Triple-negative breast cancer (TNBC) represents a distinct and often aggressive form of breast cancer. Its unique classification stems from the absence of three specific receptors commonly found in other breast cancer types: estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2). Understanding the underlying genetic factors associated with TNBC is becoming increasingly important, as these insights can significantly influence both risk assessment and treatment strategies.
What is Triple Negative Breast Cancer?
Triple-negative breast cancer (TNBC) lacks estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) on its cancer cells. This absence means TNBC does not respond to hormone therapies or HER2-targeted drugs, which are effective for other breast cancer subtypes.
TNBC exhibits more aggressive behavior compared to other breast cancer forms. It is also associated with a higher likelihood of recurrence after treatment. This aggressive nature highlights ongoing research into more effective therapies. TNBC accounts for approximately 10-15% of all breast cancers diagnosed.
The Role of Inherited Genes
While many cancers arise sporadically, a notable proportion of TNBC cases are linked to inherited genetic mutations, meaning they are passed down from a parent and are present in all cells of the body. The BRCA1 gene is significant in this context, as mutations in this gene are strongly associated with an increased risk of TNBC. BRCA1, along with BRCA2, plays a role in DNA repair, specifically in fixing double-strand breaks. When BRCA1 is mutated, this DNA repair process is disrupted, leading to an accumulation of DNA damage that can promote uncontrolled cell growth and tumor formation.
Beyond BRCA1, mutations in other genes like BRCA2, PALB2, BARD1, and RAD51D have also been associated with a higher risk of TNBC. PALB2 works closely with BRCA2 to load the RAD51 enzyme, which is central to homologous recombination, a DNA repair pathway. Similarly, BARD1 and RAD51D are involved in DNA repair mechanisms, and inherited changes in these genes can compromise the cell’s ability to repair damaged DNA, thereby increasing cancer susceptibility. These germline mutations are present from birth and can elevate an individual’s lifetime cancer risk.
Who is at Genetic Risk and Why Test?
Certain demographic groups and family histories indicate a higher likelihood of carrying inherited genetic mutations linked to TNBC. Younger women diagnosed with TNBC are considered at an increased risk for inherited mutations like BRCA1. A strong family history of breast or ovarian cancer, especially if diagnosed at young ages or involving multiple relatives, also suggests a higher genetic risk, including instances of breast cancer in both breasts or a family history of both breast and ovarian cancers.
Women of Ashkenazi Jewish descent also have a higher prevalence of specific BRCA1 and BRCA2 gene mutations, with approximately 1 in 40 individuals in this population carrying such a mutation, a rate higher than in the general population. Genetic testing in these situations helps identify inherited mutations that can influence an individual’s lifetime cancer risk. Knowing one’s genetic status allows for personalized risk management and can inform decisions regarding cancer prevention and treatment.
Genetic Insights Guiding Management
Identifying an inherited genetic mutation, such as in BRCA1 or BRCA2, has practical implications for managing TNBC. For individuals with these mutations, enhanced screening protocols are recommended, which may include earlier and more frequent magnetic resonance imaging (MRI) screenings in addition to mammograms. These intensified screenings aim to detect any potential cancers at their earliest stages.
Risk-reduction strategies are also considered, including prophylactic surgeries like a risk-reducing mastectomy to remove breast tissue or a risk-reducing salpingo-oophorectomy to remove ovaries and fallopian tubes. These procedures can lower the risk of developing breast or ovarian cancer. Understanding the genetic basis of TNBC directly impacts treatment options. For instance, TNBC patients with BRCA1 or BRCA2 mutations respond well to targeted therapies known as PARP inhibitors. These drugs exploit the DNA repair deficiencies present in cancer cells with these mutations, leading to the accumulation of DNA damage and eventual cell death.