Middle-aged doctor examining BRCA1 and BRCA2 Genetic Testing

The Broadening Clinical Relevance of BRCA1 and BRCA2 Genetic Testing

The association of BRCA1 and BRCA2 gene variants with breast and ovarian cancers has been established for decades, and more recently, these variants have also been associated with prostate and pancreatic cancers. The development of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors was based on the mechanism of disease associated with pathogenetic variants in these genes, and their efficacy in prostate and pancreatic cancers has been established.

Risk for other tumor types in patients with BRCA1 and BRCA2 gene variants has been previously reported, but there is insufficient evidence to support changes to guidelines for genetic testing. To address this gap in clinical evidence, Dr Yukihide Momozawa and colleagues conducted a large-scale sequencing study in 63,828 patients and 37,086 controls from a Japanese nationwide biobank to estimate the risk of each cancer type and assess clinical characteristics associated with BRCA1 and BRCA2 pathogenic variants. Consistent with historical research, the highest cumulative risk was in breast and ovarian cancers. Interestingly, the study found that pathogenic variants in BRCA1 were also significantly associated with increased risk of biliary tract, gastric, and pancreatic cancers, and pathogenic variants in BRCA2 were associated with increased risk of gastric, pancreatic, prostate, and esophageal cancers. The authors also observed an association with lymphoma and lung cancer for BRCA1 and endometrial, cervical, kidney, and liver cancers for BRCA2.

Those with pathogenic variants were more likely to report a family history of the 7 associated cancer types (ie, breast, ovarian, prostate, pancreatic, biliary tract, esophageal, and gastric). Reported family history of ovarian cancer was associated with an increased risk in female breast, ovarian, and pancreatic cancers for BRCA1. Similarly, for BRCA2 a family history of breast cancer was enriched in 5 cancer types. The largest proportion of cases reporting a family history of the same cancer type was among those with gastric cancer (28.1%) and the lowest was those with endometrial cancer (2.4%).

Age at diagnosis was also affected by the variants. Women with pathogenic variants in BRCA1 or BRCA2 who had breast cancer were diagnosed at an earlier age than those without the variant. Carriers with BRCA2 variants and female breast or prostate cancer were also diagnosed at an earlier age, but those with BRCA2 and ovarian cancer typically had a later diagnosis.

These results suggest that the range of cancer types associated with pathogenic variants in BRCA1 and BRCA2 is broader than previously believed. The information from this study supports expanded indications for genetic testing of individuals with family history of these cancer types, with potential implications for research of PARP inhibitors as well.

High level
The data from this study provide a broad view of cancer risks associated with pathogenic variants in BRCA1 and BRCA2, and support expansion of BRCA1/2 genetic testing as part of diagnosis and treatment decisions for more tumor types. In particular, these findings can potentially improve genetic testing of BRCA1 and BRCA2 for various cancer types for Asian countries, and the authors recommend similar research in other countries to help identify regional differences. More detailed information that accounts for population and regional differences would improve precision medicine with genetic testing of BRCA1 and BRCA2. The findings of this study and association with family history of cancer and clinical phenotypes should be considered when developing and adapting guidelines for genetic testing, treatment options, and treatability with PARP inhibitors for each cancer type.

Ground level
Biliary tract, gastric, and esophageal cancers—all associated with pathogenic variants in BRCA1 and BRCA2—are known to have a higher incidence rate in East Asian countries. While further research is expected to confirm these findings, oncologists should consider expanding their use of genetic testing when treating patients from this region. Expanded diagnostic testing can help inform treatment decisions and may help to identify patients with other tumor types for whom certain active drugs such as PARP inhibitors could be effective but may not have been otherwise considered.