Triple Negative Breast Cancer

Background

• Triple negative breast cancer is defined as breast cancer that is human epidermal growth factor receptor 2 (HER2) negative and estrogen and progesterone hormone receptor (HR) negative. It accounts for 11%-15% of all breast cancers.
• Traditionally, triple negative disease was associated with basal-like molecular subtype, but it is becoming more apparent that it is a heterogeneous disease that includes a variety of molecular subtypes. These subtypes may impact treatment options and response.
• Risk factors for triple negative breast cancer include those for any breast cancer. Additionally, younger age, Black or Hispanic race, and genetic mutations (such as BRCA1/2, PALB2, BARD1, RAD51C, RAD51D, FANCC, and FANCM) may increase the risk of triple negative disease.
• Clinical presentation of triple negative breast cancer is similar to that of other breast cancers, although it may present as a palpable mass more frequently than other subtypes. Breast cancers are most commonly detected on screening mammograms or through evaluations of a palpable mass.
• Generally, triple negative disease is associated with a poorer prognosis, with higher rates of recurrence and shorter overall survival compared to other subtypes.

Evaluation

• The diagnosis and workup of triple negative breast cancer is similar to other breast cancers. It generally includes a clinical exam, imaging and is confirmed by a pathological assessment of the biopsy, including the HR and HER2 status of the cancer.
• In the setting of recurrent or metastatic disease, further testing for biomarkers is indicated to guide decisions on the use of targeted therapies. This includes:
  • BRCA1 and BRCA2 mutation testing (Strong recommendation) to predict benefit from poly adenosine diphosphate ribose polymerase (PARP) inhibitor therapies (such as olaparib or talazoparib)
  • determination of programmed cell death ligand 1 (PD-L1) expression (Strong recommendation) to predict benefit from immunotherapy
  • assessment for NTRK fusion mutation (Weak recommendation) as presence predicts benefit from larotrectinib or entrectinib therapies
  • microsatellite instability-high (MSI-H) and mismatch repair deficiency (dMMR) testing (Weak recommendation) to predict benefit from pembrolizumab or dostarlimab-gxly therapy
  • tumor mutational burden status as high levels (TMB-H) to predict benefit from pembrolizumab therapy (Weak recommendation)

Management

• Management of nonmetastatic invasive triple negative breast cancer:
  • Surgical intervention (including lumpectomy or mastectomy) and adjuvant radiation therapy are based on tumor T stage and nodal status.
  • Additional management, including neoadjuvant and adjuvant therapy, is based on clinical or pathological T stage and nodal status.
    • For adults with early operable breast cancer and other-than-favorable histology (including ductal/no special type, lobular, mixed, micropapillary, or metaplastic):
      • if clinical T stage ≥ 2 or clinical nodal status ≥ 1, offer neoadjuvant systemic therapy (Strong recommendation)
      • if pathological T1-T3 tumor and pathological N0-N1mi (axillary node metastasis ≤ 2 mm)
        • for tumor ≤ 0.5 cm and pathological N0, only consider adjuvant chemotherapy for high-risk patients (such as those who are young and have high-grade histology) (Weak recommendation); otherwise, no adjuvant chemotherapy is recommended (Weak recommendation)
        • for tumor ≤ 0.5 cm and pathological N1mi, consider adjuvant chemotherapy (Weak recommendation)
        • for tumor 0.6-1 cm, consider adjuvant chemotherapy (Weak recommendation)
        • for tumor > 1 cm, offer adjuvant chemotherapy (Strong recommendation)
      • if pathological positive nodal disease with ≥ 1 ipsilateral nodal metastases > 2 mm, offer adjuvant chemotherapy (Strong recommendation)
    • For adults with early operable breast cancer and favorable histology (such as adenoid cystic and other salivary carcinomas, secretory carcinoma, or rare low-grade metaplastic histologies including low-grade adenosquamous carcinoma or low-grade fibromatosis-like carcinoma), adjuvant systemic or targeted therapy may be considered if pathologically positive nodal disease is detected (Weak recommendation).
• Management of metastatic triple negative breast cancer:
  • If bone disease is present, provide bone-modifying agents such as bisphosphonates or denosumab, with calcium and vitamin D supplement (Strong recommendation).
  • Offer chemotherapy and/or targeted therapy until progression or unacceptable toxicity (Strong recommendation).
    • If progression or unacceptable toxicity is present, offer another line of chemotherapy and/or targeted therapy (Strong recommendation). Most patients are candidates for multiple lines of palliative systemic therapy; use shared decision-making at each reassessment to evaluate value of ongoing treatment, risks and benefits of additional chemotherapy, performance status, and patient preferences.
    • If progression occurs and no additional systemic therapy is warranted (based on clinical factors and patient preference), consider continuing supportive care without further cytotoxic therapy (Weak recommendation).