The number of individuals affected with breast cancer has increased globally. In Japan, 89,400 females were newly diagnosed with breast cancer and there were 13,800 mortalities attributed to this disease in 2015 (1). Approximately 20% of breast cancer patients have a family history and 5–10% (2,3) are considered to be hereditary (hereditary breast cancer) HBC caused by a germline mutation such as BRCA1, BRCA2, TP53 or PTEN. Mutations in BRCA1/2 genes are associated with hereditary breast and ovarian cancer syndrome (HBOC), which is the most common form of HBC. It is also known that germline mutations of DNA mismatch repair (MMR) genes, such as MLH1, MSH2 and MSH6 are caused by Lynch syndrome, which is a hereditary colorectal cancer syndrome, and MLH1 particularly increases the risk of breast cancer (4).

Women with HBOC have a 41–90% lifetime risk of developing breast cancer (5) and HBOC is characterized by the high risk of contralateral breast cancer (6). In addition, the cumulative risk for ovarian cancer is 8–59% and is higher in BRCA1 mutation carriers compared with BRCA2 mutation carriers (5–7). It was revealed that triple-negative breast cancer, which is estrogen receptor/progesterone receptor-negative and human epidermal growth factor receptor 2, negative was associated with HBOC and that 36% of women with early-onset triple-negative breast cancer (aged <40 years) had a BRCA1 mutation and 27% of women with triple-negative breast cancer diagnosed before the age of 50 years had a BRCA1 mutation (8). Male BRCA1/2 mutation carriers are also at increased risk of cancer. The cumulative risk of breast cancer is 1.2% in male BRCA1 mutation carriers and 6.8% in male BRCA2 mutation carriers (9), and the risk of prostate cancer of BRCA2 mutation carriers is increased to ~3 times higher than that of the general population (10,11). Owing to the early onset and susceptibility of multiple cancer associated with HBOC, the importance of surveillance from a younger age has been emphasized (12). For female carriers of a BRCA1/2 mutation, a monthly breast self-examination from the age of 18, an annual breast MRI or mammography between the ages of 25 and 29 and an annual breast MRI and mammography over 30 years of age are recommended. However, the usefulness of surveillance programs for cancer risks is not clear, and an appropriate screening method has not been established. Therefore, once a BRCA1/2 mutation is identified in cancer patients and their families, the option of the risk reducing mastectomy (RRM) and the risk reducing bilateral salpingo-oophorectomy (RRSO) must be considered. In the retrospective study, the 20-year survival rate for females with a BRCA1/2 mutation who underwent contralateral prophylactic mastectomy was 88% and for those who did not was 66% (13). Also, the results of meta-analysis revealed that RRSO reduced ovarian cancer risk by 80% and breast cancer risk by 50% in female BRCA1/2 mutation carriers (14). Furthermore, in a short-term follow-up study, RRSO reduced breast cancer-specific mortality by 90%, and gynecologic cancer-specific mortality by 95% and overall mortality by 76% (15). In addition, the use of the oral poly ADP-ribose polymerase inhibitor Lynparza™ (olaparib) for patients with advanced ovarian cancer with a BRCA1/2 mutation was approved by the FDA in December 2014. Although the clinical trial for this drug has not yet been completed in Japan (16), it may become a promising new drug for patients with BRCA1/2-associated cancer once approved.

The frequency of variants of uncertain significance (VUS) on the BRCA1/2 gene was 2–6 % in the Caucasian population in the US (17,18) and this frequency is thought to be greater in other countries with varying ethnic backgrounds due to the small number of patients undergoing BRCA1/2 testing. Therefore proper assessment of VUS has become a major issue in clinical genetic testing. Furthermore, previous studies have demonstrated that BRCA1/2 mutation-negative patients harbored deleterious mutations in moderate-risk cancer genes such as CHEK2, ATM, and PALB2 and MMR (19,20). Despite an increasing number of HBC testing facilities, there is little information available regarding attitudes towards precision medicine for HBC in Japan.

In the past few years, the awareness of HBC in Japan has rapidly grown, partly in reaction to the announcement of a US actress that she underwent a double mastectomy to avoid the risk of breast cancer. Nonetheless, as presented in the current study, 66.3% of facilities who responded to this survey in Japan answered that the number of clients receiving HBC-associated genetic counseling was <10 in the last year, and 24.1% answered no genetic testing was performed in the past year. As genetic screening for HBC is not covered by public health insurance in Japan, clients taking the test must pay the cost in full (~200,000 JPY). These financial burdens on patients may be one of the negative factors.

Though the pattern of occurrence of breast and ovarian cancer in a pedigree is characteristic of HBOC, a mutation in the BRCA1/2 gene may be identified in more than ninety percent of these pedigrees (21); patients with Li-Fraumeni syndrome, Cowden syndrome and Peutz-Jeghers syndrome have a higher risk of breast cancer (22–24), and MMR, CHECK2, PALB2 and ATM gene mutations also increase breast cancer risk (25). Therefore, during the genetic counseling for HBC, a risk assessment to identify the genes including BRCA1/2 that must be examined from the patterns of cancer development in probands and within a family is essential. The current survey revealed that over sixty percent of the facilities provided the BRCA1/2 test alone. As presented in Fig. 3, approximately one half (N=23, 47.9%) of the university hospitals and cancer hospitals offered only BRCA1/2 tests for HBC. The services of genetic counseling and genetic testing based on a comprehensive risk assessment of HBC may not be available in these facilities. Although the multi-gene cancer panel test is very useful to analyze the causal genes for HBC, the test has not been widely used in the Japanese clinical setting.

Another issue identified by this survey is a lack of education for health care providers, patients with cancer and their families. In particular, ~60% of the genetic counselors recognized the needs for education of medical staff. Previous studies have revealed that the physicians' recommendation and referral to genetic counseling significantly affected the patients' motivation for receiving genetic counseling (26–28). Particularly in Asia, the physician's referral was a strong motivator (26–28). Accordingly, there is an urgent requirement for the additional education of physicians regarding appropriate referrals for cancer genetics.

Furthermore, certain respondents were concerned about the lack of clinical and genetic data on HBC in Japan. Only 260 individuals with a strong family history of breast cancer at 8 institutions in Japan were recorded and analyzed regarding BRCA1/2 genes by the end of March 2012 (29). The small sample size of this study limits its clinical significance and the results of on-going study are required. Recently, the rate of VUS results among those undergoing the BRCA1/2 genetic testing in the US has decreased 2.1% from 13%, which was accomplished by numerous efforts directed to the determining the pathogenicity of variants in over one million samples tested over 20 years (18). Therefore, accumulation of data from the Japanese population is essential for effective use of genetic testing.

The overall interpretation of VUS is currently reported in 2.1% of patients undergoing genetic analysis for HBOC at Myriad Genetic Laboratories (9,10). This represents a decline from around 13% over the past decade. The dramatic decline in the percentage of patients receiving a VUS result reflects the impact of targeted efforts directed at determining the pathogenicity of variants, as well as the availability of data from an increased number of individuals undergoing testing for HBOC (10).

When a mutation is identified in patients and their unaffected family members, they are provided the option of RRM and RRSO in order to reduce future risk of cancer. However, as presented in Table II, RRM and RRSO are not available in the majority of the facilities in japan. The current study indicates that a comprehensive medical care system is necessary to offer a wider range of options for patients.

In conclusion, the status of genetic medicine for HBC in Japan has yet to be established. To the best of our knowledge, the present study is the first to examine the frequency of use of genetic testing, RRM and RRSO in Japan. Furthermore, the type of genetic testing was mostly limited to BRCA1/2 testing. Clinical practitioners may offer the appropriate testing corresponding to the medical history of patients and their family. The use of the multigene panel testing for HBC may be useful for patients who do not exhibit family history of various cancers other than HBOC. Therefore, the current status of genetic services and the issues regarding HBC were investigated and it was identified that clinical cancer genetics requires further development in Japan.