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The prevalence of any germline HBOC-related pathogenic variant has been estimated to be about 1:70 women in the general population.

HBOC is not associated with specific phenotypic features. Individuals with breast cancer may have any histological subtypes, the most common being ductal adenocarcinoma. Early-onset of cancer, bilateral breast cancer, familial occurrence of cancer over several generations, male breast cancer, multiple tumors in a same individual, multifocality and triple negative cancer are features suggestive of hereditary HBOC.

Genes associated with HBOC are classified as 1) high-risk genes, increasing breast and/or tubo-ovarian cancer risk by at least fourfold, and 2) moderate-risk genes, increasing risk by two- to fourfold. However, there is considerable overlap between these two groups. Autosomal dominant alterations in BRCA1 and BRCA2 are likely to account for most HBOC cases. Other genes linked to hereditary breast or ovarian cancer are PALB2, ATM, CHEK2, BARD1 (only breast), RAD51C, RAD51D (breast and ovary) and BRIP1 (only ovary). TP53, PTEN, CDH1, and STK11 are linked to increased breast cancer susceptibility and also to other specific syndromes. Disease severity and age at onset may show variability within and between families harboring the same pathogenic variant, suggesting the involvement of other genetic as well as non-genetic factors. These PVs may also increase susceptibility to other cancer types such as prostate cancer and pancreatic cancer.

Diagnosis is based on suggestive clinical features associated with significant family history. Individuals should be offered genetic testing with multigene panels of clinically validated HBOC genes. Analysis of single nucleotide variants and large rearrangements are needed for comprehensive genetic testing. If a pathogenic variant is identified through tumor testing, germline testing can be considered to confirm the diagnosis.

Differential diagnosis includes familial breast cancer not associated with known genetic susceptibility.

Once the PV in HBOC-related genes has been identified in the family, prenatal and preimplantation genetic testing for known highly penetrant high cancer risk PV are possible.

HBOC-related genes are inherited in an autosomal dominant manner. The vast majority of probands inherited it from a parent, with very few being de novo. Offsprings of affected individuals have a 50% chance of inheriting the PV, but the penetrance of the disease is currently unknown. Molecular genetic testing should be offered to both parents and their at-risk relatives who should be counseled regarding their cancer risk, the risk of transmission, and recommendations for cancer screening and prophylactic surgery. Counseling should also mention possible rare autosomal recessive conditions, such as Fanconi anemia, when biallelic PVs in some genes are inherited (i.e. BRCA2, BRCA1, PALB2) and if the partner's family history is also suggestive of HBOC. Testing of asymptomatic individuals < 18 years of age is not recommended and should be deferred until they reach adulthood and can make independent decisions.

The management strategies in healthy carriers include yearly surveillance and surgical risk-reduction options. For patients with a BRCA1/2-associated cancer, there are personalized approaches based on DNA-damaging agents or targeted therapies such as poly-ADP-ribose polymerase (PARP) inhibitors. Secondary preventive measures might be considered, such as contralateral risk reducing mastectomy or prophylactic bilateral salpingoophorectomy.

Breast and/or ovarian cancers in carriers of a BRCA1 or BRCA2 pathogenic variant may have increased chemosensitivity which might be linked to a slight survival advantage in the first few years after diagnosis compared to other patients.