Specialist oncological surgery for removal of the ovaries and fallopian tubes in BRCA1 and BRCA2 pathogenic variant carriers may reduce primary peritoneal cancer risk to very low levels

Abstract

Risk‐reducing bilateral salpingo‐oophorectomy (RRBSO) is highly effective for the prevention of high‐grade serous ovarian cancer (HGSOC) in BRCA1/2 pathogenic variant carriers (PVCs), but does not completely eliminate future risk of primary peritoneal cancer (PPC). The requirement to completely remove fallopian tubes at RRBSO and carefully exclude occult cancer/serous tubal intraepithelial carcinoma (STIC) lesions may not have been appreciated historically. We calculated rates of HGSOC and PPC in confirmed BRCA1/2 PVCs registered on the regional database in those who did (cases) and did not (controls) undergo RRBSO after genetic testing. Expected annual rates of ovarian/peritoneal cancer were 1% for BRCA1 ≥ 35 years and 0.5% for BRCA2 ≥ 45 years. Follow‐up before 35/45 years was “risk free” and lead time excluded RRBSO <35 years and <45 years for BRCA1 and BRCA2, respectively. Women were followed from personal mutation report (controls) or RRBSO (cases) to death, ovarian/peritoneal cancer or last follow‐up, whichever was sooner. In total, 891 cases (BRCA1 = 468, BRCA2 = 423) and 1302 controls had follow‐up ≥35 years (BRCA1 = 736) and ≥45 years (BRCA2 = 566), respectively, over a total of 7261.1 risk eligible years (mean = 8.15 years). Twenty‐one occult ovarian cancers were found at RRBSO (2.4%), 16 at stage 1. Post RRBSO, 56.97 ovarian/peritoneal cancers were expected but only 3 were observed (HR = 0.053; 95% CI = 0.013‐0.14), with combined Kaplan‐Meier analysis HR = 0.029 (95% CI = 0.009‐0.100, P < .001). Risk reduction was greater in specialist (HR = 0.03; 95% CI = 0.001‐0.13) compared to non‐specialist centres (HR = 0.11; 95% CI = 0.02‐0.37) (P = .07). In controls, 23.35 ovarian/peritoneal cancers were expected with 32 observed (HR = 1.37; 95% CI = 0.95‐1.91). RRBSO <35/<45 years reduces the risk of ovarian/peritoneal cancer by 95% in BRCA1/2 PVCs and may be greater in specialist centres.

Full text

CANCER GENETICS AND EPIGENETICS
Specialist oncological surgery for removal of the ovaries and
fallopian tubes in BRCA1 and BRCA2 pathogenic variant
carriers may reduce primary peritoneal cancer risk to very
low levels
Emma J. Crosbie
1,2
| Nicola Flaum
3,4
| Elaine F. Harkness
5,6
|
Richard D. Clayton
2
| Cathrine Holland
2
| Pierre Martin-Hirsch
1,7
| Nick Wood
7
|
Patrick Keating
7
| Emma R. Woodward
3,4
| Fiona Lalloo
4
| Paul Donnai
2
|
Richard J. Edmondson
1,2
| D. Gareth Evans
3,4,6,8,9
1
Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science
Centre, Manchester, UK
2
Department of Obstetrics and Gynaecology, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK
3
Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester
Academic Health Science Centre, Manchester, UK
4
Genetic Medicine, Manchester Centre for Genomic Medicine and NW Laboratory Genetics Hub, Manchester University Hospitals NHS Foundation Trust,
Manchester, UK
5
Division of Informatics, Imaging and Data Sciences, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
6
Prevention Breast Cancer Centre and Nightingale Breast Screening Centre, University Hospital of South Manchester, Manchester, UK
7
Department of Obstetrics and Gynaecology, Royal Preston Hospital, Lancashire Teaching Hospitals NHS Trust, Preston, UK
8
The Christie NHS Foundation Trust, Manchester, UK
9
Manchester Breast Centre, Manchester Cancer Research Centre, University of Manchester, Manchester, UK
Correspondence
D. Gareth Evans, Manchester Centre for
Genomic Medicine, St. Mary's Hospital, Oxford
Road, Manchester M13 9WL, United Kingdom.
Email: gareth.evans@mft.nhs.uk
Funding information
Cancer Research UK, Grant/Award Numbers:
C147/A18083, C147/A25254; National
Institute for Health Research, Grant/Award
Number: IS-BRC-1215-20007
Abstract
Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is highly effective for the
prevention of high-grade serous ovarian cancer (HGSOC) in BRCA1/2 pathogenic var-
iant carriers (PVCs), but does not completely eliminate future risk of primary perito-
neal cancer (PPC). The requirement to completely remove fallopian tubes at RRBSO
and carefully exclude occult cancer/serous tubal intraepithelial carcinoma (STIC)
lesions may not have been appreciated historically. We calculated rates of HGSOC
and PPC in confirmed BRCA1/2 PVCs registered on the regional database in those
who did (cases) and did not (controls) undergo RRBSO after genetic testing. Expected
annual rates of ovarian/peritoneal cancer were 1% for BRCA1 ≥35 years and 0.5%
for BRCA2 ≥45 years. Follow-up before 35/45 years was “risk free”and lead time
excluded RRBSO <35 years and <45 years for BRCA1 and BRCA2, respectively.
Abbreviations: HGSOC, high-grade serous ovarian cancer; HR, hazard ratio; O:E, observed to expected; PARP, poly-ADP ribose polymerase; PPC, primary peritoneal cancer; PVC, pathogenic
variant carrier; RRBSO, risk-reducing bilateral salpingo-oophorectomy; SEE-FIM, sectioning and extensively examining the fimbriated end; STIC, serous tubal in-situ carcinoma.
Received: 23 July 2020 Revised: 27 September 2020 Accepted: 16 October 2020
DOI: 10.1002/ijc.33378
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
©2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.
Int. J. Cancer. 2021;148:1155–1163. wileyonlinelibrary.com/journal/ijc 1155

Women were followed from personal mutation report (controls) or RRBSO (cases) to
death, ovarian/peritoneal cancer or last follow-up, whichever was sooner. In total,
891 cases (BRCA1 = 468, BRCA2 = 423) and 1302 controls had follow-up ≥35 years
(BRCA1 = 736) and ≥45 years (BRCA2 = 566), respectively, over a total of 7261.1 risk
eligible years (mean = 8.15 years). Twenty-one occult ovarian cancers were found at
RRBSO (2.4%), 16 at stage 1. Post RRBSO, 56.97 ovarian/peritoneal cancers were
expected but only 3 were observed (HR = 0.053; 95% CI = 0.013-0.14), with com-
bined Kaplan-Meier analysis HR = 0.029 (95% CI = 0.009-0.100, P< .001). Risk
reduction was greater in specialist (HR = 0.03; 95% CI = 0.001-0.13) compared to
non-specialist centres (HR = 0.11; 95% CI = 0.02-0.37) (P= .07). In controls, 23.35
ovarian/peritoneal cancers were expected with 32 observed (HR = 1.37; 95%
CI = 0.95-1.91). RRBSO <35/<45 years reduces the risk of ovarian/peritoneal cancer
by 95% in BRCA1/2 PVCs and may be greater in specialist centres.
1|INTRODUCTION
High-grade serous ovarian cancer (HGSOC) is a strongly heritable
cancer, with a 3-fold increase in risk of developing the disease in
women with first-degree relatives with ovarian cancer.
1
Carriers of
germline pathogenic variants (PVs) in BRCA1 or BRCA2 have a high
lifetime risk of ovarian cancer, in particular high-grade serous pathol-
ogy.
2
Women with PVs in BRCA1 or BRCA2 have a cumulative lifetime
risk of ovarian cancer of 44% to 61% and 17% to 24%, respectively.
3-5
As early detection of ovarian cancer using serum CA125 and
transvaginal ultrasound scans has not been effective at reducing suffi-
cient cancers to early stage (1-2),
6,7
and cancers detected on such
screening are still associated with high mortality,
8
carriers of PVs in
these genes are strongly advised to undergo risk-reducing bilateral
salpingo-oophorectomy (RRBSO).
9
This surgery is usually encouraged
at or just before the main ovarian cancer risk period starts at 35 to
40 years for BRCA1 and 40 to 45 years for BRCA2.
10
Female carriers
of PVs in BRCA1/2 undertaking RRBSO have increased life expec-
tancy mainly due to reduction in ovarian cancer risk, although there
may be some reduction in breast cancer risk and reduced mortality
from previous breast cancer.
11-13
Women undergoing RRBSO are warned of a residual risk of pri-
mary peritoneal cancer (PPC), which was first described in 1982.
14
A
meta-analysis of studies assessing this risk suggested only a 79%
reduction in risk of an “ovarian”type cancer after RRBSO in BRCA1/2
PV carriers
15
(hazard ratio = 0.21; 95% CI = 0.12-0.39). Subsequent
review suggested that this residual risk may be mitigated by earlier
surgery and was predominantly seen in BRCA1 PV carriers.
16
The ori-
gin of PPC has been hypothesised to be due to one of three sources.
Firstly, “ovarian rest cells”displaced during the embryological journey
in the abdominal cavity may be a primary origin. Secondly, cells from
the fimbria/ovaries could be displaced during adulthood into the peri-
toneum or thirdly through dissemination at the time of RRBSO.
The latter two possibilities have become more prominent since the
description of serous tubal in-situ carcinoma (STIC) lesions in the
fimbrial end of the fallopian tube as the probable precursor lesion for
most high-grade serous ovarian/tubal cancers.
17
Indeed, the presence
of STIC lesions was predictive of future PPC in one single institution
study with 2 of 7 (28.6%) developing subsequent PPC compared to
only 1 of 287 (0.3%) without STIC.
18
The theory regarding potential
prevention of ovarian/tubal cancers by removal of the fallopian tubes
has resulted in a number of pilot studies to assess the potential bene-
fits of early tubal surgery and delayed oophorectomy to mitigate the
effects of early surgical menopause on subsequent health and quality
of life.
19,20
We have previously published an early series of RRBSO where
we noted that there were no cases of PPC following 300 surgeries
that included 160 BRCA1/2 PV carriers.
21
The recent development of
a second PPC in a BRCA2 PV carrier operated on outside a
gynaecological oncology centre prompted us to revisit the PPC risk in
891 BRCA1/2 PV carriers who have tested positive in our region and
have undergone RRBSO.
What's new?
Women who carry genetic variants in BRCA1/2 that are
linked to high-grade serous ovarian cancer are advised to
undergo risk-reducing prophylactic bilateral salpingo-
oophorectomy (RRBSO). RRBSO, however, is associated
with a significant residual risk of primary peritoneal cancer
(PPC). Here, the rate of PPC following prophylactic surgery
for high-grade serous ovarian cancer was investigated
among 2,193 BRCA1/2 mutation carriers who had under-
gone RRBSO. Estimates indicate that prophylactic surgery
reduced the overall risk of PPC by 95 percent, a far greater
reduction than previously described. Residual risk was low-
est when RRBSO was carried out at specialist centers com-
pared to non-specialist centers.
1156 CROSBIE ET AL.

2|PATIENTS AND METHODS
Female carriers of PVs in BRCA1 or BRCA2 were identified from our
regional register covering a population of 5 million in Northwest
England as previously described.
10,11
A total of 3653 female PV car-
riers were identified from 1753 families. Women were eligible if they
had undergone RRBSO without any evidence on CA125 and ultra-
sound of the prior presence of ovarian cancer. The controls were
women who had not undergone RRBSO including any time post
genetic testing before RRBSO (to avoid bias of not including this
follow-up). Cases were followed from date of RRBSO to date of
death, PPC or date of last follow-up, whichever was earlier. Controls
were followed from date of personal mutation report to date of death,
ovarian/peritoneal cancer or date of last follow-up, whichever was
earlier. Cases were censored at date of surgery if ovarian cancer was
identified as an occult lesion. As we were not aware of any PPC cases
postsurgery in any of our BRCA1/2 families and all RRBSO were
recorded in the specialty centres for high-risk women since 1980,
21,22
we included follow-up from surgery in those identified as PV carriers
after RRBSO.
2.1 |Ovarian/tubal/peritoneal primary risk
We chose a conservative estimate of ovarian cancer risk based on the
recent prospective series showing a 44% and 17% risk for BRCA1 and
BRCA2, respectively, to age 80 years.
4
This is lower than our previous
in-house estimates.
10,21
Risk for BRCA1 was considered at 1% annual
risk from age 35 years (45% risk to age 80 years) and 0.5% risk for
BRCA2 from age 45 years (17.5% risk to age 80 years). Follow-up
before 35 years was considered to be “risk free”and calculation of
“lead time”excluded RRBSO before the risk period for both genes and
<45 years for BRCA2. We also performed an analysis using 5-year
cumulative risks from a typical pedigree in BOADICEA v.3 (https://
pluto.srl.cam.ac.uk/cgi-bin/bd3/v3/bd.cgi), but this substantially
underestimated risk in our control population BRCA1 (expected 14.48;
observed 22 O:E = 1.49; P= .09) BRCA2 (expected 4.47; observed
10 O:E = 2.24; P= .033). In fact 5-year risks for ovarian cancer did not
change with different family histories (supplementary Table 1). The
model particularly underestimated risk in BRCA1 >50 years (expected
6.98; observed 15 O:E = 2.15; P= .011) and in BRCA2 > 60 years
(expected 0.89; observed 6 O:E = 6.74; P< .001). We therefore chose
to continue with our life table approach.
2.2 |Types of surgery and centre designation
Operations undertaken at two designated gynaecological cancer cen-
tres at St Mary's Hospital Manchester and Royal Preston Hospital
were considered specialty surgeries. RRBSO carried out in other units
in the region was considered nonspecialty. From 1980 to 2008, the
predominant RRBSO procedure was a total abdominal hysterectomy
and RRBSO.
21,22
This involved “bagging”of the ovaries and fallopian
tubes at surgery with peritoneal lavage after surgical removal.
21
Since
2009, the predominant procedure has been laparoscopic RRBSO
without hysterectomy. This involves complete removal of all ovarian
tissue and the full length of both fallopian tubes using specimen
retrieval bags. Since 2011, careful pathological examination of the
fallopian tubes has included an assessment for STIC lesions by special-
ist gynaecological pathologists in specialty centres using the SEE-FIM
protocol. The surgical procedures in nonspecialty hospitals did not fol-
low standardised protocols (eg, “bagging”of tubes and ovaries) or sub-
mit surgical specimens for specialist gynaecological pathology review.
2.3 |Statistics
Number and percent are reported for categorical variables with differ-
ences assessed by the Chi square or Fisher exact test where appropri-
ate. For continuous variables, such as age at surgery, we report the
range, mean and median. Lead time was estimated as the proportion
of occult cancers of those censored at RRBSO multiplied by the esti-
mated annual risk for ovarian cancer (1% in BRCA1, 0.5% in BRCA2).
Expected numbers were obtained by multiplying follow-up times by
the estimated annual risks for each PV carrier and observed to
expected ratios with 95% confidence intervals were calculated. Cumu-
lative incidence curves were obtained using Kaplan-Meier curves from
date of individual genetic test to date of RRBSO or censor (ovarian
cancer, death, or last follow-up) and from date of RRBSO to PPC or
censor (death or last follow-up). Follow-up of less than 6 months from
FIGURE 1 Study flowchart.
RRBSO, risk reducing bilateral
salpingo-oophorectomy; FU,
follow-up
CROSBIE ET AL.1157

RRBSO was set at zero. All Pvalues were based on two-sided tests
and were considered statistically significant if <0.05. Analyses were
performed in Stata version 14 (StataCorp. 2015. Stata Statistical Soft-
ware: Release 14. College Station, TX: StataCorp LP).
3|RESULTS
A total of 891 proven BRCA1/2 PV carriers (BRCA1 = 468,
BRCA2 = 423) who had undergone RRBSO were identified with a
median age of 45.1 at RRBSO (Figure 1, Table 1). Of the BRCA1 car-
riers, 236 (50.4%) had prior or prospective breast cancer with
201 (43%) having chemotherapy. For BRCA2 carriers, 230 (54.4%) had
prior or prospective breast cancer with 179 (42.3%) having chemo-
therapy. Overall, 1853 controls were identified with a mean age of
44.8 at mutation report (median = 43.45). Of those never having
undergone RRBSO, a slightly higher proportion of controls had breast
cancer (BRCA1 60.1%, BRCA2 60.4%) and chemotherapy
(51.4%/45.4%) (Table 2). There were only 1302 who had follow-up
that was eligible after age 35 years for BRCA1 (n = 736) and 45 years
for BRCA2 (n = 566) (Table 3), this included 539 women (mean age at
mutation 46.9; median 46.3) who later had RRBSO. Cases underwent
surgery aged 24.9 years to 79.3 years (median = 45.1 years) and were
27.9 years to 88.1 years at censoring (median = 53.8). Four hundred
of 891 (44.9%) had RRBSO after a breast cancer diagnosis (range
0.4-38.6 years post diagnosis; mean 6.8 years; median 4.6 years;
114 within 2 years of breast cancer). Most women (689/891-77%)
had RRBSO after their genetic test result (range = 0.016-19.8 years;
mean = 2.3 years; median = 0.83 years). Of the 104 (15%) delaying
RRBSO more than 5 years post report (BRCA1 = 57), the mean age at
testing was 36.7 years (median = 34.99; range 22.3-59.4 years), with
27 aged <31 years. The proportion without children in each age range
at RRBSO is shown in Table 4. There was no strong evidence for a
higher proportion of nulliparous women undergoing RRBSO >40 years
of age with 12.2% <40 vs 14% aged ≥40 (P= .57).
3.1 |Ovarian cancers and PPC in follow-up
and at surgery
There were 7815.1 women-years (mean = 8.7; median = 7.1) of follow-
up to censoring from RRBSO date but only 7261.1 risk eligible years
(mean = 8.15 years) (Table 1). RRBSOs occurred from 1980 to 2019
(median 2010) with 0.1 to 40 years eligible follow-up. Only three PPCs
occurred, two in women undergoing RRBSO in nonspecialty units. Of
105 RRBSO since 2011, only two STIC lesions have been identified,
and a further 4 with benign ovarian cystadenoma. Twenty-one occult
ovarian cancers were found at RRBSO (2.4%) aged 38.7 to 73.3 years
(median = 51.9 years). Sixteen were diagnosed at Stage 1 (76%) includ-
ing one STIC lesion with microinvasion, one at Stage 2 and two each at
Stages 3 and 4 (despite normal ovarian screening). One was a clear cell
carcinoma, one a granulosa cell tumour and the remainder were
HGSOC. Sixteen of the occult tumours occurred in BRCA1 PV carriers
TABLE 1 Follow-up and expected cancers in 891 BRCA1/2 PV carriers who had undergone RRBSO
Total RRBSO TAH BSO BSO
Centre/
unit Gene Number
Median age at
RRBSO (IQR)
Total follow-up
from RRBSO
(median/mean)
Eligible
follow-
up
Expected
OC PPC
Number
with
TAH
BSO
Eligible
follow-up
TAH BSO
Expected
OC PPC
Number
with
BSO
only
Eligible
follow-up
BSO only
Expected
OC PPC
St Mary's BRCA1 263 42.6 (38.6-48.1) 2551.27 (8.5/9.7) 2492.90 24.93 0 117 1621.83 16.22 0 146 871.07 8.71 0
BRCA2 226 46.3 (40.5-53.5) 2011.38 (7.6/8.9) 1737.02 8.69 1 88 969.29 4.85 0 138 767.73 3.84 1
Preston BRCA1 46 43.5 (37.8-53.8) 398.86 (8.1/8.7) 383.03 3.83 0 18 199.53 2.00 0 28 183.51 1.84 0
BRCA2 38 48.8 (44.4-53.7) 290.15 (7.9/7.6) 269.75 1.35 0 6 75.75 0.38 0 32 193.99 0.97 0
Total specialty 573 5251.66 4882.70 38.79 1 229 2886.40 23.44 0 344 2016,31 15.35 1
Other BRCA1 159 45.0 (39.9-51.6) 1268.57 (6.4/8.0) 1235.11 12.35 1 128 1083.02 10.83 1 31 152.09 1.52 0
BRCA2 159 48.1 (43.4-52.8) 1294.83 (6.5/8.1) 1143.29 5.72 1 119 955.02 4.78 1 40 188.27 0.94 0
Total other 318 2563.40 2378.40 18.07 2 247 2038.04 15.61 2 71 340.37 2.46 0
Overall total 891 45.1 (40.0-52.3) 7815.06 (7.1/8.7) 7261.10 56.86 3 476 4904.43 39.04 2 415 2356.67 17.82 1
Abbreviations: IQR, interquartile range; OC, ovarian cancer; PPC, primary peritoneal cancer; RRBSO, risk-reducing bilateral salpingo-oophorectomy; TAH BSO, total abdominal hysterectomy and bilateral
salpingo-oophorectomy.
1158 CROSBIE ET AL.

and five in BRCA2 carriers. Four hundred thirty-five RRBSO were car-
ried out in the risk period in BRCA1 PV carriers and 252 in BRCA2 PV
carriers. Using an annual incidence rate of 1% for BRCA1 and 0.5% for
BRCA2, this would suggest lead times of 3.7 years for BRCA1 and
3.9 years for BRCA2. However, confining analysis to only those who
were known carriers at RRBSO, this drops to 2.89 and 2.07 years,
respectively. There were 63 breast cancers post RRBSO (range
0.1-38.8 years post RRBSO; mean-7.4 years; median 6.26 years).
3.2 |Expected ovarian cancers
A total of 56.97 ovarian cancers were expected using life tables
(Table 1) with only three PPCs occurring (HR = 0.053 95%
CI = 0.013-0.14), with a rate of 0.4 per 1000 women-years. Within
the designated cancer centres, 38.79 were expected with one cancer
observed (HR = 0.03 95% CI = 0.001-0.13) compared to 18.07
expected and 2 observed in the nonspecialty units (HR = 0.11 95%
CI = 0.02-0.37) (P= .07). In the control group, there were
2958.8 years of eligible follow-up in 1302 women (mean = 2.3;
median = 0.92; range 0.01-43.2). Controls eligible for follow-up had a
mean age of 50.3 (median 48.4) with those undergoing RRBSO, a
mean age of 47.5 (median 46.3). The annual incidence of ovarian can-
cer was 10.8 per 1000 (odds ratio for RRBSO = 0.037, 95% CI
0.002-0.342). There were 17.1 ovarian cancers expected with
22 observed in BRCA1 PV carriers, and 6.25 expected and 10 observed
in BRCA2 PV carriers. The overall difference among controls was not
significant (HR = 1.37; 95% CI = 0.95-1.91). This provided an
observed:expected ratio of 1.28 and 1.6, respectively, for BRCA1 and
BRCA2 genes. If these were extrapolated to the post RRBSO follow-
up, the expected cancers would rise to 52.8 for the specialty centres.
Two PPCs occurred after hysterectomy and RRBSO procedures, one
aged 56.0 years (4.2 years post-surgery) following a vaginal hysterectomy
with abdominal-assisted RRBSO in a BRCA1 carrier and one aged
72.1 years (9.5 years postsurgery) in a BRCA2 carrier. The third was in a
laparoscopicRRBSOatStMary's3.9yearspostsurgeryinaBRCA2 car-
rier. There were therefore two PPCs in hysterectomy cases with 38.9
expected (HR = 0.051, 95% CI = 0.01-0.17) with one in RRBSO only sur-
gery with 17.65 expected (HR = 0.06; 95% CI = 0.003-0.28).
We next performed Kaplan-Meier analysis comparing RRBSO vs
no RRBSO (Figure 2A,B). For BRCA1, RRBSO (1/449-PPC) vs no
RRBSO (21/367-ovarian cancer), total follow-up 5769.8 years, was
associated with a HR for ovarian/peritoneal cancer of 0.014 (95%
CI = 0.002-0.106) (P< .001), and for BRCA2, RRBSO (2/357-PPC) vs
no RRBSO (9/347-ovarian cancer), total follow-up 4174.5 years, was
associated with a HR for ovarian/peritoneal cancer of 0.072 (95%
CI = 0.014-0.366) (P= .002) (Figure 2A). In combined analysis of
BRCA1 and BRCA2, RRBSO (3/806) vs non-RRBSO (30/714), total
follow-up 9944.3 years was associated with a HR of 0.029 (95%
CI = 0.009-0.100) (P< .001) (Figure 2B, Supplementary Figure 1).
Table 2 presents potential risk factors for ovarian cancer and
potential motivators for RRBSO. There was no apparent effect of
nulliparity on ovarian cancer risk. Women with ovarian cancer were
TABLE 2 Demographics and potential risk factors in women undergoing or not undergoing RRBSO
Ovarian cancer
or PPC Number
Mean age at
RRBSO or
mutation report
if no RRBSO Range
Age at
ovarian
cancer Range Nulliparous %
Breast
cancer %
Chemotherapy
for prior
breast cancer
% with
ovarian
cancer
Ovarian family
history
BRCA1 RRBSO 17 51.7 38.7-73.3 52.0 38.7-73.3 1 6% 10 58.82% 7 41.18% 8 47.06%
BRCA2 RRBSO 7 57.0 45.4-62.6 58.9 45.4-72.1 0 0% 6 85.71% 3 42.86% 2 28.57%
BRCA1 no RRBSO 22 52.7 30.7-66.3 55.6 37.7-68.0 3 14% 16 72.73% 12 54.55% 10 45.45%
BRCA2 no RRBSO 10 59.8 43.4-68.5 61.6 49.7-70.6 0 0% 7 70.00% 4 40.00% 4 40.00%
No ovarian cancer
BRCA1 RRBSO 451 44.9 24.8-76.3 N/a N/a 67 15% 226 50.11% 194 43.02% 242 53.66%
BRCA2 RRBSO 416 48.1 28.4-79.3 N/a N/a 54 13% 223 53.61% 176 42.31% 124 29.81%
BRCA1 no RRBSO 544 42.8 18.1-89.5 N/a N/a 134 25% 324 59.56% 279 51.29% 201 36.95%
BRCA2 no RRBSO 624 46.6 19.1-89.5 N/a N/a 122 20% 376 60.26% 284 45.51% 114 18.27%
Abbreviation: RRBSO, risk-reducing bilateral salpingo-oophorectomy.
CROSBIE ET AL.1159

more likely to have had a previous breast cancer (39/56-69.6%) than
women without (1149/2035-56.5%); P= .055. However, chemother-
apy associated with breast cancer was equally common in women
with ovarian cancer (26/56-46.4%) compared to women without
(933/2035-45.8%). Although women undergoing RRBSO were less
likely to have had a previous/incident breast cancer [465/891-52.2%
vs 723/1200-60.3% in controls (P= .0003)], or to have had chemo-
therapy [380/891-42.6% vs 579/1200-48.3% (P= .011)], women with
ovarian cancer were more likely to have a family history of ovarian
cancer (24/56-42.9%) than those without (681/2035-33.5%), but this
was not significant (P= .15). Women who undertook RRBSO were sig-
nificantly more likely (376/891-42.2%) to have an ovarian cancer fam-
ily history than those who did not (329/1200-27.4%) (P< .0001).
3.3 |Deaths in follow-up
In the 891 RRBSO cases, there were 30 BRCA1 carriers (6.4%) who
died during follow-up, six due to ovarian cancer, five of whom were
diagnosed at RRBSO, including three Stage 1 cancers and one post
RRBSO PPC. There were 14 breast cancer deaths, 2 pancreatic can-
cers, and 1 each of gastric and liver cancer as well as 6 noncancer
deaths. Among BRCA2 carriers, there were 34 deaths (8.0%), 1 from
an occult ovarian cancer at RRBSO and 26 breast cancer deaths,
1 from melanoma, lymphoma, pancreatic, endometrial, lung and
TABLE 3 Follow-up and observed and expected cancers in controls postgenetic testing
Number
Number
with
eligible
follow-up
Eligible
follow-up
(mean)
Expected
OC
OC no
RRBSO
OC @
RRBSO
Stage
1
PPC
post-
RRSBSO
Censored
at RRBSO
RRBSO
before
eligible
age
Estimated
lead time
from OC
at RRBSO
BRCA1 907 736 1709.66 (2.31) 17.10 22 16 12 1 346 18 2.89
BRCA2 946 566 1249.18 (2.21) 6.25 10 5 4 2 193 129 2.07
Total 1853 1302 2958.84 23.35 32 21 16 3 539 147
Abbreviations: RRBSO, risk-reducing bilateral salpingo-oophorectomy; OC, ovarian cancer.
TABLE 4 Proportion nulliparous at each age range at RRBSO
Gene BRCA1 BRCA2
RRBSO <35 years 33 13
Number nulliparous 6 3
% 18.18% 23.08%
RRBSO 35 to 39 years 114 61
Number nulliparous 17 1
% 14.91% 1.64%
RRBSO 40 to 44 years 123 98
Number nulliparous 20 21
% 16.26% 21.43%
RRBSO 45 to 49 years 77 92
Number nulliparous 9 12
% 11.69% 13.04%
RRBSO ≥50 years 122 160
Number nulliparous 15 17
% 12.30% 10.63%
Abbreviation: RRBSO, risk-reducing bilateral salpingo-oophorectomy.
0.00 0.05 0.10 0.15 0.20 0.25
Cumulative incidence
357 135 23 5 1 0BRCA2: RRBSO
347 17 0 0 0 0BRCA2: no RRBSO
449 209 46 9 2 0BRCA1: RRBSO
367 20 1 0 0 0BRCA1: no RRBSO
Number at risk
0 10 20 30 40 50
Time to ovarian cancer (years)
BRCA1: no RRBSO BRCA1: RRBSO
BRCA2: no RRBSO BRCA2: RRBSO
0.00 0.05 0.10 0.15 0.20 0.25
Cumulative incidence
806 344 69 14 3 0RRBSO
714371000No RRBSO
Number at risk
0 10 20 30 40 50
Time to ovarian cancer (years)
No RRBSO RRBSO
(A)
(B)
FIGURE 2 Kaplan–Meier analysis comparing ovarian/peritoneal
cancer incidence in women undergoing RRBSO vs no RRBSO. A,
RRBSO was associated with significant risk reduction for ovarian/
peritoneal cancers for both BRCA1 (HR 0.014, 95% CI = 0.002-0.106,
P< .001) and BRCA2 pathogenic variant carriers (HR 0.072, 95%
CI = 0.014-0.366, P= .002). B, RRBSO was associated with reduced
risk of ovarian/peritoneal cancers when considering BRCA1 and
BRCA2 pathogenic variant carriers combined (HR 0.029, 95%
CI = 0.009-0.100, P< .001)
1160 CROSBIE ET AL.

stomach cancer, plus 2 noncancer deaths. Overall, only 7 of
891 (0.78%) died from an ovarian-related cancer and only 1 from PPC
post RRBSO. Of those not having undergone RRBSO who had follow-
up in the risk period, 15 of 763 (2% age range = 39.7-72 years;
median = 60.6 years; BRCA1 = 12) died from ovarian cancer post
genetic testing. There were 108 breast cancer deaths (many had
breast cancer before genetic testing) and 13 other cancer deaths likely
to be unrelated to BRCA1/2.
3.4 |PPC in whole series
We assessed the proportion of all ovarian cancers in the regional reg-
ister who had a proven PV. There were 27 reported PPCs of 752 total
ovary-related cancers (3.6%) in BRCA1 with age at diagnosis ranging
from 39 to 81 years (median 59). This was slightly older than all ovar-
ian cancers (range 29-83 years, median 50.6 years). For BRCA2, there
were 28 of 421 PPCs (6.7%—range 36-87, median 63 years) slightly
older than all BRCA2 ovarian cancers (range 32-89 years, median
58.0 years). These are in addition to the 3 of 56 (5.4%) presented in
this report.
4|DISCUSSION
The current study is to our knowledge the largest single centre report
on RRBSO in BRCA1/2 PV carriers. The findings support early RRBSO
ideally just before the main risk periods for ovarian cancer in BRCA1
aged 35 years (there were two ovarian cancers aged 37.7 and
38.7 years) and BRCA2 aged 45 years. The presence of only one PPC in
our extended series of RRBSO carried out in specialty centres is
encouraging because although this does not necessarily eliminate PPC
risk, the remaining risk is low and almost certainly below 10% of the
rate without surgery (HR = 0.03). This was supported by a combined
analysis of BRCA1 and BRCA2 in Kaplan-Meier analysis with RRBSO
having a HR for ovarian/peritoneal cancer of 0.029 (95%
CI = 0.009-0.100, P< .001). The upper confidence range of a HR of
0.10 to 0.13 substantially excludes the HR of 0.21 from the meta-anal-
ysis.
15
Compared to a predicted risk of 8.8% to 12.6% of PPC for a
35-year-old BRCA1 carrier based on only a 79% reduction in the 40%
to 60% lifetime risk,
15
the risks would be reduced to 0.4% to 7.8%
using the 95% CI by reducing risks by 87% to 99%. Results from
another large series of 238 BRCA1/2 carriers found a 20-year risk of
3.9% for BRCA1, which extrapolated to lifetime risk of >8%.
23
Two of
the three PPCs occurred outside the specialty centres but still repre-
sented an 89% reduction in ovarian type cancer risk in those units.
Given that this study used conservative estimates of ovarian cancer
incidence lower than those in our previous reports,
10,21
the findings
could suggest even greater reductions in risk. However, there remains a
definite risk of occult malignancy at surgery of around 3.7% in BRCA1
and 2.4% in BRCA2 when surgeries are undertaken during the risk
period. Unfortunately while most of these cancers were detected at
Stage 1, three of these cases subsequently died from their ovarian
cancer. There is evidence that PARP inhibitor treatment may alter this
course when used as a first-line maintenance after primary chemother-
apy.
24
However, cancer prevention strategies through RRBSO remain
the first-line management approach, as PARP inhibitors are not curative
due to the development of chemoresistance. The absence of occult
lesions and postsurgical PPCs in those undergoing RRBSO before the
risk period (n = 203) lends support to early RRBSO if a woman has
completed her family
18
even though this may not now reduce breast
cancer risk particularly in BRCA1 carriers.
25,26
The low level of PPC in the specialty series fits well with the con-
cept that most PPC derives from fimbrial STIC cells that get displaced
from the fimbrial ends of the fallopian tubes into the peritoneal cav-
ity.
26
This may even occur at the time of RRBSO if care is not taken
to prevent this by careful bagging of the tubes and ovaries prior to
removal from the peritoneal cavity. Furthermore, the rather poor-risk
reduction from the meta-analysis
15
may be due to inclusion of cases
where the fallopian tubes were not removed and/or careful pathologi-
cal examination of the fallopian tubes was not performed to exclude
STIC lesions or occult malignancies.
27,28
Further assessment of PPC
risk after RRBSO in BRCA1/2 PV carriers where STIC lesions were
identified may justify some sort of an intervention, such as staging CT
scan to exclude metastatic disease or even a course of PARP inhibitor
treatment if substantial rates continue to be reported.
18
Certainly a
more vigilant follow-up may be justified. We are only aware of two
STIC lesions in our series without microinvasion, and this low rate
may reflect the earlier surgery particularly in more recent years with
RRBSO driven by presymptomatic testing in BRCA1/2 families.
Although the results from the meta-analysis show only a 79%
reduction in overall ovarian type cancer risk with RRBSO, some
reviews have perhaps misled those counselling about risk after sur-
gery that these are small and of the order of just 1% to 2%.
29
The last
review quoted a 1.53% incidence of PPC (28/1830); however, this
represents short-term follow-up rather than lifetime risk.
27
The two
papers that assessed risk at 20 years came up with risks of 4.3% based
on 7 PPCs post RRBSO
30
and 3.9% in BRCA1 carriers based on
5 PPCs.
23
If incidence continued at the same rates, these would be
equivalent to at least a risk of 8% by age 80 for a BRCA1 carrier hav-
ing surgery before 40 years of age. The present study shows convinc-
ing evidence for the first time that risks can be reduced below these
levels when RRBSO is carried out in a careful, oncologically driven
fashion, as the upper 95% CI excludes 8% as described earlier.
Another publication that may have confused the issue was an early
report on fallopian tube and peritoneal cancers that suggested risks of
only 0.6% and 1.3%, respectively, based on identification of BRCA1/2
in 5/29 (17.2%) and 9/22 (40%) of primary-site tumours analysed.
31
Clearly these risk estimates are incorrect for fallopian tube malig-
nancy
27
and also do not reflect the fact that so many BRCA1/2 PV
carriers are identified and opt for RRBSO and that PPC may be due to
implantation of cells at the time of surgery.
The current study also identified a high rate of occult Stage
1 cancers at RRBSO. This suggested lead times of up to 3.9 years,
although this reduced to 2 to 3 years if only those known to have
aBRCA1/2 PV at RRBSO were included. Nonetheless, this may
CROSBIE ET AL.1161

provide hope of a reasonable sojourn time at Stage 1 to encourage
more research on early detection of high-grade serous cancers in
BRCA1/2 carriers.
There are some limitations to the present study. We do not
have full details of procedures carried out beyond the two specialty
centres. However, we have good long-term follow-up of a very
large series of BRCA1 and BRCA2 PV carriers showing a very low
rate of PPC when surgery is carried out in an oncology-driven fash-
ion in a specialty centre. We have not carried out a formal statisti-
cal adjustment for factors that might increase ovarian cancer risk.
However, as these factors including an ovarian cancer family his-
tory and not having had chemotherapy were significantly more
likely in the RRBSO group, this should mean our results are even
more robust.
In conclusion, we have shown a very low rate PPC in women
undergoing careful RRBSO in a specialist oncology centre. Although
even longer follow-up is required to confirm this low PPC rate espe-
cially with PPC occurring at older ages, we can already exclude the
point estimate of only a 79% reduction in risk from the meta-analy-
sis.
15
Therefore, the rate of PPC may be lower than previously
thought if surgery is carried out early in the risk period, performed in
a specialty centre and no STIC lesions identified following careful
pathological assessment of entire fallopian tubes. Women undergoing
such surgery should be told that this reduces their risk by 90% to
95%, and this may be more in those undergoing surgery before the
risk period.
ACKNOWLEDGEMENTS
DGE, EFH and EJC are supported by a National Institute for Health
Research grant to the Biomedical Research Centre, Manchester
(IS-BRC-1215-20007). NF is supported by CRUK via the funding to
Cancer Research UK Manchester Cancer Research Centre (C147/
A18083 and C147/A25254).
CONFLICT OF INTEREST
RJE reports personal fees from Astra Zeneca and Arquer Diagnostics,
and grants from Tesaro Inc. outside the submitted work. DGE reports
personal fees from Astra Zeneca outside the submitted work. The
other authors report no conflicts of interest.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the
corresponding author upon reasonable request.
ETHICS STATEMENT
All patients provided a priori consent for their data to be used in
research; data are anonymized and analysed as part of clinical audit,
and so no ethical review was required.
ORCID
Emma J. Crosbie https://orcid.org/0000-0003-0284-8630
Richard J. Edmondson https://orcid.org/0000-0003-2553-4423
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SUPPORTING INFORMATION
Additional supporting information may be found online in the
Supporting Information section at the end of this article.
How to cite this article: Crosbie EJ, Flaum N, Harkness EF,
et al. Specialist oncological surgery for removal of the ovaries
and fallopian tubes in BRCA1 and BRCA2 pathogenic variant
carriers may reduce primary peritoneal cancer risk to very low
levels. Int. J. Cancer. 2021;148:1155–1163. https://doi.org/
10.1002/ijc.33378
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