What are the recent guidelines for neoadjuvant chemotherapy (NACT) in triple-negative breast cancer (TNBC)?

Recent Guidelines for Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer

For stage II-III TNBC, the preferred neoadjuvant regimen is pembrolizumab combined with carboplatin and paclitaxel, followed by pembrolizumab with anthracycline (doxorubicin or epirubicin) and cyclophosphamide, then continued as adjuvant pembrolizumab for up to one year regardless of pathologic response. 1, 2, 3

Standard Neoadjuvant Approach by Stage

Stage II-III TNBC (Preferred Regimen)

• Neoadjuvant pembrolizumab 200 mg IV every 3 weeks combined with:

  • Carboplatin (AUC 5-6) every 3 weeks + paclitaxel 80 mg/m² weekly for 12 weeks
  • Followed by cyclophosphamide + doxorubicin or epirubicin every 2-3 weeks for 4 cycles
  • Then adjuvant pembrolizumab 200 mg every 3 weeks for up to 9 additional cycles (total 1 year of pembrolizumab) 1, 2, 3

• The pembrolizumab benefit is independent of PD-L1 status—do not withhold based on PD-L1 testing 2, 4

Stage I TNBC

• T1a (≤5 mm): Consider case-by-case; chemotherapy may be omitted in select patients 1
• T1b (6-10 mm): Taxane-cyclophosphamide (TC) regimen 1
• T1c (11-20 mm): Anthracycline-taxane (AC/T) chemotherapy; consider adding carboplatin and pembrolizumab for higher-risk features (young age, high-grade histology) 1, 2

Alternative Neoadjuvant Regimens (When Pembrolizumab Not Used)

Acceptable Sequential Anthracycline-Taxane Regimens

• Dose-dense AC followed by paclitaxel every 2 weeks (preferred alternative) 1, 2
• Dose-dense AC followed by weekly paclitaxel 1
• AC followed by docetaxel every 3 weeks 1

Carboplatin Addition Without Immunotherapy

• The St. Gallen 2021 consensus showed 60% of panelists voted against routine carboplatin addition to anthracycline-taxane-alkylator therapy 1
• However, carboplatin addition increases pCR rates (60% vs 44%, p=0.0018) and improves DFS (HR 0.63,95% CI 0.53-0.75) and OS (HR 0.69,95% CI 0.55-0.86) 5, 6
• Consider carboplatin addition in select patients with BRCA mutations or high-risk features when pembrolizumab is not available 1, 6

Post-Neoadjuvant Therapy Based on Response

Residual Disease After Standard Neoadjuvant Chemotherapy

• Add capecitabine 1000-1250 mg/m² twice daily for 14 days every 3 weeks for 6-8 cycles if germline BRCA1/2 wild-type 1, 2, 4
• Do not substitute platinum for capecitabine in this setting—outcomes are not improved 1

After Pembrolizumab-Based Neoadjuvant Therapy

• Continue adjuvant pembrolizumab regardless of pCR achievement 2, 4
• The benefit of ongoing pembrolizumab applies to both responders and non-responders 2

Patients with Germline BRCA1/2 Mutations

• Add adjuvant olaparib 300 mg twice daily for 1 year if:
  • ≥pT2 or ≥pN1 disease after adjuvant chemotherapy, OR
  • Residual disease after neoadjuvant chemotherapy 1
• Olaparib can be given concurrently with capecitabine if both are indicated 1

Critical Treatment Principles

Pre-Treatment Requirements

• Obtain core biopsy confirming invasive TNBC with ER/PR/HER2 status before starting therapy 7
• Refer to breast surgeon and radiation oncologist before initiating neoadjuvant therapy 7
• Test all TNBC patients for germline BRCA1/2 mutations to guide adjuvant therapy decisions 4

Treatment Duration and Timing

• Administer at least 6 cycles of anthracycline-taxane regimen over 4-6 months 7
• Perform surgery 2-4 weeks after completing neoadjuvant chemotherapy 7
• Total pembrolizumab duration is 1 year (neoadjuvant + adjuvant combined) 1, 3

Common Pitfalls to Avoid

Toxicity Management

• Expect increased hematologic toxicity with carboplatin: grade 3/4 neutropenia (RR 1.53), anemia (RR 8.20), and thrombocytopenia (RR 7.59) 6
• Chemotherapy delays (RR 2.23) and dose reductions (RR 1.77) are more common with platinum-containing regimens 6
• Monitor for immune-related endocrinopathies with pembrolizumab, some of which are irreversible 1

Regimen Selection Errors

• Do not use anthracycline-free regimens as standard—the ESO-ESMO 2022 consensus does not support routine non-anthracycline regimens for TNBC 1
• Do not give concurrent anthracycline and trastuzumab (not applicable to TNBC, but avoid confusion in mixed practices) 7
• Do not delay neoadjuvant therapy beyond 2-4 weeks after diagnosis completion 7

Axillary Management After Neoadjuvant Therapy

• Perform completion axillary dissection if residual macrometastases (>2 mm) found in sentinel nodes 1
• 73% of St. Gallen panelists recommend ALND for any residual macrometastatic disease in even one of three sentinel nodes 1
• Patients with clinically positive nodes after neoadjuvant therapy require axillary dissection 1