Analysis of the conditions for applying BRCA genetic testing to women with breast cancer using the Japanese HBOC consortium and the Japanese organization of hereditary breast and ovarian cancer (JOHBOC) registry project database.

Background: Considering past research in Europe and the USA, the conditions for medical insurance coverage of BRCA1/2 genetic testing (GT) in Japan have been established as follows: 1. Breast cancer onset at 45 years or younger age; 2. Triple-negative breast cancer (TNBC) onset at 60 years or younger age; 3. Onset of two or more primary breast cancers; 4. Family history of breast cancer, ovarian cancer, or pancreatic cancer up to the third degree; 5. Male breast cancer, 6. Ovarian, fallopian, or peritoneal cancers. However, data to determine the importance and extent of each factor in the current conditions are insufficient. Consequently, this study aimed to assess the validity of insurance coverage conditions in Japan, elucidate the relationship between these conditions, and explore the possibility of proposing new indicators.

Methods: A total of 5987 breast cancer patients were enrolled from 92 centers participating in the HBOC consortium and the JOHBOC registry project. Of these, 5904 patients were analyzed after excluding 48 male breast cancer patients due to insufficient numbers for analysis and 35 patients whose age at breast cancer onset was unknown or unregistered. We compared 1,091 cases in which pathogenic variants (PVs) (BRCA1(B1s): 543, BRCA2(B2s): 548) were detected with 4580 cases in which no variants (non-Vs) were detected. Variants of uncertain significance (VUS: 233 cases) were not classified as either PVs or non-Vs for subsequent analysis. We investigated the validity of each condition under which an HBOC diagnosis could be considered for medical insurance coverage.

Results: Regardless of the insurance coverage conditions, the detection rate of pathogenic variants (DRPV) of all analyzed cases was 19.2%. The DRPV under the insurance coverage conditions for GT-'Age of breast cancer onset ≤ 45 years,' 'TNBC onset at ≤ 60 years,' ' ≥ 2 primary breast cancers,' 'Patients with breast cancer concurrent with ovarian cancer,' and ' ≥ 1 family history of breast or ovarian cancer up to the third degree'-was 25.4%, 31.6%, 24.6%, 48.8%, and 25.6%, respectively. Those within the insurance coverage group showed a pathogenic variant detection rate of 21.1%, compared to only 5.6% outside of the coverage. Our analysis indicates that medical insurance coverage conditions effectively identify candidates for GT. Furthermore, when examining the number of conditions met and the positivity rate, the positivity rate was 11.2%, with only one condition met. This rate increases exponentially as more conditions are met, underscoring the importance of multiple matching conditions. Additionally, those with comorbid ovarian cancer or a family history of ovarian cancer are more likely to have a pathogenic variant. Additionally, we reevaluated cases who did not meet the medical insurance conditions. TNBC occurrence was significantly associated with B1s, even when restricted to onset age ≥ 61 years. Familial history of prostate cancer also significantly associated with B2s.

Conclusion: This study determined that the Japanese medical insurance coverage conditions effectively identified candidates eligible for GT. Consequently, it is imperative to disseminate information to all patients with breast cancer covered by insurance, emphasizing the opportunity for GT, particularly if they have ovarian cancer complications or a family history of ovarian cancer.