Medical practices for hereditary breast and ovarian cancer（HBOC）have been partly covered by public medical insurance in Japan．BRCA1 or BRCA2（BRCA1/2）genetic testing, surveillance, risk-reducing mastectomy（RRM）and risk-reducing salpingo-oophorectomy for BRCA1/2 pathogenic variant carriers for all patients with ovarian cancer and some patients with breast cancer are approved under national health insurance in 2020. However, relatives among HBOC pedigree and BRCA1/2 pathogenic variant carriers who do not have breast cancer or ovarian cancer are not covered by public health insurance. Furthermore, clinical application of multi-gene panel testing（MGPT）is an urgent issue.

　In Japan, the number of genetic medical management for BRCA1/2 pathogenic variant carriers is increasing due to the appearance of PARP inhibitors and partial insurance coverage of BRCA1/2 genetic medicine for patients with breast cancer and ovarian cancer. On the other hand, in Europe and the United States, multigene panel testing has become the mainstream of genetic testing. As a result, diagnosis and genetic medicine for various hereditary cancer syndromes have been initiated. Against this background, as the next step in medical treatment for hereditary breast and ovarian cancer syndrome (HBOC), I will discuss the five challenges (purpose, target, gene, risk management, education) to aim for in Japan as well,with evidence from overseas.

　It is known that 1-3% of BRCA1 pathogenic variant carriers and 2-7% of BRCA2 pathogenic variant carriers develop pancreatic cancer in their lifetime. Recruitment and surveillance of hereditary or familial pancreatic cancer families as high-risk individuals for pancreatic cancer using magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic ultrasonography (EUS), showed to improve the early detection rate and overall survival rate of pancreatic cancer. Therefore, the Hereditary Breast and Ovarian Cancer syndrome (HBOC) Clinical Guideline 2021 recommends pancreatic surveillance for patients with a strong family history of pancreatic cancer or with pathogenic variants of a total of 10 genes including BRCA1/2. In April 2021, the HBOC Center was established by seven departments of Obstetrics and Gynecology, Gastroenterological Surgery （Breast, Hepatobiliary and Pancreas), Urology, Center for Medical Genetics, and Oncology Center, and since October 2021, the department of dermatology, psychiatry and neuroscience have also joined the center, which now operates as nine departments. Pancreatic surveillance has been performed by MRCP or EUS once or twice a year, and we focus on intraductal papillary mucinous neoplasm （IPMN), a precancerous lesion of pancreatic cancer detected during the surveillance, in order not only to explore the risk and interaction of environmental and genetic factors, but also to work on early detection and prevention before IPMN becomes malignant. Furthermore, in January 2021, the germline BRCA1/2 genetic testing for pancreatic cancer as well as breast and ovarian cancer will be covered by insurance as a companion diagnosis to poly ADP-ribose polymerase （PARP) inhibitors, and the test is becoming widely used in our hospital for pancreatic cancer patients, but the indication is still limited only to metastatic pancreatic cancer and insurance has not been covered for HBOC diagnosis or pancreatic cancer surveillance. We believe that it is essential to promote BRCA1/2 genetic testing, as well as genetic counseling, for prevention and early detection of pancreatic cancer in high-risk individuals as well as HBOC syndrome.

　Hereditary breast and ovarian cancer syndrome （HBOC） is one of hereditary tumor patients whose fertility is a problem. This disease is characterized by the onset of early-onset breast cancer， and it causes great conflict for patients in trying to balance both cancer treatment and pregnancy， both of which are time-constrained. Embryo cryopreservation， oocyte cryopreservation， and ovarian tissue cryopreservation are considered as possible fertility preservation treatment for HBOC patients with cancer. However， there are concerns about reduced ovarian reserve in patients with HBOC， and the debate is still ongoing. Currently， in Japan， evidence regarding fertility preservation treatment being reported. Especially in HBOC patients， it is essential to accurately assess individual patient's ovarian reserve and implement optimal fertility preservation treatment.

　Our hospital established a "Hereditary Cancer Clinic" in 1991, and has been providing genetic testing and counseling for hereditary cancer diseases including HBOC for over 30 years. Since the genetic testing for BRCA genes and risk-reducing surgeries for HBOC became covered by the National Health Insurance in April, 2020, it has been essential in clinical practice not only for definitive diagnosis of HBOC but also for the selection of surgical procedures including those for risk-reduction. It has a significant impact on the choice of therapeutic agents for recurrent breast cancer, advanced ovarian cancer, prostate cancer, pancreatic cancer have also been greatly affected. Currently, however, we can provide only limited supports for genetic problems.

　Our hospital is located in Koriyama City,Fukushima Prefecture, and has established a collaborative system for genetic testing and counseling, with 1 clinic and 5 hospitals in the vicinity. Since genetic testing for BRCA genes became covered by the health insurance system, it was performed in 258 patients from 247 families (4 cases were referred from outside hospitals). 27 patients from 24 families have been identified to carry pathogenic variants in BRCA1/2 genes. In order to provide medical care for hereditary tumors in rural areas without regional disparities, it is necessary not only to operate a collaborative system but also to educate medical professionals involved in breast cancer treatment about hereditary tumors.

　Although the location of BRCA1/2 gene mutations and the pathophysiology that results have been widely reported, there are still many unknowns. Early detection of the lesions and measures taken may contribute to an improved prognosis, especially in the life-threatening state, where treatment options are limited and the prognosis is grim. In this report, we describe two cases of early brain metastasis, including the clinicopathological features.

　Case 1 was a 42-year-old woman with bilateral breast cancer who had undergone preoperative chemotherapy. Postoperative BRACAnalysis® showed BRCA1 c. 5558A≠G (p. Tyr1853Cys). One year after surgery, metastases appeared in the brain, lung, and kidney. After whole-brain irradiation, the patient was treated with olaparib, but she became progressive and passed away 1 year and 5 months after breast cancer surgery.

　Case 2 was a 40-year-old woman who underwent surgery after preoperative chemotherapy for left breast cancer, and BRACAnalysis® showed BRCA1 c. 5278-1G>A. Brain metastasis appeared 11 months after surgery, and she underwent craniotomy and radiation, but died 1 year and 3 months after breast cancer surgery. Both cases were PD-L1 positive. At present, there are no known factors that predict early brain metastasis, and further search for surveillance is important for early detection of metastasis and appropriate treatment.

　The patient is a 70-year-old man. His younger brother had Stage IV male breast cancer, and a companion diagnostic of a PARP inhibitor was performed at another hospital. The result showed that the younger brother had a pathogenic variant of BRCA2. The patient was informed by his younger brother that he was a carrier of a pathogenic variant of BRCA2. However, the patient lived far away from his younger brother and did not go for genetic counseling. Three years later, the patient noticed a lump under the skin on the outside of the right areola. Consequently, he visited his family doctor. However, at that time, he did not inform the doctor about his family history of breast cancer and the genetic test result of his younger brother. The doctor decided to follow up on the lump. The size of the lump at the right breast continued to increase. Thus, four months later, the patient visited his family doctor again. At this time, he told the doctor that his younger brother, three years earlier, had breast cancer and a gene mutation deeply related to breast cancer. At this point, the doctor referred him to our department of breast surgery. The lump was diagnosed as right breast cancer by core needle biopsy. Total right mastectomy and sentinel lymph node biopsy were performed, and the final pathological diagnosis was pT2N1M0 pStage IIB breast cancer. We report a case of delayed diagnosis of male breast cancer without informing family history of male breast cancer with BRCA2 pathogenic variant.

　We report a case of breast cancer in the nipple-areola component after Nipple-sparing mastectomy（NSM） with a pathogenic variant of BRCA2. The patient was a 49-year-old woman. At the age of 33, she underwent NSM and axillary dissection for left breast cancer pT3N1M0 Stage ⅢA, and the resection margins were negative. At the age of 43, she underwent NSM for right breast cancer pTisN0M0 Stage 0. At the age of 49, she came to hospital because she was aware of a mass just below the left nipple. A hypoechoic mass of 5.3 mm in size was found on ultrasonography, and left breast cancer was diagnosed by excisional biopsy. A total excision including the left nipple and areola was performed as a radical surgery. Genetic testing performed due to 3 breast cancers under age 50. The results of the genetic testing showed that pathogenic variant of c.9076C>T (p.Gln3026*) in BRCA2.

　NSM is also performed in the treatment of cancer in patients with HBOC. Reports of therapeutic NSM for HBOC cases are fewer than reports of NSM for sporadic breast cancer cases, but there have been no reports of recurrence in the nipple-areola component for HBOC cases. However, the observation period of most of these reports is short (2-5 years), and there is a possibility that breast cancer may develop in HBOC after a long period of time after surgery, as in this case, so long-term accumulation of cases is necessary.

　For breast cancer patients with suspected hereditary breast and ovarian cancer, our institution has established an outpatient genetic counseling clinic since 2015, where genetic counseling and testing are provided after pre-counseling. We encountered a patient who did not prefer to undergo genetic testing; however, showed a pathogenic variant in the results of a later genetic test. This experience reminded us of the importance of follow-up. Therefore, we examined the background and follow-up status of patients who did not prefer to undergo genetic testing and discussed recommended follow-up after pre-counseling. Eighty-eight percent of the patients did not wish to undergo genetic testing, and the top three most common reasons included psychological burden, impact on blood relatives, and financial burden, respectively. Nine patients were actually followed up. The trigger for follow-up was a prior appointment to confirm intent for genetic testing and a non-genetic related consultation. Based on our experiences, follow-up after pre-counseling should establish policies and standards at the facility. Additionally, it would be useful to have someone like the HTC who connects genetic medicine and breast cancer care to help facilitate collaboration within and outside the institution.