Breast Cancer – Genetic Predisposition – Rodrigo Arrangoiz MS, MD, FACS, FSSO

Approximately 10% of breast cancers are inherited and associated with a family history:
- Although this varies frequently by ethnicity and across countries:
  - In the context of early-onset, bilateral and / or TNBC
Individuals with a first-degree relative who had breast cancer:
- Have an elevated relative risk (RR) of 3 of early-onset breast cancer:
  - Before 35 years of age:
    - However, a family history of breast cancer is associated with an ‘erratic’ individual risk of breast cancer:
      - Composed of different variables, including:
        The size of the family
        Environmental factors
    - To determine the family’s risk, models such as the family history score have been developed
Mutations in two high-penetrance tumor suppressor genes:
- BRCA1 (17q21) and BRCA2 (13q13):
  - Whose proteins are involved in DNA repair through homologous repair
- Show an autosomal-dominant inheritance pattern:
  - Loss of function greater than missense mutations
- BRCA1 and BRCA2 mutations are associated with:
  - An average cumulative risk of developing breast cancer by the age of 80 years of:
    - 72% and 69%, respectively
  - The relative risk of breast cancer in men harboring BRCA2 mutations:
    - Is 6%
- More than 2,000 BRCA gene alterations have been described (mutations and large rearrangements):
  - But only few have been found repeatedly in unrelated families:
    - For example, founder mutations in:
      - Ashkenazi Jewish families (BRCA1 185delAG or BRCA2 6174delT) or
      - Icelandic families (BRCA2 999del5)
- Germline BRCA testing will now be performed:
  - As a companion diagnostic in patients with metastatic breast cancer:
    - Given the availability of poly(ADP-ribose) polymerase (PARP) inhibitors:
      - Which prolong progression-free survival (PFS) and improve quality of life:
        As a targeted therapy for BRCA mutation carriers in HER2-negative metastatic breast cancer
- Several syndromes related to germ-line mutations of genes involved in DNA repair and maintaining genomic integrity:
  - Have been shown to be linked to, to a lesser degree, the inherited breast cancer risk (see table below)
  - Next-generation sequencing has enabled panels of genes to be screened:
    - Beyond BRCA1 and BRCA2 :
      - To determine the inherited breast cancer risk, and include:
        ATM, CHEK2, PALB2, PTEN, STK11 and TP53