Genetics of Triple Negative Breast Cancer

• TNBCs arising in BRCA1 carriers have many similarities with sporadic basal-like tumors:
  • There being considerable overlap in tumor phenotypes
• Carriers of a deleterious BRCA1 mutation are more likely to have TNBCs than patients with sporadic cancers; in fact:
  • TNBC is the most common histologic subtype of breast cancer arising in BRCA1 mutation carriers
• The likelihood that breast cancer in a BRCA1 carrier will be of the TNBC variety is high according to numerous authors:
  • 56% to 87%
  • 60% to 80%
  • 69%
• Penault-Llorca and Viale report even higher rates:
  • Up to 90% of BRCA1-mutated tumors:
    • Being of the TNBC or basal type
  • For carriers of BRCA2, however:
    • Breast cancers are less likely to be TNBC:
      • 25%
• Another question posed by several researchers is, what is the likelihood of a patient with TNBC being the carrier of a deleterious genetic mutation?
  • Couch and colleagues examined the frequency of gene mutations in 1,824 patients with TNBC unselected for family history of breast or ovarian cancer:
    • Moreover, 8.5% had mutations of BRCA1 and 2.7% had mutations in BRCA2
  • Deleterious mutations in 15 other predisposition genes were detected in 3.7%, including:
    • PALB2, BARD1, RAD51D, RAD51C, and BRIP1
  • No mutations were found in CHEK2, CDH1, or STK11
  • The frequency of BRCA mutations varied according to the patient’s age:
    • Of all the deleterious mutations detected in Couch and colleagues’ cohort:
      • 38% were found in patients with TNBC diagnosed at the age of less than 40 years
• Wang and colleagues studied a group of 956 Chinese women with TNBC and found similar rates of BRCA1 and BRCA2 carrier status:
  • 7.1% and 2.3%, respectively
  • When examined by age, however, for patients aged 50 years or older:
    • The BRCA1 mutation rate was 10.5% compared with 3.7% for those aged older than 50 years
• BRCA1 mutation carrier status in patients with TNBC also varies by ethnicity:
  • In women of Ashkenazi Jewish descent with TNBC:
    • Up to 29% were BRCA1 mutation carriers
• Greenup and colleagues reported on 450 racially diverse patients with TNBC who had evaluable test results referred for genetic counseling to two academic hereditary cancer clinics:
  • Moreover, 30.8% patients carried a BRCA mutation, 23.5% BRCA1, 7% BRCA2, and one patient carried both BRCA1 and BRCA2
  • These authors also found differences in BRCA carrier status according to age and ethnicity:
    • In those patients diagnosed at less than 40 years of age, 44% were BRCA positive:
      • With majority being BRCA1 positive:
        • 84%, 54 patients
      • In that same age group 14% (nine patients) were BRCA2 positive
    • With regard to ethnicity, 20.4% of African American women were BRCA carriers, 20% of Hispanics, 33.3% of Caucasians, 28.5% of Asians, and

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