Introduction

Hereditary breast and ovarian cancer (HBOC) is among the most common hereditary tumors and is known to be inherited in an autosomal dominant form, involving the BRCA1 and BRCA2 genes [1, 2]. The percentage of BRCA gene pathological variant carriers in the general Japanese population is reportedly 0.21% [3]. The efficacy of Poly (ADP-ribose) polymerase (PARP) inhibitors in the treatment of patients with cancer with known BRCA pathological variants has resulted in the use of the BRCA gene as a companion diagnosis [4,5,6,7]. Following the Food and Drug Administration’s approval of PARP inhibitors (Olaparib) for treating ovarian cancer in 2014, the drug was initially covered by public insurance in Japan in April 2018 for recurrent ovarian cancer, followed by the extension of coverage to inoperable or recurrent breast cancer, metastatic prostate cancer, and pancreatic cancer not curatively resectable [8,9,10]. In addition, the opportunity for HBOC to be diagnosed is increasing because cancer gene panel testing has also been covered by public insurance since 2019 [11].

Risk-reducing salpingo-oophorectomy (RRSO) for BRCA pathological variant carriers has been recommended by various guidelines [9, 12], because it prevents the development of ovarian and fallopian tube cancers, prolongs overall survival [13,14,15,16,17,18,19], and reduces cancer mortality through risk-based health management by identifying genetic disposition. In April 2020, in addition to genetic counseling, surveillance, and risk-reducing surgery, BRCA genetic testing (GT) for diagnosing HBOC was also covered by public insurance for some patients with breast and all patients with ovarian cancers in Japan. Although the results of this GT for cancer diagnosis and treatment is expected to lead to future diagnoses of HBOC, as well as an increase in blood-relative diagnoses, public insurance coverage is currently limited to patients with breast and ovarian cancer. Those without cancer are currently forced to pay their own expenses [20]. This study examined the current status of RRSOs in Japan and the impact of public insurance coverage by determining behavioral changes before and after public insurance coverage in April 2020.

Materials and methods

Study registration

The data used in this study were obtained from data registered with the Japanese Organization of HBOC (JOHBOC) [21]. JOHBOC has a nationwide database based on families that have undergone BRCA GT. In the JOHBOC database, medical institutions register probands that received BRCA1 and/or BRCA2 GT and their relatives. Any purposes for GT are acceptable, including for clinical practice and translational research. Almost all GT, including sequence and large rearrangement analysis, is performed at Myriad Genetic Laboratories or FALCO Biosystems. The detected variants are interpreted according to the criteria followed at Myriad Genetic Laboratories. Previous studies have outlined details regarding the registration procedures [22, 23]. They have also identified relevant factors related to HBOC and given recommendations to women with HBOC in the guidelines. This study used the following data: number of germline BRCA1/2 mutants; number of RRSO; duration from GT to RRSO (comparing before and after insurance coverage); number and age of patients with first-time breast cancer who underwent RRSO; breast cancer onset and timing of RRSO; duration to RRSO divided by breast cancer onset age; timing of RRSO and risk-reducing mastectomy (RRM) for breast cancer patients; background of clients who received GT (comparing before and after insurance coverage); and RRSO rate (comparing before and after insurance coverage).

Informed consent was obtained from all participants at the time of enrollment in JOHBOC. In cases where informed consent could not be obtained in person, such as those wherein treatment had been completed or the patient had died, the candidate or the candidate’s family could opt out of the JOHBOC and each participating institution’s website. All patients received genetic counseling and GT of their own free will. Informed consent for this study disclosed that the study was being conducted with opt out as designated by a paper on the JOHBOC website.

To analyze how each survey item was affected by insurance coverage as of April 2020, when HBOC treatment was included under insurance coverage in Japan, the period from March 2006 to March 2020 was defined as pre-insurance coverage (Pre), and that from April 2020 to August 2021 was defined as post-insurance coverage (Post). As this study compared the impact of insurance coverage on RRSOs, the difference between Pre (14 years) and Post (1 year and 5 months) were considered significant. To establish a period equivalent to Post when assessing the impact of insurance coverage, the short period before insurance coverage (short-Pre) was defined as the 2 years immediately preceding April 2018 to March 2020. For each period, the applicable cases were those that underwent GT and RRSO within that period.

Statistical analyses

A two-sample t-test was conducted to compare the means of the two groups. Regarding the categorical variables, a chi-squared test was conducted as a test of independence. Additionally, a Wilcoxon rank sum test was performed to compare the two groups’ medians. Further, a Kruskal–Wallis rank sum test was used to compare the medians of the three groups. A two-sample test for equality of proportions was conducted to compare the proportions of two groups. Considering the small sample size and low frequency of events, statistical analysis was performed using Fisher’s exact test to compare the proportions between the two groups. The significance level was set at α = 0.05. All statistical analyses were performed using R programming version 4.1.2 (R Development Core Team, Vienna, Austria).

Results

A total of 13,642 women who had undergone BRCA GT between March 2006 and August 2021 were included in JOHBOC. Of the 2605 pathogenic variants, this study included 544 cases of either BRCA1 or BRCA2 variants that underwent RRSO. Among them, 299 RRSOs were performed from March 2006 to March 2020 and 220 from April 2020 to August 2021, except for 25 cases for which the date of examination or the date of RRSO was unknown. Ultimately, 508 cases were included, excluding 11 cases that received GT after the RRSO date (Fig. 1). First, we analyzed the “background factors influencing the decision to conduct an RRSO” for the entire study period, and then compared the “impact of insurance coverage on RRSO” before and after public insurance coverage was applied to RRSO.

Fig. 1
figure 1

Flowchart of selection of eligible studies

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Duration from GT to RRSO

For the period March 2006 to August 2021, the median time from GT to RRSO for all cases was 0.66 years (15 days to 18.5 years) (Supplementary Fig. S1). When BRCA1 and BRCA2 were examined separately, BRCA2 tended to have a shorter time from GT to RRSO (Wilcoxon rank sum test, p = 0.05) (Fig. 2).

Fig. 2
figure 2

Duration from GT to RRSO for BRCA1 and BRCA2, respectively

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Breast cancer onset and timing of RRSO

Of the 508 patients who had undergone RRSO after GT, 476 (93.7%) had breast cancer. Regarding the timing of RRSO, RRSO was performed in intervals after breast cancer surgery (more than 2 weeks) in 414 cases (87.0%), and at approximately the same time as breast cancer surgery (within 2 weeks) in 57 cases (12.0%). Additionally, four patients (0.8%) developed breast cancer after RRSO and were operated on, and one patient (0.2%) had not provided details on the timing.

Duration to RRSO divided by breast cancer onset age

This survey was conducted between March 2006 and August 2021. The median time to RRSO was 8 years for individuals <40 years, 3 years for those 40–50 years, and 2 years for those ≥51 years, indicating that the time to RRSO was longer for younger age groups (<40 years) at breast cancer’s first onset (Kruskal–Wallis rank sum test, p < 0.001) (Fig. 3).

Fig. 3
figure 3

Duration to RRSO divided by breast cancer onset age

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Timing of RRSO and RRM for breast cancer patients

The timing of surgery in the 127 cases in which both RRSO and RRM were performed was evaluated. Of these, 69 cases (54.3%) had both procedures performed within a 1-month interval, 31 cases (24.4%) had RRSO followed by RRM, and 27 cases (21.3%) had RRSO followed by RRM. The majority of patients underwent simultaneous RRM and RRSO. Details of the timing of surgery are shown in Supplementary Table S1, pre and post, BRCA1 and BRCA2, respectively.

Impact of insurance coverage on GT

This study compared a 2-year period from April 2018 to March 2020 (short-Pre) with a 1-year and 5-month period from April 2020 to August 2021 (Post). Table 1 presents the participants’ backgrounds. No significant differences in background were identified in short-Pre and Post, including the ratio of BRCA1 and BRCA2, average age at GT, age groups at GT, and history of cancer. However, significant differences were identified in the purpose for GT (multiple choice): chemotherapy options (p < 0.01) and research (p < 0.01) were often the purpose for GT in short-Pre, whereas individuals’ healthcare (p < 0.01) and surgical decisions (p < 0.01) were often the purpose for GT in Post. No difference was identified in family purpose between short-Pre and Post (P = 0.21).

Table 1 Background of clients who received GT
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RRSO rates before and after insurance coverage

Of the 641 patients who underwent GT in short-Pre, 383 breast cancer patients were included, excluding ovarian cancer patients and those who underwent RRSO during Post. Similarly, of the 913 patients who underwent GT in Post, 623 breast cancer patients were included, excluding ovarian cancer patients and those who underwent RRSO at or below the recommended age (35 years for BRCA1 and 40 years for BRCA2). A significant difference was observed between the two groups (two-sample test for equality of proportions, p < 0.01). Furthermore, RRSO rates at Post increased significantly when BRCA1 and BRCA2 were evaluated, respectively (two-sample test for equality of proportions, p < 0.01 for BRCA1 and BRCA2). In addition, the cases of no breast cancer and no ovarian cancer were also examined. Contrary to breast cancer patients, the RRSO rate was significantly higher (p = 0.03) for short-Pre among these cases (Table 2).

Table 2 “Breast cancer patient” is evaluated by 2-sample test for equality of proportions, but ‘No Breast cancer and no Ovarian cancer’ is evaluated by Fisher 's exact test
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Duration from GT to RRSO before and after insurance coverage

There were no significant differences in median time from GT to RRSO t before and after insurance coverage (Short-Pre: Median (Q1,Q3) = 177.5 (108.8,251.0) IQR = 142.2, Post: Median (Q1,Q3) = 143 (93.3,215.3) IQR = 122. Wilcoxon rank sum test, p = 0.11).

Discussion

HBOC practice aims to reduce mortality from related cancers by identifying patients’ genetic makeup and providing risk-based healthcare [24, 25]. This study suggests that the prognosis can be improved by performing GT on appropriate individuals and promoting treatment, prevention, and surveillance suited to their constitutions. However, the environment in Japan is not yet conducive to providing RRSO to all applicants. In April 2020, RRSO and RRM was added to coverage for some patients with breast cancer and for all patients with ovarian cancer. This was a major paradigm shift; however, many eligible patients who wish to undergo risk-reducing surgery, including those who have not yet developed the disease, must pay their own high expenses [21]. Although psychosocial factors such as cultural norms, social values, and the attitudes of healthcare providers are intricately involved in RRSO decision-making [26], this study evaluated the status of RRSO and examined the impact of insurance coverage by reviewing data before and after insurance coverage. One of this study’s strengths was that the analysis was based on a Japanese nationwide database in JOHBOC.

This study first examined the entire period from GT to RRSO (March 2006 to August 2021), during which time HBOC practice in Japan changed significantly. For most of this period, RRSO was expensive, with a median time from GT to RRSO of 241 days (0.66 years) (Supplementary Fig. S1). When BRCA1 and BRCA2 were examined separately, BRCA2 showed a trend toward a shorter time from GT to RRSO (Wilcoxon rank sum test, p = 0.05) (Fig. 2). By contrast, to examine the impact of insurance, short-Pre and Post were compared separately, but there was no significant difference in the time from GT to RRSO.

In breast cancer patients, the RRSO implementation rates before and after insurance coverage were examined separately for short-Pre and Post, the short-Pre RRSO implementation rate was 11.0% and the Post RRSO implementation rate was 22.8%, revealing a considerable difference. The same was true when RRSO rates were examined separately for BRCA1 and BRCA2, with significantly increased RRSO rates in Post. We simultaneously added data for those with no breast cancer and no ovarian cancer and found that the RRSO rate was higher for short-Pre with a significant difference (Table 2). As a result, breast cancer patients whom RRSO could be performed by insurance had significantly higher RRSO rates in Post. Additionally, those with no breast cancer and no ovarian cancer whom RRSO was not covered by insurance, had significantly higher RRSO rates in short-Pre. It is unclear why the RRSO rate was higher for short-Pre in those with no breast cancer and no ovarian cancer, but the rate did not increase after insurance coverage. Thus, if breast cancer patients are considered the insured group and those with no breast cancer and no ovarian cancer are considered the co-payments group, the decrease in co-payments could have led to an increase in the rate of RRSO implementation.

This study also examined the background of clients tested during short-Pre and Post (Table 1). Significant differences between the short-Pre and Post periods were found regarding the purpose of GT. The common objectives for being tested during short-Pre were chemotherapy options and research, while the common objectives for undergoing GT during Post were healthcare of the individual and surgical decision. The reason that chemotherapy options were often selected as the purpose of GT during short-Pre was presumably because BRCA had been used as a companion diagnosis for breast and ovarian cancer in Japan since 2018. Additionally, this study suggested that the reason for undergoing GT during short-Pre was often research, to avoid the high private expenses. However, the significant increase in GT during Post due to the healthcare of the individual and surgical decision may be due to the inclusion of insurance coverage in 2020. If insurance coverage of BRCA is expanded to cancer-naïve clients in the future, more individuals are expected to request GT. One bias to consider, as Table 1 shows, is the occurrence of chemotherapy after breast cancer surgery in some cases. It is inferred that there are cases where the Post has received GT but not yet received RRSO because the Post period was of a short duration.

Since patients who request RRSO are often assumed to be breast cancer patients, this study examined the association between breast cancer patients and RRSO. In this study, 93.7% of the patients who underwent RRSO were breast cancer patients; 87.0% of breast cancer patients underwent RRSO at a different time from breast cancer surgery. RRSO is covered by insurance now, and the number of cases in which RRSO is performed simultaneously with breast cancer surgery may increase in the future [27].

When the time from breast cancer onset to RRSO was compared separately by age of breast cancer onset, the time for patients younger than 40 years tended to be significantly longer (Fig. 3). Additionally, unique circumstances of young adults (<40), such as pregnancy, childbirth, and childcare, may also result in a longer interval before RRSO. However, in the group of patients <40 years of age, who are presumed to be economically disadvantaged, the period may be shortened in the future owing to the introduction of insurance treatment. The European Society for Medical Oncology (ESMO) guidelines generally recommend that RRSO should be performed between 35 and 40 years of age, while the National Comprehensive Cancer Network (NCCN) guidelines recommend it between 35 and 40 years of age for BRCA1 and between 40 and 45 years of age for BRCA2. In the group of patients <40 years of age, the time to RRSO is expected to be longer if the disease occurs at a younger age. As RRSO and RRM were expensive procedures before insurance coverage, the timing of each risk-reducing procedure was evaluated. In this study, both RRSO and RRM were performed in 127 cases, with over half of these cases opting for simultaneous RRSO and RRM. Performing both procedures simultaneously when they were not covered by insurance would have required the patient to pay a high out-of-pocket cost at once. If insurance coverage becomes available in the future, it is expected that more and more patients will request both surgeries simultaneously (Supplementary Table S1).

In conclusion, this nationwide study shows that insurance coverage of RRSOs in Japan has increased the RRSO implementation rate. Due to the short period of time since the RRSO was covered by insurance only for patients with some indications in this study, data are insufficient to show future trends. However, as the number of cases increases in the future, the impact of insurance coverage will become clearer. If the usefulness of insurance coverage for RRSOs is found in Japan, we hope that this information will be used to expand insurance coverage for those who have not yet developed the disease.