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Abstract
Background In Japan, the public insurance policy was revised in 2020 to cover hereditary breast and ovarian cancer (HBOC), including genetic testing and surveillance, for patients with breast cancer (BC). Consequently, the demand for risk-reducing salpingo-oophorectomy (RRSO) has increased. This study aimed to clarify the changes in the demand and timing of genetic testing and RRSO associated with public insurance coverage for HBOC in Japan.
Methods This retrospective analysis included 350 women with germline BRCA (gBRCA) pathogenic variants (PVs) who had visited gynaecologists; they received gBRCA genetic testing at 45.1±10.6 (20–74) years. The use of medical testing and preventive treatment was compared between the preinsurance and postinsurance groups using Mann-Whitney U and Fisher’s exact tests.
Results The findings indicate that RRSO rates doubled from 31.4% to 62.6% among patients with gBRCA-PV. The implementation rate was 32.4% among unaffected carriers and 70.3% among BC-affected patients. Younger patients received genetic testing with significantly shorter intervals between BC diagnosis and genetic testing and between genetic testing and RRSO.
Conclusion Overall, the insurance coverage for HBOC patients with BC has increased the frequency of RRSO in Japan. However, a comparison between the number of probands and family members indicated that the diagnosis among family members is inadequate. The inequality in the use of genetic services by socioeconomic groups is an issue of further concern.
- women's health services
Data availability statement
Data are available upon reasonable request. The datasets generated and/or analysed during this study are not publicly available owing to ethical restrictions but are available from the corresponding author upon reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Time required to perform risk-reducing surgery on hereditary breast and ovarian cancer (HBOC) patients depends on the reported psychological impact of disclosure.
WHAT THIS STUDY ADDS
This study demonstrates the importance of the past/present of HBOC management based on public insurance, shortening the time elapsed between the diagnosis of breast cancer and genetic testing or risk-reducing salpingo-oophorectomy.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Comparing probands with relatives, the inequality in the use of genetic services is an issue of further concern under the current public insurance policy in Japan. The expansion of the public insurance coverage to unaffected patients who are not currently covered by the insurance should be considered.
Introduction
The BRCA1 gene was identified in 1994 by Dr Miki,1 a long-time mentor at our hospital in Japan, and the BRCA2 gene was identified in 1995.2 Pathogenic variants (PVs) of germline BRCA (gBRCA) are responsible for hereditary breast and ovarian cancer (HBOC), defined as gBRCA1/2-PVs. Primary fallopian tube, peritoneal and ovarian carcinomas (OC) remain the most lethal gynaecological malignancy in women,3 primarily because of their late-stage diagnosis, frequent recurrence and treatment resistance.3 4
The prevalence of gBRCA1/2-PVs in a study of patients with OC was 11.7%–15.4%,5–7 whereas the prevalence of gBRCA1/2-PVs among patients with OC of high-grade serous carcinoma in the Japanese population was reportedly 27.7%–29.7%,5–7 a higher percentage than among Caucasians.8 9 According to Japanese data, the age of the onset of OC was 51.310 and 55.811 years for gBRCA1 and 58.310 and 57.511 years for gBRCA2. The cumulative risk of developing OC by age 85 years is 65.6% for gBRCA1 and 14.8% for gBRCA2.11 Similarly, the age of the onset of breast cancer (BC) in Japanese women was 43.612 and 50.711 years for gBRCA1 and 45.212 and 50.711 years for gBRCA2.
Although several screening tools have been proposed for OC, such as serial transvaginal ultrasound and serum cancer antigen 125 (CA-125),13 the only strategy shown to reduce OC mortality in women at high risk of developing OC is primary prevention, such as risk-reducing salpingo-oophorectomy (RRSO). RRSO decreased OC-specific and overall mortality in women with gBRCA1/2-PVs by approximately 80% and 70%, respectively.14 15 Women diagnosed with HBOC after menopause should be provided RRSO concurrently16; RRSO reduces OC risk by 80%–95%17–21 and reduces BC risk by up to 50% in premenopausal women.22 Sekine et al reported that for all gBRCA1 carriers, the preventive effect was 97% and 92% when RRSO was administered by the age of 35 and 40 years, respectively.10 Moreover, this effect was reduced to 89% when RRSO was administered after the age of 40.
The first RRSO for a woman with a gBRCA1-PV in her early 40s was performed at our hospital at our own expense in 2011. This patient was diagnosed with BC in her late 30s and tested for gBRCA the following year. In May 2013, American actress Angelina Jolie made public her experience of having a gBRCA1-PV and undergoing bilateral risk-reducing mastectomy (RRM).23 Subsequently, the so-called ‘Angelina effect’ led to increased referrals to genetic services and increased public interest worldwide.24 The first guidelines for HBOC were published in Japan in 2017. Since 2018, gBRCA1/2 genetic testing was covered for applicable cases by the National Health Insurance System as a companion diagnostic for Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor for only advanced OC. However, since 2020, it has been covered as a definitive diagnosis of HBOC as a preventive intervention for secondary cancers in all OC cases. The details of public health insurance according to gBRCA genetic testing and RRSO are presented in table 1. The current public insurance in Japan’s coverage system benefits those who have already developed a disease. The purpose of gBRCA genetic testing is to help determine the PARP inhibitor for patients with breast, ovarian, pancreatic or prostate cancer. In Japan, even if a person is diagnosed with a hereditary disease, public medical care is not provided to them unless they develop the disease.
Changes in public health insurance policy according to gBRCA genetic testing and RRSO in Japan
They must pay the full amount for their medical care, even if their relative is confirmed to have a highly penetrant hereditary disease. In Japan, there are no data on the differences in public insurance system indications or whether the choice of risk-reducing surgery or surveillance differs between unaffected and affected carriers. Therefore, we compared the outcomes among the carriers with gBRCA-PV who were affected and unaffected, considering their choice between RRSO or surveillance, and also examined the timing of genetic testing before and after the availability of the public insurance coverage for HBOC.
Methods
This study was designed as a retrospective cohort study at the Cancer Institute Hospital in Tokyo, Japan, which has the highest number of BC surgeries in Japan.
We reviewed all the records between 2009 and 2022. The exclusion criteria comprised patients who had ovarian cancer at the time of genetic testing (n=145), followed up at another hospital (n=6) and did not consult a gynaecologist (n=17) or received optimal supportive care when a cure was not achievable using the existing treatments (n=13; figure 1). We evaluated the medical records of women with gBRCA- PV and collected self-reported information, including familial cancer history. Each woman with a gBRCA-PV was identified by genetic testing and counselled by genetic counsellors or a gynaecological oncologist. Given the difficulty of early detection of OC and the scarcity of good risk-reduction approaches for the affected carriers with BC, one appropriate option is concurrent surgery, including surgery for BC and RRSO. In accordance with various guidelines, we recommend RRSO after completing childbearing for women with gBRCA1-PVs, typically at 35–40 years of age, and those with gBRCA2-PVs, at 40–45 years of age; on average, this is 8–10 years later than in the case of patients with gBRCA1 variants.13 The choice between RRSO and surveillance was completely individualised and based on patients’ free will. Before RRSO, surveillance for OC was recommended every 3 months, based on our guiding principles. After RRSO, surveillance for peritoneal cancer was performed every 6–12 months. Data on clinical information (age at that time, parity, menopausal status, personal BC history (at primary BC age), family history, age at genetic testing, RRSO or surveillance, age at RRSO, concurrent breast surgery and gBRCA1/2 status) were collected on 30 December 2022.
Flow diagram of participants. In total, 531 carriers of BRCA1/2 pathogenic variants were identified. PV, pathogenic variant; RRSO, risk-reducing salpingo-oophorectomy.
We analysed the differences observed before and after public insurance coverage was provided to patients with gBRCA-PVs. Some RRSO cases overlapped with those examined in Nomura et al.25 The RRSO implementation rate was calculated as the number of cases in which RRSO was performed divided by the total number of cases with gBRCA-PV. We calculated continuous variables as medians and compared them using the Mann-Whitney U test. We used Fisher’s exact test to compare categorical variables, and JMP software, V.17.0, for statistical analysis.
Results
We reviewed 350 cases of patients diagnosed with HBOC, referred to our gynaecology department (figure 1) in January 2023: 219 RRSO cases and 131 surveillance cases. The implementation rate of RRSO was 62.6% (219/350).
The surveillance group included 11 dropouts (eight for self-funded reasons), 4 cases of pregnancy or infertility treatment and 8 cases awaiting RRSO. We observed an increase in diagnosed cases in 2018, when the test was covered as a companion test, and in 2020, when it was covered by public insurance for affected cases (BC survivors). Recently, we observed a slight increase in the number of unaffected cases not covered by public insurance.
Table 2 shows the characteristics of 350 patients according to their gBRCA status (gBRCA1, n=181, 138 (76.2%) affected cases; gBRCA2, n=169,141 (83.4%) affected cases, p=0.095). Family history of HBOC-associated cancer (breast, ovarian, stomach, pancreatic and prostate) in first-degree and second-degree relatives was very high (92.3% and 95.3%, respectively), 66.9% and 82.8% for BC (p=0.0006) and 49.7% and 24.5%, for OC (p<0.001), respectively. Family history of OC was more common in gBRCA1 than in gBRCA2.
Characteristics of patients, according to germline gBRCA status
Genetic testing was performed at the age of 44.0 (± 10.6) for gBRCA1 vs 46.3 (± 10.6) for gBRCA2 (p=0.004). The mean age at first BC diagnosis was 41.1 (± 8.71) for gBRCA1 vs 42.8 (± 8.31) for gBRCA2 (p=0.095), while age at RRSO was 48.8 (± 8.52) for gBRCA1 vs 51.1 (± 8.51) for gBRCA2 (p=0.049). Both showed a trend toward younger age gBRCA1 patients.
Table 3 shows a comparison of patients’ characteristics before and after the public insurance coverage was provided. By 2019, 186 HBOC cases were diagnosed and confirmed by genetic testing, and 164 cases were diagnosed after 2020. There were no significant differences in gBRCA status, childbearing status, menopausal status (including iatrogenic amenorrhea) or BC incidence by time (p=0.414, 0.394, 0.097 and 0.467, respectively). Of the patients who underwent genetic testing after 2020, 46.1% had a history of BC before public insurance coverage was provided.
Comparison of the characteristics of patients before and after the revision of the public insurance coverage
The age at first BC onset was 40.8 (± 8.85; 19–70) for those who underwent genetic testing before 2019 and 43.5 (± 7.95; 26–63) after 2020, with more cases of older adults undergoing genetic testing after 2020 (p=0.008).
Regarding family history, there was a trend toward less HBOC associated with a family history of BC or OC in first-degree and second-degree relatives after 2020 (p=0.007, <0.001 and <0.001). Initially, testing was based on a dense family history. However, this could have been influenced by the fact that the tests can now be conducted in younger patients with no family history, owing to the expansion of test coverage.
Furthermore, 71.0% of cases with HBOC diagnosed before 2019 and 53% of cases with HBOC diagnosed after 2020 have already undergone RRSO.
We also compared the ages at which RRSO was performed. The mean age at which the RRSO was performed for those who received genetic testing before 2019 was 51.4 (± 8.1; 38–74), while the age at which RRSO was performed for those who took the genetic test after 2020 was 48.8 (± 8.72; 31–73). Comparing the before 2019 and after 2020 groups, RRSO was performed at younger ages in the latter (p=0.026).
Table 4 shows a comparison of participants with and without RRSO. gBRCA status showed no significant difference (p=0.294). The RRSO rate was 4.1% (9/219) in those aged under 40 and 73.4% in those aged over 40 (p<0.001). The rates were 32.4% (23/71) and 70.3% (196/279) among unaffected and affected carriers, respectively (p<0.001).
Comparison between the patients undergoing RRSO and surveillance
A trend of performing RRSO was observed for those with a history of childbirth, menopausal status (including iatrogenic amenorrhea) and affected carriers (p=0.001, <0.001 and <0.001, respectively).
The median age of BC onset was 42.0 (± 8.54; 19–70) for the 279 affected BC cases. Genetic testing was performed at the age of 47.6 (± 10.6; 22–74) for cases with the onset before 2019 and 44.0 (± 8.38; 26–65) for those with the onset after 2020.
There was no significant difference when comparing the presence or absence of family history of BC (p=0.497). However, an increasing trend was observed for RRSO being performed on those with HBOC associated with a family history of first-degree and second-degree relatives or a family history of OC (p=0.035 and <0.001 respectively). No effect of family history was observed in unaffected carriers.
Table 5 shows the age at which genetic testing was performed, the interval between age at BC diagnosis and genetic testing among the affected carriers and the interval between age at genetic testing and RRSO. There were fewer than 71 unaffected patients, compared with 279 affected carriers. This indicates that the number of relatives undergoing genetic testing was small.
Timing of genetic testing and RRSO, based on the personal history of BC
The ages at genetic testing were 39.0 (± 10.2), 47.6 (± 10.6) and 44.0 (± 8.38) for unaffected carriers, those who had BC before the public insurance coverage was introduced in 2020 and those who developed BC after 2020, respectively (p=0.013). A trend toward testing at younger ages was observed among the unaffected carriers and among those who had BC since 2020.
After 2020, when the public insurance coverage was added, the intervals from BC diagnosis to genetic testing were reduced (from 6.96 (±8.55) to 0.56 (±2.16) months, p<0.001), and the time from genetic testing to RRSO was shortened (from 2.07 (± 2.75) to 0.52 (± 0.32) months, p=0.0003).
RRSO and concurrent breast surgery were not performed on the unaffected carriers. The concurrent breast surgery with RRSO (surgery for cancer treatment or RRM, including reconstruction) increased 3.5-fold, from 19.9% to 68.9%, around 2020 among those with prior BC (p<0.001).
Discussion
This study aimed to clarify the changes associated with public insurance coverage for HBOC in Japan. The availability of public insurance coverage doubled the rate of RRSO from 31.4%16 to 62.6%; this means that the rate of risk-reducing surgery in Japan has become comparable to that in the USA and Europe. The implementation rate was 32.4% for unaffected carriers and 70.3% for BC-affected patients. The difference in these rates implies that RRSO performed on unaffected carriers was not covered by public insurance or self-payment.
Public healthcare insurance covers approximately 86% of the Japanese healthcare system. However, in principle preventive care is not covered by public insurance, and genetic testing for gBRCA is expensive—approximately US$2000. At the time of the 2018 report, it was a self-pay-only service.26 Under public insurance coverage, it is now possible to perform genetic testing for eligible cases within the Japanese Organization of Hereditary Breast and Ovarian Cancer guidelines,27 based on the National Comprehensive Cancer Network guideline13 and concurrently with BC diagnosis; RRM and RRSO can be concurrently performed with BC treatment. The copayment is 30% for public insurance coverage, and genetic testing can be inexpensive. We believe that one reason for the increased number of HBOC and RRSO cases is that these tests can now be performed as part of a series of cancer treatment procedures. Further, patient age at genetic testing has decreased, and the time intervals between BC diagnosis and genetic testing and between genetic testing and RRSO have shortened significantly.
Considering the status of HBOC treatment in some countries, in South Korea, HBOC was covered by the national health insurance from 2012. After insurance reimbursement was established, the number of HBOC diagnoses began to increase, as did the number of RRSO performed (67.5% for affected carriers and 41.8% for unaffected carriers, similar to the status in our hospital).28 The mean time from genetic testing to surgery after public insurance coverage was 7.3 months (range=0.6–33.9) in South Korea.29
In the UK, testing for gBRCA1/2 has been available since the 1990s. Within 2 years of genetic testing, 30% of the unaffected carriers aged 45 or older had an RRSO and 50% had it within 4 years30; among those aged 36–45, 50% had an RRSO within 2 years and 70% within 5 years. Even patients who initially did not want an RRSO changed their minds, later preferring RRSO; they made their surgical decision at least 7 years after the examination, suggesting the importance of long-term decision support during surveillance. Similarly, in Japan, surveillance is based on counselling about the appropriate timing of RRSO and education of relatives.
In France, the cost of cancer genetic consultations, gBRCA1/2 testing, and any subsequent medical management for people at risk are covered by the Gene Etude Prospective Sein Ovaire, which has had a gBRCA registry since 2000.17 The age at RRSO among unaffected carriers was 45.6 (28.3–72.3) years, the interval between HBOC diagnosis and RRSO was 0.75 (0.41–2.1) years,1 and the implementation rate was 15.9% among those under 40 years and 63.2% among those over 40 years.31 In the USA, the Preventive Services Task Force has been working to ensure that primary care clinicians have access to the recommended screening tools for asymptomatic women for increased risk of gBRCA1/2-PV.32 Thus, preventive medicine is recognised as important in various countries. However, the Japanese healthcare system does not provide sufficient intervention in preventive medicine.
We found a trend toward RRSO among those with a history of childbearing, menopausal status and BC diagnoses; among BC cases with a family history of OC, gBRCA1/2 status did not affect RRSO decisions. At the time of genetic counselling, amenorrhea was cited as a determinant of RRSO (OR 16.44; 95% CI, (1.16 to 232.82); p=0.038).17 Patients with iatrogenic amenorrhea with BC therapy or menopause status tended to choose RRSO.20 33 They were expected to have fewer symptoms owing to ovarian dysfunction after RRSO. The oldest patient currently being monitored is 84 years old. However, no upper age limit exists for HBOC treatment or general screening, an issue that should be addressed in future studies. The biggest obstacles to RRSO were ‘not having BC yet’ (60%),34 patients’ concerns about taking time off for work, and their worries about being unable to take care of their families during hospitalisation.35 They also wanted reassurance and encouragement before deciding on RRSO.14
The diagnosis of unaffected carriers is triggered by HBOC diagnosis in close relatives. The percentage of willingness to disclose gBRCA1/2 test results to family members was lower in reports from South Korea than in Western countries.29 34 36 Are there cultural or ethnic influences on family communication regarding genetic test results? Decision-making regarding genetics is inherently different from other cancer screenings because genetic information can directly affect both the person being tested and their biological family members. To evaluate such decisions, cultural issues and medical and legal systems must be considered. In Japan, unaffected carriers are currently diagnosed and treated at their own expense. Therefore, we encountered several dropouts due to financial reasons, even after HBOC diagnosis. However, some cases continue to receive RRSO and surveillance, even at their own expense. Hence, the precise cause of the discrepancy is unknown. When the number of probands was compared with the number of family members selected, it was clear that the diagnosis of family members was inadequate. Inequality in the use of genetic services by socioeconomic groups is an issue of further concern.
In our cohort, RRSO was performed 1–2 years after diagnosing the genetic abnormality. These results were comparable to the time intervals found in the literature.37 38 The greatest strength of this study is that it was a single-centre study conducted immediately after the introduction of public insurance coverage in 2020. However, this study has several limitations. First, it is difficult to measure the extent to which the benefits of OC risk reduction are offset by other adverse health events in Japanese women over their lifetime. Second, the results were only collected from a single institution, which could have led to a population bias. In the future, we plan to conduct an exploratory study on the reasons for selecting RRSO and surveillance among gBRCA1/2-PVs through an ongoing survey to provide decision support.
Data availability statement
Data are available upon reasonable request. The datasets generated and/or analysed during this study are not publicly available owing to ethical restrictions but are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants. This study was approved by the institutional review board of the Cancer Institute Hospital, Japanese Foundation for Cancer Research (approval number: 2010-1101) and was conducted in accordance with the principles of the Declaration of Helsinki. Participants gave informed consent to participate in the study before taking part.
References
Footnotes
Contributors AA designed the study and directed its implementation, including quality assurance and control. HN and AU helped supervised the field activities and designed the study’s analytic strategy. The other authors (AF, MY, EH, HA, KK, YM, HI, TU and HK) helped prepare the text. Guarantor: AA.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.