What is the recommended treatment approach for stage 3 triple-negative (TN) breast cancer?

Treatment of Stage 3 Triple-Negative Breast Cancer

For stage 3 triple-negative breast cancer, neoadjuvant chemotherapy with pembrolizumab plus anthracyclines, taxanes, carboplatin, and cyclophosphamide is the standard of care, followed by definitive surgery and adjuvant pembrolizumab regardless of pathologic response. 1, 2

Neoadjuvant Systemic Therapy

The preferred neoadjuvant regimen is the KEYNOTE-522 protocol: 1, 2

• Pembrolizumab combined with chemotherapy (taxanes, carboplatin, anthracyclines, and cyclophosphamide)
• Sequential administration: anthracycline-based therapy (doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide) for 4 cycles over 8-12 weeks, followed by taxane plus carboplatin for 4 cycles over 8-12 weeks 1, 2
• Pembrolizumab is given concurrently throughout neoadjuvant treatment 1, 2
• The benefit from pembrolizumab is independent of PD-L1 status 1, 2
• The benefit from carboplatin is independent of germline BRCA1/2 status 1

Dose-dense regimens are standard options: 1

• Fortnightly AC/EC with weekly paclitaxel 1
• However, there is no consensus on using dose-dense every-2-week schedules with pembrolizumab due to limited safety data 1

Surgical Management

Neoadjuvant therapy is the standard approach for stage 3 TNBC, allowing for tumor downstaging before surgery. 1, 2

Axillary management: 3

• For patients with clinically positive nodes at baseline who become clinically node-negative after neoadjuvant therapy, sentinel lymph node biopsy may be considered 3
• Axillary lymph node dissection is recommended for residual nodal disease after neoadjuvant therapy, especially for macrometastases >2mm 3

Radiation therapy: 3

• Post-mastectomy radiation therapy should be administered for patients with positive lymph nodes or positive/close margins 3
• Post-lumpectomy radiation to the breast is standard after breast-conserving surgery 3

Adjuvant Therapy Based on Neoadjuvant Response

For patients who received neoadjuvant pembrolizumab plus chemotherapy: 1, 2

• Continue adjuvant pembrolizumab for 9 additional courses regardless of pathologic response 1, 2
• The clinical value of this adjuvant phase is not definitively proven, but it is the standard recommendation 1

For patients with residual invasive disease after neoadjuvant chemotherapy: 1, 2

• If germline BRCA1/2 wild-type: administer capecitabine every 3 weeks for 6-8 cycles 1, 2
• If germline BRCA1/2 mutation: administer olaparib for 1 year 1, 2, 3

For patients who achieve pathologic complete response (pCR): 1

• pCR is associated with significantly improved long-term outcomes 1
• Continue adjuvant pembrolizumab as planned 1, 2

Special Considerations

Genetic testing is mandatory: 2, 4

• All patients with stage 3 TNBC should undergo genetic counseling and germline BRCA1/2 testing 2, 4
• Results directly impact adjuvant therapy decisions (olaparib eligibility) 2, 4

Prophylactic contralateral mastectomy: 4, 3

• Not routinely recommended based solely on TNBC status 4, 3
• Should only be considered for patients with germline BRCA1/2 mutations, young age, or strong family history 4, 3

Common Pitfalls to Avoid

Do not omit pembrolizumab based on PD-L1 status - the benefit is independent of PD-L1 expression 1, 2

Do not omit carboplatin based on BRCA status - the benefit is independent of germline BRCA1/2 status 1

Do not skip adjuvant pembrolizumab even if pCR is achieved - ongoing adjuvant pembrolizumab is recommended regardless of neoadjuvant response 1, 2

Monitor closely for immune-related adverse events during pembrolizumab treatment, which can affect any organ system 4

Ensure adequate premedication before paclitaxel administration to prevent severe hypersensitivity reactions: dexamethasone 20 mg PO at 12 and 6 hours before, diphenhydramine 50 mg IV 30-60 minutes before, and H2-blocker 30-60 minutes before paclitaxel 5