What is the recommended neo-adjuvant therapy regimen for triple-negative breast cancer?

Neoadjuvant Therapy for Triple-Negative Breast Cancer

The preferred neoadjuvant regimen for stage II/III triple-negative breast cancer is the KN522 trial protocol: chemotherapy with taxanes, carboplatin, anthracyclines, cyclophosphamide, combined with concurrent pembrolizumab. 1

Standard Approach and Rationale

• Neoadjuvant therapy is the standard approach for treating patients with stage II and III early triple-negative breast cancer (TNBC) 1
• This approach allows for:
  • Effective downstaging of tumors for surgical purposes 1
  • Assessment of pathologic complete response (pCR), which remains a strong prognostic factor regardless of germline BRCA1/2 status 1
  • Opportunity to tailor adjuvant therapy based on response 1

Recommended Regimens for Stage II/III TNBC

First-Line Recommendation:

• KN522 trial protocol: Chemotherapy with taxanes, carboplatin, anthracyclines, cyclophosphamide, plus concurrent pembrolizumab 1
• The benefit from pembrolizumab is independent of PD-L1 status 1
• Pembrolizumab is FDA-approved for high-risk early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery 2

Evidence-Based Sequential Therapy Options:

• Anthracycline-based regimens followed by taxanes 1, 3
• Taxanes combined with carboplatin in sequence with anthracycline-based therapy 1, 3
• Standard anthracycline regimens include:
  • Doxorubicin-cyclophosphamide (AC) for four cycles over 8 or 12 weeks, followed by a taxane for four cycles or 8-12 weeks 1
  • Epirubicin-cyclophosphamide (EC) for four cycles over 8 or 12 weeks, followed by a taxane for four cycles or 8-12 weeks 1

Dosing Considerations:

• Dose-dense therapies are standard, such as:
  • Fortnightly AC/EC/paclitaxel 1
  • Weekly paclitaxel 1
• The panel was split on whether to use dose-dense every-2-week AC/EC regimens (30% support) or standard every 3-week schedule (38% support) when combined with pembrolizumab 1

Carboplatin's Role in TNBC

• The benefit from carboplatin is independent of germline BRCA1/2 status 1
• Recent studies show reduced risk of recurrence with regimens that incorporate carboplatin in addition to pembrolizumab-based regimen for stage I TNBC 1
• In the CALGB 40603 trial, addition of carboplatin significantly increased pCR rates in breast (60% vs 44%) and breast/axilla (54% vs 41%) 4
• However, carboplatin increases the risk of grade ≥3 neutropenia and thrombocytopenia 4

Post-Neoadjuvant Therapy

• For patients with residual disease after standard neoadjuvant chemotherapy, consider adjuvant capecitabine for six to eight cycles if germline BRCA1/2 wild-type 1
• Regardless of the extent of response to neoadjuvant chemotherapy plus pembrolizumab, ongoing adjuvant pembrolizumab is favored 1

Stage-Specific Recommendations

Stage I TNBC:

• T1a: Chemotherapy considered case by case 1
• T1b: TC (docetaxel and cyclophosphamide) or AC/EC chemotherapy 1
• T1c: AC/T (anthracycline-cyclophosphamide followed by taxane) chemotherapy 1
• Consider adding carboplatin and pembrolizumab for higher-risk stage I disease 1

Stage II TNBC:

• AC/T chemotherapy 1
• For cT2 cN0, consider addition of pembrolizumab 1
• Neoadjuvant therapy is preferred 1

Stage III TNBC:

• AC/T chemotherapy with pembrolizumab 1
• Neoadjuvant therapy is strongly preferred 1

Common Pitfalls and Considerations

• Hematologic toxicity is a significant concern with carboplatin-containing regimens:
  • 96% of patients may experience grade ≥3 leucopenia
  • 40% may experience grade ≥3 anemia
  • 15% may experience grade ≥3 thrombocytopenia
  • 22% may develop neutropenic fever 5
• Patients assigned to carboplatin are less likely to complete weekly paclitaxel and dose-dense AC without dose modifications or early discontinuation due to toxicity 4
• Careful patient selection is essential when using intensive regimens with higher toxicity profiles 5
• Regular monitoring of blood counts and appropriate supportive care are crucial during treatment 5

Algorithm for Selecting Neoadjuvant Therapy for TNBC

1. Determine disease stage (I, II, or III)
2. For Stage II-III TNBC:
   • First choice: KN522 protocol (taxanes, carboplatin, anthracyclines, cyclophosphamide with pembrolizumab) 1
   • Alternative if immunotherapy contraindicated: Sequential anthracycline-taxane based therapy with consideration of carboplatin 1, 3
3. For Stage I TNBC:
   • T1a: Individualize based on risk factors 1
   • T1b-c: Standard chemotherapy with consideration of carboplatin addition 1
4. Assess response after neoadjuvant therapy to guide adjuvant treatment 1
5. For residual disease: Consider capecitabine (if BRCA wild-type) or continue pembrolizumab if used in neoadjuvant setting 1