Early TUbectomy with delayed oophorectomy to improve quality of life as alternative for risk reducing salpingo-oophorectomy in BRCA1/2 gene mutation carriers

In BRCA 1/2 gene mutation carriers, a risk-reducing salpingo-oophorectomy
(RRSO) is recommended around the age of 40, based on first, a 10-40% life-time
risk of ovarian cancer in this population, second, disappointing results of
ovarian cancer surveillance for early detection and third, the high mortality
rate of ovarian cancer. Effects of RRSO are reduced ovarian (80-96%) cancer and
disputable reduction of breast cancer (50%?) on one hand and immediate onset of
menopause and non-cancer related morbidity on the other hand. Based on recent
studies showing that most high-grade serous ovarian cancers develop at the
distal end of the Fallopian tube, an alternative strategy for RRSO has been
developed for this study proposal: risk-reducing salpingectomy (RRS) with
delayed risk-reducing oophorectomy (RRO). However, the safety of this strategy
has not been proven yet. Before offering this alternative strategy to BRCA 1/2
gene germline mutation carriers, consequences of implementation need to be
studied.

To evaluate RRS after childbearing with delayed RRO as an alternative for RRSO
in BRCA1/2 gene germline mutation carriers. We hypothesize that delay of
menopause leads to an improvement of quality of life and sexual functioning,
and a decrease in cardiovascular risk factors without a significant increase in
ovarian cancer mortality.

A prospective non-randomized study.

Innovative treatment: RRS when childbearing is completed with a delayed RRO
(BRCA1 at age 40-45; BRCA2 at age 45-50)
Standard treatment: RRSO (BRCA1 at age 35-40; BRCA2 at age 40-45); BRCA 1/2
gene germline mutation carriers who opt for early RRS but still want RRO at the
age of the current standard treatment (BRCA1 35- 40, BRCA2 40-45), can choose
for the innovative treatment as well, provided that at least a 2-year interval
between RRS and RRO is expected at baseline. However, they do not contribute to
the calculated 510 inclusions.

Participants will be asked to fill in questionnaires on quality of life and
medical conditions at several time points (1 week before and 3 and 12 months
after surgery; subsequently biennial until 15 years after RR(S)O). Fasting
blood samples to measure cardiovascular risk factors are taken around the time
of surgery and after 5 years after each surgery. Therefore, one or two extra
site visits are required. The most important risk for participants is the risk
of developing ovarian cancer within the interval between RRS and RRO. We
estimate that risk about 1% when RRO is postponed for five years. Furthermore,
in the alternative treatment, the participant will undergo a laparoscopy twice.
Known complication rates for RRSO in a comparable population vary from 1.5-5%
for major and 3.9-10% for minor complications. Risks might be lower for RRS
alone.