Retrospective evaluation of risk-reducing salpingo-oophorectomy for BRCA1/2 pathogenic variant carriers among a cohort study in a single institution

Abstract

Background

Risk-reducing salpingo-oophorectomy is performed for the primary prevention of ovarian cancer in patients with hereditary breast–ovarian cancer syndrome. We performed risk-reducing salpingo-oophorectomy for the first time in Japan in 2008, and we experienced 20 cases of risk-reducing salpingo-oophorectomy through 2019. In the past, the use of risk-reducing salpingo-oophorectomy in Japan was restricted because it was not covered by a Japanese National Health Insurance. Since April 2020, risk-reducing salpingo-oophorectomy has been covered by insurance for patients with breast–ovarian cancer syndrome and pre-existing breast cancer, and this surgery is expected to become more widely implemented in Japan.

Methods

To contribute to the widespread use of risk-reducing salpingo-oophorectomy in the future, we retrospectively reviewed 20 cases of risk-reducing salpingo-oophorectomy at our hospital cohort study to clarify the issues in its implementation.

Results

The variant genes for which risk-reducing salpingo-oophorectomy was indicated were BRCA1 and BRCA2 in 13 (65%) and 7 patients (35%), respectively. The median age at which risk-reducing salpingo-oophorectomy was performed was 49 years (range, 38–58), 13 patients (65%) had gone through menopause, and 16 patients (80%) had a history of breast cancer. Of the five patients (25%) with vasomotor symptoms, four received Chinese medicine, and only one received hormone replacement therapy. Occult cancer was detected in the removed ovaries in two patients (10%), although no postoperative peritoneal carcinogenesis has been observed to date.

Conclusions

Women who paid for risk-reducing salpingo-oophorectomy out of pocket were older than the recommended age at which the procedure should be performed, and this may explain the higher rate of occult cancers than previously reported. We need to perform risk-reducing salpingo-oophorectomy at the recommended age to ensure that the procedure is effective for primary prevention.

risk-reducing salpingo-oophorectomy, hereditary breast–ovarian cancer syndrome, occult cancer

Introduction

Hereditary breast–ovarian cancer syndrome (HBOC) is a disease associated with a loss-of-function variant or deletion of the tumour suppressor gene BRCA1 or BRCA2, which increases the risk of developing breast, pancreatic, prostate and ovarian cancers, including fallopian tube and peritoneal cancers (1). The risk of developing ovarian cancer to age 80 years is 44% for carriers of the pathogenic variant of BRCA1 and 17% for carriers of the pathogenic variant of BRCA2 (2). The effects of risk-reducing salpingo-oophorectomy (RRSO) and oral contraceptives have been reported for the primary prevention of ovarian cancer in carriers of a pathogenic variant of BRCA1/2. RRSO is currently the most effective primary prevention method for cancer, and it has been thought to reduce the risks of ovarian and breast cancers and improve life outcomes, including overall mortality (3–7). Regarding the age at which RRSO is performed, it is recommended that RRSO should be performed by 35–40 years of age or by the end of the last delivery for BRCA1 pathogenic variant carriers and by 40–45 years of age for BRCA2 pathogenic variant carriers (8). RRSO is already covered by insurance in several countries and regions, including the UK and some parts of the USA, but in Japan, patients were previously required to pay for the procedure out of pocket (9). RRSO for patients with pre-existing HBOC-related breast cancer was finally covered by National Health Insurance system in Japan in April 2020. Thus, it is expected that RRSO will become more popular in the future. We performed the first RRSO in Japan in 2008 (10), and in total, we performed 20 cases in the 12 years before the procedure gained insurance coverage. This study examined our experience with 20 previous cases of RRSO in detail and identified the current problems with the procedure.

Patients and methods

We retrospectively reviewed the medical records of 20 patients who underwent RRSO at our hospital between 2008 and 2019 to identify variables including the patients’ clinical and genetic backgrounds, surgical duration and blood loss, intraoperative and postoperative complications, treatment for iatrogenic ovarian failure, postoperative peritoneal carcinogenesis and occult cancer in the resected specimens. All patients underwent surveillance with cancer antigen 125 and ultrasound before as well as after RRSO. Similarly, genetic counselling by a clinical genetic specialist was conducted with sufficient time to confirm the patient’s intention before and after RRSO. In addition, because each Japanese guideline requires that each case must be reviewed by an ethics committee, the ethics committee at our hospital conducted a face-to-face review of each case. Concerning pathological examination, occult cancer was found by chance in the first case, and the subsequent cases were diagnosed according to the Sectioning and Extensively Examining the Fimbriated End Protocol (11). This study was approved by the Institutional Review Board of Keio University School of Medicine (No. 20160443).

Results

The details and summary of the clinicopathological features and procedures performed at RRSO of each client are shown in Tables 1 and 2. The use of RRSO increased starting in 2018 in our hospital. The indicated genetic variants were BRCA1 and BRCA2 in 13 (65%) and 7 patients (35%), respectively. The median age at which RRSO was performed was 49 years (range, 38–58), 13 patients (65%) had gone through menopause, and 16 patients (80%) had a history of breast cancer. Two patients had previously undergone laparotomy, and all such procedures have been performed laparoscopically since 2014. A total of 19 out of 20 clients hoped to remove uterus at the time at RRSO, simultaneously. The median operative time was 111 min (range, 53–173), blood loss was generally low, the median duration of hospitalization was 6 days (range, 5–10) and there were no intraoperative or postoperative surgical complications. All cases underwent peritoneal washing cytology, which were negative, except for one case, which was suspicious. Of the five patients (25%) with vasomotor symptoms, four received Chinese medicine because they had breast cancer and did not choose hormone replacement therapy (HRT), and only one patient without a history of breast cancer received HRT. No postoperative peritoneal carcinogenesis has been observed to date. Occult cancer was present in two patients (10%), and one case was already reported (12). The patient was 47 years old and had a history of breast cancer. Genetic testing revealed a pathogenic variant of BRCA1 (c.4327C > T/p.Arg1443Ter), so RRSO was requested and performed. Occult serous adenocarcinoma on the right ovary’s surface was diagnosed based on the pathological examination. The other case involved a 50-year-old woman with a BRCA1 variant and a history of breast cancer (Client 20) (Fig. 1). Although her bilateral ovaries were grossly normal sized, the pathology revealed serous tubal intraepithelial carcinoma in the right fimbria of fallopian tube, and the right ovary had highly atypical cells that formed multiple follicles within the ovary and that were exposed on the ovarian surface. The left ovary also had similar cancerous cells congregating on its surface. Both bilateral ovarian carcinomas were histologically diagnosed as high-grade serous carcinoma. Subsequently, the patient underwent radical surgery for ovarian cancer, and she received adjuvant chemotherapy after being diagnosed with stage IC2.

Table 1

The clinical feature of the 20 clients who underwent risk-reducing salpingo-oophorectomy

Client No.	Year	Gene	Variant (HGVS nucleotide/HGVS protein)	Age at RRSO	Menopausea	Personal history of breast cancer	Surgical procedure	Duration of surgery (min)	Blood loss (ml)	Hospitalization (days)	Surgical complication	Peritoneal washing cytology	Treatment for vasomotor symptoms	Peritoneal cancer after RRSO	Occult cancer
1	2008	BRCA1	c.4327C > T/p.Arg1443Ter	47	+	+	RRSO+ATH	94	Minimal	10	None	Negative	+ (Chinese medicine)	−	Ovary
2	2013	BRCA1	c.5161C > T/p.Gln1721Ter	58	+	+	RRSO+TLH	109	100	5	None	Negative	−	−	−
3	2013	BRCA1	c.191G > A/p.Cys64Tyr	39	−	+	RRSO+ATH	173	160	7	None	Negative	+ (Chinese medicine)	−	−
4	2014	BRCA1	c.5095C > T/p.Arg1699Trp	43	−	−	RRSO+TLH	110	Minimal	5	None	Negative	−	−	−
5	2015	BRCA2	c.5560_5561del/p.Val1854PhefsTer3	51	+	+	RRSO+TLH	162	50	7	None	Negative	−	−	−
6	2015	BRCA2	c.8223del/p.Asn2742MetfsTer4	40	−	−	RRSO+TLH	100	50	5	None	Negative	+ (Chinese medicine)	−	−
7	2016	BRCA1	c.2860_2864del/p.Leu954llefsTer15	46	+	+	RRSO+TLH	74	Minimal	5	None	Negative	−	−	−
8	2016	BRCA2	c.755_758del/p.Asp252ValfsTer24	51	+	+	RRSO+TLH	87	Minimal	6	None	Negative	+ (Chinese medicine)	−	−
9	2018	BRCA1	c.5558A > G/p.Tyr1853Cys	47	−	+	RRSO+TLH	125	120	5	None	Negative	−	−	−
10	2018	BRCA1	c.2389_2390del/p.Glu797ThrfsTer3	42	+	+	RRSO+TLH	93	Minimal	5	None	Negative	−	−	−
11	2018	BRCA1	c.4579del/p.Asp1527fs	54	+	+	RRSO+TLH	133	Minimal	5	None	Negative	−	−	−
12	2018	BRCA2	c.426-2A > G	53	+	+	RRSO+TLH	132	Minimal	7	None	Negative	−	−	−
13	2018	BRCA1	c.1961del/p.Lys654SerfsTer47	42	−	−	RRSO+TLH	111	Minimal	7	None	Negative	+ (HRT)	−	−
14	2019	BRCA2	c.403_410dup/p.Cys138Ter	57	+	+	RRSO+TLH	122	25	6	None	Negative	−	−	−
15	2019	BRCA2	c.5709del/p.Leu1904PhefsTer5	50	−	+	RRSO+TLH	163	75	7	None	Negative	−	−	−
16	2019	BRCA2	c.8225_8232del/p.Asn2742ThrfsTer19	54	+	−	RRSO+TLH	145	25	6	None	Negative	−	−	−
17	2019	BRCA1	c.5558A > G/p.Tyr1853Cys	49	+	+	RRSO+TLH	151	Minimal	7	None	Negative	−	−	−
18	2019	BRCA1	c.4335_4338dup/p.Gln1447ArgfsTer16	46	+	+	RRSO+TLH	101	Minimal	7	None	Negative	−	−	−
19	2019	BRCA1	c.3640G > T/p.Glu1214Ter	38	−	+	RRSO+TLH	109	Minimal	6	None	Negative	−	−	−
20	2019	BRCA1	c.188 T > A/p.Leu63Ter	50	+	+	RRSO	53	Minimal	6	None	Suspicious	−	−	Ovary

HGVS, Human Genome Variation Society; RRSO, risk-reducing salpingo-oophorectomy; ATH, abdominal total hysterectomy; TLH, total laparoscopic hysterectomy; HRT, hormone replacement therapy.

^aIncluding menopause by chemotherapy.

Table 2

Summary of the 20 patients

Variable
Variant gene
BRCA1 (%)	13 (65%)
BRCA2 (%)	7 (35%)
Age (years)
Median	48
Range	38–58
Postmenopausal	13 (65%)
History of breast cancer (%)	16 (80%)
Duration of surgery (min)
Median	111
Range	53–173
Blood loss (ml)
Median	Minimal
Range	Minimal–160
Hospital stay (days)
Median	6
Range	5–10
Surgical complication	0
Peritoneal washing cytology
Negative	19 (95%)
Suspicious	1 (5%)
Vasomotor symptoms (%)	5 (25%)
Vasomotor symptom treatment
Chinese medicine	3
HRT	1
Peritoneal cancer after RRSO	0
Occult cancer (%)	2 (10%)

Figure 1.

A patient with occult cancer in the ovaries (Client 20). A–C: Right ovary; A: the ovary was grossly normal sized; B: the right ovary had highly atypical cells forming multiple follicles; C: the alveolar proliferating lesion was positive for p53. D and E: Right fallopian tube; D: pathological examination according to the SEE-FIM protocol; E: serous tubal intraepithelial carcinoma in the right fimbria. F–I: Left ovary; F and G: pathological examination according to the SEE-FIM protocol; H: cancerous cells congregating on the surface of the ovary; I: the congregating lesion was positive for p53. SEE-FIM, Sectioning and Extensively Examining the Fimbriated End.

Discussion

Although the implementation of RRSO has widely varied globally, a multi-institution, a prospective study found that 70–80% of BRCA1/2 pathogenic variants carriers underwent RRSO (13). In South Korea, BRCA1/2 genetic test and RRSO in cases suspected of having BRCA1/2 pathogenic variants are currently covered by the National Health Insurance Service, and RRSO rates have recently risen to 52.4% (14). Conversely, the spread of RRSO in Japan has been slow because the procedure was not previously covered by national governmental health insurance system, and the implementation rate was only 31.4% (15). Meanwhile, some physicians will be performing RRSO for the first time, and thus, the details of our hospital’s cases were examined to clarify the important points. The 20 surgeries were minimally invasive and safe. However, the current study results support prior findings that most RRSOs in Japan are performed in patients in their late 40s or older (15). The reasons for the delayed performance of RRSO in Japan include the possibility that patients who were already diagnosed with HBOC are taking them first because RRSO has only just begun to become popular. It is also hypothesized that the burden of self-funded surgery is too great for the recommended age group, and thus, they delay surgery until they are financially stable. In patients with the BRCA2 pathological variant, a delay in the timing of RRSO may not affect patient outcomes because this variant is associated with a slower increase in the risk of ovarian cancer than BRCA1. Conversely, in the case of the BRCA1 pathological variant, the cancer risk begins to rise around age 35, and thus, there is a concern that a delay in the timing of RRSO could eliminate its preventative effect and increase the risk of occult cancer. In fact, the rate of occult cancers in our hospital was considerably higher than the previously reported figure of 2.6–5.4% (16, 17). The high occult cancer detection rate at our hospital may be attributable to a shift in the median age of occult cancer testing to 49 years, which is older than the recommended age. Because RRSO is currently covered by insurance, the age at which the surgery is performed is expected to approach the recommended age in the future; however, from the perspective of primary prevention, which is the original purpose of RRSO, attending physicians must be strongly aware of the importance of performing RRSO at the recommended age and encourage patients to undergo the procedure. To do so, we need to contribute to the penetration of genetics throughout our country by holding genetic seminars for medical staffs, supporting the activities of patient advocacy group for clients and holding open lectures for the general public. It should be noted that in our case group, hysterectomy was performed in nearly all patients. A higher risk of serous endometrial cancer has been observed in patients carrying the BRCA1 pathological variant (18), and a 40-year-old woman who underwent total hysterectomy with RRSO experienced an increase of overall survival of 4.9 months versus RRSO alone (19). To allow patients to make an informed decision, we thoroughly explain the benefits and risks of total hysterectomy, including cancer risk, surgical complication and quality of life after surgery and cost. As a result, 95% of patients opted for total hysterectomy, but no occult cancer in the uterus was found.

Conclusions

In a retrospective review of 20 cases at our hospital, although the surgery itself was safe, the age at which RRSO was performed was older than the recommended age for RRSO, and occult cancers were therefore found more frequently than previously reported. In promoting the use of RRSO in the future, we must be keenly aware that RRSO should be performed at the recommended age to ensure its primary preventative effect, which is the original purpose of RRSO.

Conflict of Interest

None declared.

Funding

None declared.