ACTBRCA®

Comprehensive BRCA1/2 Genetic Testing

Provides BRCA1/2 Genetic Information for PARP Inhibitor Treatment Selection

BRCA1/2 is the most common gene mutation in hereditary breast cancer and has also been found to be associated with ovarian cancer, pancreatic cancer, prostate cancer, etc. In recent years, the selection of cancer patients who would most likely benefit from PARP inhibitor treatment has also relied on the detection of BRCA1/2 mutations, thus emphasizing the importance of BRCA1/2 genetic testing.

BRCA1/2 Genetic Information

Individuals with deleterious or likely deleterious germline BRCA1/2 mutations are known to have an increased lifetime risk of breast, ovarian, pancreatic or prostate cancers¹. Therefore, genetic testing for germline BRCA1/2 mutations allows the lifetime risk of hereditary cancers to be determined, so that risk mitigation actions, such as active surveillance and other preventive measures, can be taken timely through appropriate genetic counseling. According to the latest NCCN guidelines, genetic counseling is recommended for breast cancer patients and their families if they fulfill any of the following criteria²:

(1) Have a known pathogenic/likely pathogenic variant in a cancer susceptibility gene;
(2) Personal or family history of ovarian cancer;
(3) Personal or family history of bilateral breast cancer;
(4) Early-onset breast cancer at ≤45 years of age;
(5) Triple-negative breast cancer at ≤60 years of age;
(6) At least one close blood relative with breast cancer at ≤50 years of age or at least three total diagnoses of breast cancer in a family;
(7) Family history of pancreatic cancer;
(8) Family history of male breast cancer.

*Consultation with a physician or a professional genetic counselor is highly recommended before, during and/or after the test*
 

PARP Inhibitor Treatment

PARP inhibitors are pharmacological agents that block the activity of a family of DNA damage repair (DDR) proteins called PARPs, which are responsible for repairing single-strand breaks before DNA replication and cell division. If the single-strand breaks remain unrepaired and persist through the DNA replication process, double-strand breaks are formed as a result. PARP inhibitors cause the formation of double-strand breaks by trapping at the sites of single-strand DNA breaks^3,4.

In tumors with homologous recombination repair (HRR) deficiency (also known as HRD, which is caused by mutations in BRCA1/2 or other HRR genes), these double-strand breaks cannot be properly repaired, ultimately leading to cell death in a phenomenon called synthetic lethality whereby the combination of two individually non-lethal defects (i.e., PARP inhibition and HRD) leads to a unique vulnerability⁵.

Clinical Experience from Ovarian Cancer: Both Germline and Somatic BRCA1/2 Mutations Play an Important Role in Cancer

The normal and tumor tissue samples of 99 patients with ovarian cancer were analyzed for BRCA1/2 mutations using next-generation genetic sequencing and Sanger gene sequencing. Pathogenic BRCA1/2 variants were found in 12 patients. It is notable in one patient that both germline BRCA1 and somatic BRCA2 mutations were found. Interestingly, all of the 12 patients with pathogenic BRCA1/2 mutations had serous carcinoma, suggesting that ovarian cancer with these BRCA gene mutations exhibit similar pathological morphology. Five of these 12 patients (~42%) had a BRCA gene mutation that was solely detectable in tumor tissue and not in normal tissue, indicative of the sporadic nature of these mutations. This study exemplifies that BRCA gene mutations, whether inherited or acquired, can play a key role in the pathogenesis of ovarian cancer.

*Abbreviations: gBRCA: germline BRCA; sBRCA: somatic BRCA.