THE ROLE OF HYSTERECTOMY ON BRCA 1/2 MUTATION CARRIERS ON PREVENTING UTERINE CANCER

VALENTINA METSAVAHT CARÁOBSERVER – THE WILLIAM J. HARRINGTON PROGRAMGYO MAY/2015

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).

◼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.

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.

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

◼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.

◼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??

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.

◼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).

◼ 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?

SO, WHAT’S THE CONCLUSION?

◼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.

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 

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).

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

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%.

2013. STAN D. ET ALChallenging 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.

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.

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

controlso Cases= 83 women with endometrial cancero 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 use was 3.50 (95% CI 1.51-8.10, P=0.003

◼Attributable risk for endometrial cancer was estimated at 2% with a 5 year course of tamoxifen use.