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.

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?

12. SO, WHAT’S THE
CONCLUSION?

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