Stephanie Percich, MS, CGC
Breast cancer is the most common malignancy diagnosed in women (excluding basal and squamous cell skin cancers), and as many as 10% of breast cancers in women are hereditary.1,2,3 The genes most commonly mutated in hereditary breast cancer are BRCA1 and BRCA2.2,4,5 One in 300 to 1 in 500 individuals in the general population (excluding those of Ashkenazi Jewish ancestry) carry a pathogenic mutation in BRCA1/2.6 Ideally, germline BRCA1/2 testing occurs at the time of cancer diagnosis since information about a patient’s BRCA1/2 status is crucial when making treatment decisions. The current NCCN guidelines recommend germline BRCA1/2 testing for anyone diagnosed with pancreatic cancer or ovarian cancer (regardless of stage or age at diagnosis). Additionally, women diagnosed with breast cancer at a young age (≤45 years) or with a suggestive family history, are also candidates for germline testing.8 Women with breast cancer and a germline BRCA1/2 mutation may opt for a bilateral mastectomy due to the increased risk of a second primary breast cancer. Studies have also shown that BRCA1/2-mutated cancers respond better to platinum-based chemotherapy than to standard chemotherapy, so knowledge of germline BRCA1/2 mutation status can help determine the most appropriate first-line chemotherapy regimen.9,10,11
The BRCA1 and BRCA2 genes aid in repair of double-strand DNA breaks via homologous recombination. Cells with deficient homologous recombination (e.g. those with BRCA1/2 mutations) are sensitive to PARP (poly (ADP-ribose) polymerase) inhibitors. Molecular characteristics have been found to be similar among tumors with somatic BRCA1/2 mutations and those with germline BRCA1/2 mutations, and both germline and somatic BRCA1/2 mutated cancers are thought to respond to PARP inhibitors.7 Recent clinical trials have shown that those with a BRCA1/2 mutation and advanced ovarian cancer, metastatic pancreatic cancer, or HER2-negative metastatic breast cancer may benefit from maintenance therapy with a PARP inhibitor, such as olaparib.12,13,14 In the OlympiAD trial, olaparib monotherapy showed promising benefits in individuals with HER2-negative metastatic breast cancer and a germline BRCA1/2 mutation.12 Consequently, NCCN recommends that patients with HER2-negative recurrent or stage IV breast cancer strongly consider BRCA1/2 germline testing so those with a germline mutation can consider PARP inhibitor monotherapy.9
Similarly, the goal of tumor testing is to identify somatic driver mutations in the tumor in order to guide treatment decisions. In some cases, a germline mutation may be identified during tumor testing; however, tumor testing alone is not enough to rule out a hereditary cancer syndrome. Absence of a BRCA1/2 mutation on tumor profiling does not negate the need for germline testing in cases where the patient’s personal and/or family history is suggestive of a germline BRCA1/2 mutation or other hereditary cancer syndromes. Moreover, a somatic gene panel may not include all the genes associated with a hereditary cancer risk.15 Additionally, there are differing criteria for how germline and somatic variants are classified as pathogenic, benign, or uncertain.16 There are also often limitations to tumor testing technology to be aware of in this setting. Tumor sequencing may not cover all relevant areas of the gene, deletion/duplication analysis may not be part of the tumor analysis, a germline mutation could be mosaic and not present in the tumor specimen, and in rare cases, the germline mutation may have reverted to wildtype in the tumor.
That being said, BRCA1/2 mutations identified via tumor testing (without paired germline analysis) may represent somatic or germline mutations. In tumor profiling of 1000 cancers, Meric-Bernstam et al. found that somatic mutations in BRCA1/2 are rare and the identification of a somatic BRCA1/2 mutation should be followed with germline testing.17 Winter et al. analyzed normal and tumor DNA from a cohort of breast cancer patients and found that 1/3 of the BRCA1/2 mutations identified were somatic; whereas 2/3 were germline.7 Hence, NCCN recommends germline BRCA1/2 testing for anyone with a pathogenic or likely pathogenic variant in BRCA1/2 identified on somatic testing of any tumor type (that was not already paired with germline analysis).8
Not all somatic BRCA1/2 mutations will be present in the germline, so it is essential that tumor testing be followed by confirmatory germline analysis if a BRCA1/2 mutation is identified. Only germline analysis can determine whether there is a hereditary risk of a second primary cancer and risks to family members. Individuals with cancer and a germline BRCA1/2 mutation would have an increased risk for additional primary cancers and knowledge of these risks can impact surgical decisions and allow them to be screened appropriately. Conversely, those with a somatic BRCA1/2 mutation that is not present in the germline would not be at elevated risk for a second BRCA-associated cancer. Importantly, those with a germline BRCA1/2 mutation may have family members who could be at risk to carry the same germline mutation. Somatic BRCA1/2 mutations are not passed on in families. Once a BRCA1/2 mutation is identified in a family, other relatives can be tested and can undergo individualized screening/surveillance for BRCA-associated cancers if they carry the familial mutation. Learn more about Hereditary Breast and Ovarian Cancer Syndrome
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8. NCCN Clinical Practice Guidelines in Oncology. Genetic/Familial High-Risk Assessment: Breast and Ovarian (Version 3.2019). https://www.nccn.org/professionals/physician_gls/pdf/genetics_ screening.pdf Accessed Sept. 6, 2019.
9. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer (Version 2.2019).
https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf Accessed Sept. 6, 2019.
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16. Lee LA, et al. Annotation of sequence variants in cancer samples: Processes and pitfalls for routine assays in the clinical laboratory. J Mol Diag. 2015;17(4):339-51.
17. Meric-Bernstam F, et al. Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol. Ann Oncol. 2016;27(5):795-800.