What are the management strategies for patients with Triple Negative Breast Cancer (TNBC) with and without metastasis (mets)?

Management of Triple-Negative Breast Cancer: Metastatic vs Non-Metastatic

For non-metastatic TNBC (stages I-III), dose-dense anthracycline and taxane-based neoadjuvant chemotherapy is the standard approach for stage II-III disease, while for metastatic TNBC, first-line treatment is determined by PD-L1 status (≥10% CPS) and germline BRCA mutation status, with immune checkpoint inhibitors plus chemotherapy preferred for PD-L1-positive disease and PARP inhibitors for BRCA-mutated disease. 1, 2

Non-Metastatic TNBC (Early-Stage, Stages I-III)

Mandatory Pre-Treatment Assessment

• Confirm triple-negative status (ER/PR negative, HER2 negative) via biopsy with complete pathologic assessment including histological grade and Ki67 markers 3
• Test for germline BRCA1/2 mutations in all patients with early-stage TNBC to identify candidates for adjuvant PARP inhibitor therapy 1, 2

Surgical Management

• Sentinel lymph node biopsy is standard for clinically node-negative patients at initial presentation 1
• For clinically positive nodes that become negative after neoadjuvant chemotherapy, sentinel lymph node biopsy may be considered 1
• Axillary lymph node dissection is required for residual nodal disease after neoadjuvant therapy, particularly for macrometastases >2mm 1
• For very small tumors (<5 mm, stage I), surgical excision alone may be appropriate, though nearly half of experts still recommend adjuvant chemotherapy even for these minimal tumors 1

Systemic Therapy

• Dose-dense anthracycline and taxane combinations are the standard neoadjuvant approach for stage II-III disease, achieving pathological complete response rates exceeding 20% 1
• Neoadjuvant chemotherapy is preferred over adjuvant therapy for stage II-III TNBC to assess treatment response 4
• For patients with germline BRCA1/2 mutations and high-risk early-stage TNBC, adjuvant olaparib for 1 year should be considered after completing standard chemotherapy 1

Radiation Therapy

• Post-lumpectomy radiation to the breast is standard after breast-conserving surgery 1
• Post-mastectomy radiation should be considered for patients with positive lymph nodes or positive/close margins 1

Prophylactic Surgery Considerations

• Do not routinely recommend prophylactic contralateral mastectomy based solely on TNBC status; this should only be considered for patients with germline BRCA1/2 mutations, young age, or strong family history 1

Metastatic TNBC

Mandatory Pre-Treatment Testing

• PD-L1 status testing is paramount to determine eligibility for immune checkpoint inhibitor therapy 3, 2
• Germline BRCA1/2 mutation testing is essential to identify candidates for PARP inhibitor therapy 3, 2
• Re-biopsy of metastatic lesions should be performed if technically feasible to confirm histology and reassess biomarkers, as tumor biology may change from primary to metastatic disease 3

First-Line Treatment Algorithm

For PD-L1-Positive Disease (CPS ≥10)

• Pembrolizumab plus chemotherapy is the preferred first-line regimen, providing significant survival benefit with median OS of 23.0 versus 16.1 months (HR 0.73; P=0.0093) 2
• Alternatively, atezolizumab plus nab-paclitaxel demonstrated PFS benefit of 7.5 versus 5 months (HR 0.62) in PD-L1-positive patients 3
• Patients receiving checkpoint inhibitors must be monitored closely for immune-related adverse events, which can affect any organ system 1

For Germline BRCA-Mutated Disease

• PARP inhibitors are recommended rather than chemotherapy in the first-through third-line setting, as they are superior to standard chemotherapy options 1, 2
• This applies regardless of PD-L1 status 2

For PD-L1-Negative and gBRCA Wild-Type Disease

• Single-agent chemotherapy is preferred for first-line treatment to minimize toxicity 3, 2
• Taxanes (paclitaxel or docetaxel) are preferred first-line options if not previously used in the adjuvant setting 1, 5
• Anthracyclines are recommended if not previously administered 1
• Combination chemotherapy may be offered only for symptomatic or immediately life-threatening disease where rapid response is critical, recognizing that combinations achieve higher objective response rates but with increased toxicity 3, 1, 2
• Platinum agents (carboplatin/cisplatin) with or without taxanes are appropriate options, with selection based on individual risk-benefit assessment, recognizing increased toxicity including nausea, vomiting, and anemia 1, 5

Second-Line and Beyond

After Progression on First-Line Therapy

• For patients who have received at least two prior therapies for metastatic disease, sacituzumab govitecan is strongly recommended, with significant improvements in both progression-free survival and overall survival 1, 2
• After progression to first-line chemotherapy, anthracyclines are an option for patients who received taxanes and vice versa 5
• For patients who progressed to taxanes and anthracyclines, or who present contraindications to these agents, fluorouracil/capecitabine, eribulin, gemcitabine, cisplatin/carboplatin, vinorelbine are alternatives 5

Late-Line Therapy Considerations

• Immune checkpoint inhibitors may be considered as monotherapy in further lines in case of high PD-L1 positivity and no previous exposure to ICI 3
• Chemotherapy should be maintained until the occurrence of disease progression or limiting toxicities 5

Agents with Limited Recommendation

• Bevacizumab combined with chemotherapy has shown improved progression-free survival but not overall survival, limiting its routine recommendation 1

Critical Pitfalls to Avoid

In Non-Metastatic Disease

• Do not delay germline BRCA testing until after completion of neoadjuvant/adjuvant chemotherapy, as this determines eligibility for adjuvant olaparib 1
• Do not perform axillary lymph node dissection in all patients with positive sentinel nodes after neoadjuvant therapy; this can be avoided if nodes become clinically negative 1

In Metastatic Disease

• Do not delay PD-L1 and gBRCAm testing before initiating first-line therapy, as these biomarkers fundamentally change treatment selection and survival outcomes 2
• Avoid routine combination chemotherapy in PD-L1-negative/gBRCA wild-type disease unless imminent organ failure exists, due to toxicity outweighing modest survival benefit 2
• Do not use single-agent chemotherapy as first-line in PD-L1-positive disease when immune checkpoint inhibitors are available, as this represents a missed opportunity for survival benefit 2
• Do not sequence PARP inhibitors after platinum-based chemotherapy in BRCA-mutated patients; PARP inhibitors should be used first-line 2, 5

Key Differences Between Non-Metastatic and Metastatic Management

The fundamental distinction is that non-metastatic TNBC is treated with curative intent using multimodality therapy (surgery, chemotherapy, radiation), while metastatic TNBC is treated with palliative intent using biomarker-directed systemic therapy 3, 1. In non-metastatic disease, the goal is to achieve pathological complete response and prevent recurrence, whereas in metastatic disease, the goal is to prolong survival and maintain quality of life while managing treatment-related toxicity 1, 2.