What is the recommended management approach for a patient with non-metastatic triple-negative breast cancer (TNBC)?

Management of Non-Metastatic Triple-Negative Breast Cancer

For stage II-III non-metastatic TNBC, neoadjuvant chemotherapy with pembrolizumab plus anthracycline-taxane-carboplatin regimen is the standard of care, followed by surgery, adjuvant pembrolizumab completion, and radiation therapy. 1

Treatment Algorithm by Stage

Stage I TNBC (Tumors <5 mm)

• Surgical excision alone may be appropriate for very small tumors (<5 mm), though nearly half of experts still recommend adjuvant chemotherapy even for these minimal tumors 2, 3
• For tumors 1 cm or less without node metastasis, observation without systemic therapy has shown all patients alive without recurrence beyond 4 years 4

Stage II-III TNBC (Standard Approach)

Neoadjuvant therapy is the preferred standard approach rather than upfront surgery, as it allows for tumor downstaging and provides prognostic information based on pathologic response 1

Neoadjuvant Chemotherapy Regimen

The preferred regimen is the KEYNOTE-522 protocol: 1

• Chemotherapy backbone: Taxanes + carboplatin + anthracyclines (doxorubicin or epirubicin) + cyclophosphamide
• Immunotherapy: Concurrent pembrolizumab throughout neoadjuvant phase
• Sequencing: Either anthracycline-based (AC or EC for 4 cycles over 8-12 weeks) followed by taxanes (4 cycles over 8-12 weeks), OR taxanes with carboplatin followed by anthracycline-based therapy 1
• Dose-dense options: Fortnightly AC/EC/paclitaxel or weekly paclitaxel are standard 1

Critical point: The benefit from pembrolizumab is independent of PD-L1 status, and carboplatin benefit is independent of germline BRCA1/2 status 1

Surgical Management

Timing: Surgery performed after completion of neoadjuvant chemotherapy 1

Breast surgery options:

• Breast-conserving therapy (BCT) is appropriate when adequate margins can be achieved, as TNBC characteristically shows expanding growth without extensive intraductal spread 4
• Mastectomy for larger tumors or when margins cannot be achieved 2

Axillary management: 2, 3

• Sentinel lymph node biopsy (SLNB) is standard for clinically node-negative patients at presentation
• For patients with clinically positive nodes at baseline who become clinically negative after neoadjuvant therapy, SLNB may be considered
• Axillary lymph node dissection is required for residual nodal disease after neoadjuvant therapy, especially for macrometastases >2mm

Adjuvant Therapy After Surgery

Immunotherapy completion: 1

• Continue adjuvant pembrolizumab to complete the full treatment course, regardless of pathologic response (pCR vs. residual disease)
• The clinical value of this adjuvant phase is not definitively proven, but panelists favor its continuation

For patients with germline BRCA1/2 mutations: 2, 3

• Add adjuvant olaparib for 1 year after completion of chemotherapy and surgery

Radiation Therapy

Post-lumpectomy: 3

• Radiation to the breast is standard after breast-conserving surgery

Post-mastectomy radiation therapy (PMRT) indications: 2, 3

• Positive lymph nodes (any number)
• Positive or close surgical margins
• Consider for stage IIB disease based on nodal burden

Special Considerations

Contralateral Breast Management

• No routine prophylactic contralateral mastectomy based solely on TNBC status 2, 3
• Consider bilateral mastectomy only for: 2, 3
  • Germline BRCA1/2 mutations (due to 40-60% lifetime risk of contralateral breast cancer)
  • Very young age at diagnosis
  • Strong family history suggesting hereditary predisposition
  • Patient preference after thorough counseling

Breast Reconstruction Timing

• Delayed reconstruction may be more appropriate than immediate reconstruction in TNBC patients likely to require post-mastectomy radiation, as radiation can compromise cosmetic outcomes 2

Biomarker Testing Requirements

At diagnosis, obtain: 1, 3

• Germline BRCA1/2 mutation testing (essential for all HER2-negative breast cancer, including TNBC)
• PD-L1 status by immunohistochemistry (though pembrolizumab benefit is independent of PD-L1 status in the neoadjuvant setting)
• Consider PALB2 assessment (optional, ESCAT II-A)

Prognostic Factors

• Pathologic complete response (pCR) is a strong prognostic indicator regardless of BRCA status 1
• After 3 years, pCR is associated with excellent outcomes 4
• Non-pCR, even with minimal residual disease, carries risk of distant recurrence and requires close surveillance 4

Common Pitfalls to Avoid

1. Do not delay neoadjuvant chemotherapy for stage II-III disease to perform upfront surgery—neoadjuvant approach is standard 1

2. Do not omit pembrolizumab from the neoadjuvant regimen based on PD-L1 negativity—benefit is PD-L1-independent 1

3. Do not omit carboplatin from the regimen in BRCA wild-type patients—benefit is BRCA-independent 1

4. Monitor closely during neoadjuvant therapy: If tumor progression occurs, modify the regimen or proceed to surgery immediately to avoid losing the opportunity for effective treatment 4

5. Do not perform immediate reconstruction without considering the high likelihood of post-mastectomy radiation in TNBC 2

6. Do not forget germline BRCA testing at diagnosis, as this determines eligibility for adjuvant olaparib 1, 2, 3