly associated with ER/PR/HER2neu negative tumors. ◼BRCA 2 → Discovered in 1994, over 1800 mutations identified so far. Located on the long arm of chromosome 13. BRCA2 Cycle Path, between Addenbrooke’s Hospital and Great Shelford, Cambridge - UK. 10,000 stripes of four different colors, each representing a nucleotide base and collectively spelling out the entirety of the gene BRCA2.
- 5. Hereditary Breast and Ovarian Cancer syndrome (HBOC) ◼5% of total breast cancers and 10-15% of total ovarian cancers. ◼Women with BRCA mutations have a lifetime risk of breast cancer of 50 to 85% and a 15 to 40% chance of developing ovarian cancer (early onset). ◼BRCA1→ prostate and male breast cancer (1%-2%) ◼BRCA2→ prostate cancer, male breast cancer (10%-20%), and 6% risk of pancreatic cancer.
- 6. WHAT IS THE IMPACT AND WHAT ARE THE RISK FACTORS OF ENDOMETRIAL CANCER? ◼ENDOMETRIAL CANCER → The most common malignancy of the female genital tract in Western countries (6% of all newly- diagnosed cancers in women). ◼RISK FACTORS: ◼hormone replacement therapy (HRT) ◼exposure to tamoxifen ◼excess body weight ◼lack of physical activity ◼early menarche ◼infertility and anovulation ◼low parity and late menopause ◼And family history of endometrial cancer. → BRCA mutations as risk factor? → BRCA mutation carriers vs. General population: exposure to progestin vs. estrogen
- 7. ◼HORMONE REPLACEMENT THERAPY (HRT) → used to alleviate symptoms of surgical or physiological menopause. ◼In general population, the risk of endometrial cancer is related to both the estrogen dose and the duration of hormone replacement and can be reduced by the concomitant administration of a progestin. ◼However, studies show a borderline significant increased risk of endometrial cancer among BRCA carriers who used a progesterone-only formulation and a decreased risk among carriers who used an estrogen-only formulation.
- 8. ◼TAMOXIFEN → Selective estrogen-receptor modulator. ◼ Risk of breast cancer in women at high risk ◼ Risk of endometrial cancer ◼Role in BRCA mutations ? ◼AROMATASE INHIBITORS (AI) → Inhibit peripheral conversion of androgens to estrogens. ◼ Risk of breast cancer post-menopausal (surgical or physiological) women ◼Not effective in women with intact ovarian function. ◼ endometrial cancer risk??
- 9. WHAT IS THE ROLE OF RISK-REDUCING SURGERY ON BRCA MUTATIONS? ◼MASTECTOMY → breast cancer risk by 90% in BRCA mutation carriers. ◼BILATERAL SALPINGO-OOPHORECTOMY (BSO) → risk of ovarian cancer by 85–90%. ◼When performed pre-menopausally, there is an approximate 50% reduction in breast cancer risk. ◼NCCN recommends BSO between ages 35 and 40 years and upon completion of childbearing, regardless of the type of BRCA mutation.
- 10. ◼HYSTERECTOMY → BRCA mutation carriers might benefit from performing a hysterectomy at the time of BSO if therapy with tamoxifen is contemplated, and it would allow estrogen-only HT (alleviating need for progestogen) use. ◼For women not on tamoxifen, the balance of risks and benefits is less clear. ◼In women from the general population, hysterectomy plus BSO may increase the risk of overall mortality: ◼Surgical mortality in USA is 0.08% for open hysterectomy and 0.07% for laparoscopic hysterectomy. ◼Intercurrent disease (cardiovascular, osteoporosis with fractures).
- 11. ◼The incidence of ureteral injury during laparoscopic gynecologic surgery is low, ranging from 0.025%–2%; →→→ the risk is two- to four-fold higher in laparoscopically-assisted hysterectomy than in laparoscopic BSO. ◼Abdominal hysterectomy plus BSO increases the risk of: ◼ Bladder injury by 0.3% ◼ Pelvic abscess, 0.3% ◼ Cuff cellulitis, 3% ◼ Transfusion, 4% ◼ Urinary fistula rate, 0.4% ◼ Wound infection, 4% ◼ Re-hospitalization, 3%; ◼ Reoperation, 1.5%. ◼ Although the surgical risks of minimally-invasive hysterectomies tend to be lower than the risks of laparotomy, the rate of vaginal cuff dehiscence after laparoscopic and robotic hysterectomy ranges between 1% and 5%, respectively. WHAT ABOUT THE RISKS?
- 13. ◼INDIVIDUALIZED DECISION ◼EVIDENCE-BASED ◼It is not certain that BRCA mutations increase risk of endometrial cancer, whereas the use of tamoxifen is proved to increase this risk. Therefore, women who take tamoxifen might benefit from a hysterectomy in addition to oophorectomy to prevent endometrial cancer. ◼The use of aromatase inhibitors might be a "non- endometrial cancer increasing risk” option of chemoprevention of breast cancer in post-menopausal women.
- 14. Intervention Advantages Disadvantages Bilateral Mastectomy →Breast cancer risk reduction by 90% →Body-image issues →Surgical risks: seromas, wound infection, skin flap necrosis, pain, lymphedema, shoulder dysfunction BSO → Ovarian cancer risk reduction by 72% → Breast cancer risk reduction by 50% if completed before onset of menopause → Decreases overall mortality by 60%, breast cancer mortality by 56% and ovarian cancer mortality by 79% → Laparoscopic procedure → Increases risk of symptoms of premature menopause: vasomotor symptoms, sexual dysfunction, cardiovascular disease, stroke, cognitive decline, depression, anxiety, osteoporosis, mortality → Surgical risks: urinary tract injury, wound infection, pelvic abscess BSO + Hysterectomy → As for benefits of BSO (above) → Allows for estrogen-only HT (alleviating need for progestogen) use → Eliminates risk of uterine cancer if tamoxifen is used → Surgical risks: similar to RRSO but greater risk plus vaginal cuff dehiscence, transfusion, rehospitalization, reoperation
- 15. References ◼ Lu, KH. Kauff, ND. Does a BRCA mutation plus tamoxifen equal hysterectomy? Gynecologic Oncology 104, 3–4 (2007) ◼ M.E. Beiner et al. The risk of endometrial cancer in women with BRCA1 and BRCA2 mutations. A prospective study. Gynecologic Oncology 104, 7–10 (2007) ◼ Obermair, A et al. The impact of risk-reducing hysterectomy and bilateral salpingo- oophorectomy on survival in patients with a history of breast cancer—A population- based data linkage study. nt. J. Cancer: 134, 2211–2222 (2014). ◼ Stan, D. et al. Challenging and Complex Decisions in the Management of the BRCA Mutation Carrier. JOURNAL OF WOMEN’S HEALTH Volume 22, Number 10, 825-834 (2013) ◼ Y. Segev et al. The incidence of endometrial cancer in women with BRCA1 and BRCA2 mutations: An international prospective cohort study. Gynecologic Oncology 130, 127–131 (2013) ◼ Y. Segev et al. Risk factors for endometrial cancer among women with a BRCA1 or BRCA2 mutation: a case control study. Familial Cancer. Published online: 03 April 2015. ◼ Chlebowski, T. et al. Aromatase Inhibitors, Tamoxifen, and Endometrial Cancer in Breast Cancer Survivors. Cancer (2015).
- 16. 2013. Y SEGEV ET AL. The incidence of endometrial cancer in women with BRCA1 and BRCA2 mutations: An international prospective cohort study. ◼n=4456 women with BRCA1 or BRCA2 mutation ◼Followed for incident cases of endometrial cancer. ◼Mean follow up= 5.7 years ◼Results: 17 endometrial cancers (13 in BRCA1 and 4 in BRCA2), versus 9.06 expected. ◼Incidence rate: 67.1 per 100,000 per year
- 17. 2013. Y SEGEV ET AL. (cont.) ◼SIR (standardized incidence ratio) for BRCA1 carriers was 1.91 (95%CI: 1.06-3.19, p=0.03) and for BRCA 2 carriers was 1.75 (95% CI: 0.55-4.23, p=0.2) ◼Among patients treated with tamoxifen, 8 endometrial cancers were observed, versus 1.82 expected. ◼SIR for women who used tamoxifen = 4.14. SIR for those who didn't use it = 1.67. ◼Ten-year cumulative risk of endometrial cancer in women treated with tamoxifen was 2.0%.
- 18. 2013. STAN D. ET AL Challenging and Complex Decisions in the Management of the BRCA Mutation Carrier. ◼Review of literature ◼One prospective study suggested that tamoxifen use accounted for the increased incidence of uterine cancer in BRCA 1 and BRCA2 mutation carriers ◼GOG 199 found no increase in uterine cancer among BRCA mutation carriers.
- 19. 2014. OBERMAIR ET AL. The impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy on survival in patients with a history of breast cancer—A population-based data linkage study. ◼n= 21.067 women diagnosed with primary breast cancer ◼Followed to assess the impact of risk-reducing surgery ◼Dit not provide details of BRCA status ◼In premenopausal women diagnosed with breast cancer, BSO and Hysterectomy increased breast cancer-specific survival from 83% to 93% after 10 years.
- 20. 2015. Y SEGEV ET AL. Risk factors for endometrial cancer among women with a BRCA1 or BRCA2 mutation: a case control study. ◼Expanded cohort of women with BRCA mutation, matched controls o Cases= 83 women with endometrial cancer o Controls=1027. ◼Multivariate analysis ◼Odds ratio for endometrial cancer associated with estrogen- only HRT was 0.23 (95% CI: 0.03-1.78 p=0.16). Odds ratio for progesterone=only HRT was 6.91 (95% CI: 0.99-98.1, p=0.05) ◼BRCA 1 mutation have higher than expected serum progesterone levels than non-carriers. Luteal phase levels of progesterone were 121% higher. ◼Odds ratio for endometrial cancer associated with tamoxifen