Six years have passed since the publication of the “2019 Clinical Practice Guidelines for Li-Fraumeni Syndrome, Version 1.1.” During this period, awareness of Li-Fraumeni syndrome (LFS) has increased in Japan, partly due to the expansion of cancer genomic medicine and improved access to TP53 genetic testing. Internationally, clinical guidelines, including those addressing surveillance, have also been updated. In this revision, the Japanese Society for Hereditary Tumors has assumed the lead role in developing the guidelines. While retaining the basic principles of the first edition, we added new Clinical Questions (CQs) on breast cancer, gastrointestinal tumors, lung cancer, malignant bone and soft tissue tumors, and brain tumors, as well as new Background Questions (BQs) on genetic counseling. Although the rarity of LFS limits the available evidence, we provide recommendations and explanatory text to support clinical decision-making, with consideration of international guidelines and the feasibility of implementation in Japan. We hope that these guidelines will be used to explain LFS to patients and their families, guide treatment planning, and contribute to the implementation of preventive oncology for individuals with LFS.

　In this study, we retrospectively examined treatment strategies and clinical outcomes in 139 women with breast cancer harboring BRCA1/2 pathogenic variants at a single institution. Patients diagnosed on or before March 31, 2020 were classified as the earlier era, and those diagnosed on or after April 1, 2020 as the later era. Surgical procedures, contralateral breast surgery, MRI surveillance, risk-reducing mastectomy (RRM), and risk-reducing salpingo-oophorectomy (RRSO) were recorded. Overall survival was assessed using the Kaplan–Meier method, whereas distant recurrence and metachronous contralateral breast cancer were evaluated using competing risk analysis with death as a competing event. No significant difference was observed in the cumulative incidence of distant recurrence between the two eras. However, patients with Stage Ⅱ-Ⅲ disease had a higher risk of distant recurrence than those with Stage 0-Ⅰ disease, and this difference was significant in the later era. A trend toward a higher risk of distant recurrence was also observed in triple-negative breast cancer and BRCA1-associated cases in the later era. Ipsilateral breast events after breast-conserving surgery occurred in 17.6% of cases, most of which were lesions arising in different quadrants after long-term follow-up. These findings suggest that distant recurrence is influenced more strongly by disease stage and tumor biology than by surgical procedure itself.

　We conducted a survey on the health management practices of individuals who are unaffected carriers with BRCA1 or BRCA2 pathogenic variants, to examine factors that promote or inhibit improvement in health behaviors.

　The survey targeted clients with a history of visits to University Hospital or cancer specialty hospital, and blood relatives of HBOC support group members.

　Among 36 individuals diagnosed with HBOC who had not developed cancer, 34 (94％ of all respondents) were undergoing or planned to undergo regular surveillance. For breast cancer surveillance, the implementation rate for breast MRI examinations was 66.7％, and 51.9％ were performing the examinations recommended surveillance protocols based on Japanese HBOC guidelines.

　For unaffected carriers with BRCA1 or BRCA2 pathogenic variants the promoting factors for promoting health behaviors were the results of BRCA genetic testing and recognition of the benefits of health behaviors, whereas disincentive factors were economic burden, time burden, and lack of the recognition of the importance for appropriate management. In order to improve health behavior, one strategy involves continued information to confirm the benefits of healthy behaviors and enhance awareness of them.

　This study aimed to clarify the psychosocial burden, informational needs, and health-related quality of life (QOL) of patients with Peutz-Jeghers syndrome, juvenile polyposis syndrome, and Cowden syndrome/PTEN hamartoma tumor syndrome, as well as their families. A web-based questionnaire survey was conducted between January 2023 and December 2024. Data from 39 responses were analyzed using descriptive statistics and the Japanese standard version of the SF-12v2.

　Patients frequently reported anxiety about future disease progression, concerns about having children, and difficulties in communicating hereditary risks to family members. These concerns affected major life decisions, including marriage, reproduction, and family relationships. Families also experienced difficulties in supporting children who were reluctant to undergo examinations and in explaining the disease and heredity to them.

　High informational needs were identified regarding financial assistance, lifestyle measures to reduce cancer risk, communication with partners and children, endoscopic discomfort management, transitional care, and genetic counseling. SF-12v2 results showed that physical health was relatively preserved, whereas the role/social component summary score was lower than the national norm. The vitality subscale was also reduced, suggesting decreased energy and activity.

　These findings indicate that patients with hereditary gastrointestinal hamartomatous polyposis syndromes experience substantial psychosocial burdens despite relatively preserved physical QOL. Comprehensive support should include multidisciplinary medical collaboration, accessible information provision, genetic counseling, financial support, and psychosocial care addressing life events such as marriage and reproduction.

Background : The risk of contralateral breast cancer (CBC) among breast cancer survivors with pathogenic BRCA1/2 variants varies according to clinical factors such as age at first cancer, yet evidence in Japanese populations remains limited. Understanding CBC risk in this population is essential for counseling and preventive decision making.

Methods : We analyzed 56 Japanese patients with pathogenic BRCA1/2 variants who had undergone surgery for primary breast cancer more than 5 years earlier. Patients were classified into CBC (n=17) and non CBC (n=39) groups, and clinical and treatment related factors were compared. Risk stratification was explored by counting the number of risk factors present.

Results : Younger age at first breast cancer (<40 years) was more common in the CBC group, whereas lymph node positivity, receipt of chemotherapy, and risk reducing salpingo oophorectomy (RRSO) were more frequent in the non CBC group. Longer endocrine therapy duration (≥5 years) also tended to be more common in the non CBC group. CBC incidence increased progressively with the number of risk factors. In a time fixed Cox model, absence of chemotherapy and absence of RRSO were independently associated with CBC. Because RRSO is performed during follow up, its timing could not be modeled, representing a methodological limitation. These findings highlight the importance of treatment history and preventive interventions in CBC risk.

Conclusions : Multiple clinical factors were associated with CBC development, and combining these factors enabled practical risk stratification. This study provides foundational evidence for developing individualized CBC risk prediction models tailored to Japanese patients with pathogenic BRCA1/2 variants.

　The Tohoku region includes six prefectures with vast geographic areas and is characterized by a relatively low population density compared with other regions of Japan. This situation similarly affects healthcare professionals and specialists in genetic medicine. To compensate for the limited human resources, cross-prefectural mobility and collaboration are often required. In this article, we describe the activities of two networks that were established and developed in the Tohoku region under these circumstances. The Tohoku Familial Tumor Association was established in 1997 with the primary aims of raising awareness and providing education on familial tumor research among general clinicians, promoting collaborative research, coordinating and facilitating genetic testing for familial tumors, and offering genetic counseling to clients. The Genetic-Hand was launched in 2015 as a platform to provide peer support for individuals with pathogenic variants concerning hereditary tumors. To advance the clinical practice and research of familial and hereditary tumors, networks are essential for both healthcare professionals and patients.

　Breast cancer with pathogenic variants in germline BRCA2 (gBRCA2) has been reported to show distinct clinicopathological features compared with breast cancers without pathogenic variants. Estrogen receptor (ER)-positive breast cancer with gBRCA2 pathogenic variant (PV) is often characterized by relatively low ER expression and reduced sensitivity to endocrine therapy. We report a case of a woman in her 50s with bilateral breast cancer carrying a gBRCA2 PV who underwent surgery following neoadjuvant chemotherapy. Despite postoperative radiotherapy and endocrine therapy, she suddenly developed dyspnea and fever at an early postoperative stage. Though computed tomography revealed massive right pleural effusion, no malignant cells were detected cytologically. During hospitalization, nodular lesions suspicious for metastases rapidly appeared in the lung, liver, and abdominal wall. Biopsies of these metastatic lesions confirmed the recurrences of ER-negative breast cancer. Disease progression remained rapid despite the initiation of olaparib, and the treatment strategy was subsequently shifted to palliative care.

　For further examination of the potential association between this aggressive clinical course and functional decline of BRCA2 protein, we retrospectively reviewed 17 cases with gBRCA2 PV treated with neoadjuvant chemotherapy at our institution. We found biological changes in ER or HER2 expression in 5 cases out of 11 cases with residual tumors after chemotherapy. Such biological characteristics may be associated with aggressive disease behavior in gBRCA2-positive breast cancer. These findings suggest that early re-biopsy and timely reassessment of treatment strategy is very important during clinical course, particularly in cases showing rapid disease progression.

　Three sisters developed early-onset breast cancer. After confirmation of negative BRCA1/2 genetic testing, multigene panel testing identified a TP53 missense variant (c.643A>G p.Ser215Gly). Although this variant was initially classified as a variant of unknown significance, it was managed clinically as suspected likely pathogenic based on functional analyses and an expert panel review. As a result of cascade testing and surveillance among relatives, breast cancer in the youngest sister was detected at an early stage. The TP53 variant was subsequently reclassified as likely pathogenic.

　Li-Fraumeni syndrome (LFS) carries a high risk of multiple primary malignancies in various organs, including breast cancer. Therefore, patients with LFS require lifelong surveillance, such as whole-body MRI, and experience substantial associated psychosocial and economic burdens. This case reaffirms the necessity of careful interpretation of variant of unknown significance findings and the need for comprehensive support, including for family members with potential LFS.