What are the adjuvant treatment options for a patient with non-metastatic triple-negative breast cancer (TNBC) who has completed neoadjuvant chemotherapy and surgery?

Adjuvant Treatment Options for Triple-Negative Breast Cancer After Neoadjuvant Chemotherapy and Surgery

For patients with TNBC who have completed neoadjuvant chemotherapy and surgery, adjuvant pembrolizumab should be continued to complete the full treatment course regardless of pathologic response, and additional therapy should be determined based on germline BRCA status and presence of residual disease. 1, 2, 3, 4

Primary Adjuvant Strategy: Pembrolizumab Continuation

• Complete the full pembrolizumab course (9 cycles of 200 mg IV every 3 weeks) after surgery, regardless of whether pathologic complete response (pCR) was achieved or residual disease remains. 1, 2, 3, 4
• This recommendation applies to all patients who received neoadjuvant pembrolizumab as part of the KEYNOTE-522 protocol (pembrolizumab + carboplatin + paclitaxel followed by anthracycline + cyclophosphamide). 2, 4
• The benefit of pembrolizumab is independent of PD-L1 expression status. 2, 3

Algorithm for Additional Adjuvant Therapy Based on Residual Disease and BRCA Status

For Patients with Germline BRCA1/2 Pathogenic Variants:

Add adjuvant olaparib 300 mg orally twice daily for 1 year after completing all chemotherapy, surgery, and radiation therapy. 1, 3

Specific Eligibility Criteria for Olaparib:

If surgery was performed first (adjuvant chemotherapy setting):

• Tumor size >2 cm OR any involved axillary lymph nodes 1
• At least 4 involved axillary lymph nodes if hormone receptor-positive disease 1

If neoadjuvant chemotherapy was given:

• Any residual invasive cancer in TNBC 1
• For hormone receptor-positive disease: residual disease with clinical stage, pathologic stage, estrogen receptor, and tumor grade score ≥3 1

For Patients WITHOUT Germline BRCA1/2 Mutations and WITH Residual Disease:

Offer adjuvant capecitabine 1,250 mg/m² orally twice daily on days 1-14 of a 21-day cycle for 6-8 cycles. 1, 3

Key Considerations for Capecitabine:

• Preferentially use capecitabine in patients with hormone receptor-negative (triple-negative) disease rather than hormone receptor-positive disease. 1
• The CREATE-X trial demonstrated improved disease-free survival (HR 0.53, P=0.02) and overall survival (HR 0.55, P=0.03) in TNBC patients with residual disease after neoadjuvant anthracycline and taxane therapy. 1
• Reduce capecitabine dose in patients ≥65 years old, as the standard 1,250 mg/m² dose is associated with higher toxicity in this population. 1
• Hand-foot syndrome occurs in 73.4% of patients (11.1% grade 3), which is the most frequent adverse event. 1

For Patients WITHOUT Germline BRCA1/2 Mutations and WITH pCR:

Continue adjuvant pembrolizumab only; no additional chemotherapy is indicated. 2, 3, 4

Critical Implementation Points

Timing Sequence:

1. Complete neoadjuvant pembrolizumab + chemotherapy (8 cycles total: 4 cycles paclitaxel-carboplatin-pembrolizumab, then 4 cycles anthracycline-cyclophosphamide-pembrolizumab) 2, 4
2. Perform definitive surgery 2-4 weeks after completing neoadjuvant therapy 5
3. Administer radiation therapy as indicated 3
4. Begin adjuvant pembrolizumab (9 cycles) after surgery and radiation 2, 4
5. For BRCA mutation carriers: start olaparib after completing all chemotherapy, surgery, and radiation 1, 3
6. For patients with residual disease and wild-type BRCA: consider capecitabine (can be given concurrently with pembrolizumab or sequentially) 1, 3

Important Caveats and Pitfalls

Capecitabine Considerations:

• The OlympiA trial (which established olaparib's role) did not permit postneoadjuvant capecitabine, so the relative efficacy of olaparib versus capecitabine in BRCA-mutated patients with residual disease cannot be directly compared. 1
• In clinical practice, if a patient has both a BRCA mutation and residual disease, prioritize olaparib over capecitabine based on the stronger evidence and targeted mechanism. 1, 3

Pembrolizumab Safety Monitoring:

• Continue monitoring for immune-related adverse events throughout the adjuvant pembrolizumab course, including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. 4
• The safety profile in the adjuvant setting mirrors that of the neoadjuvant phase. 4

Olaparib Safety Monitoring:

• Monitor complete blood counts regularly for myelodysplastic syndrome and acute myelogenous leukemia, as PARP inhibitors are DNA-interacting drugs with potential to induce hematologic malignancies. 1
• Further long-term follow-up is needed to fully characterize this risk. 1

Quality of Life:

• No significant problems with global quality of life measurements were noted in the OlympiA trial at interim analysis (2.5-year median follow-up). 1
• Pembrolizumab safety and tolerability in KEYNOTE-522 were manageable. 1

Radiation Therapy Integration

• Radiation to the breast is standard after breast-conserving surgery. 3
• Post-mastectomy radiation therapy is indicated for positive lymph nodes, positive or close surgical margins, and should be considered for stage IIB disease based on nodal burden. 3
• Radiation should be completed before starting olaparib in BRCA mutation carriers. 1, 3

Prognostic Context

• Pathologic complete response (pCR) is a strong prognostic indicator regardless of BRCA status, with significantly improved long-term outcomes. 1, 3
• However, even patients achieving pCR should complete adjuvant pembrolizumab as the KEYNOTE-522 protocol demonstrated event-free survival benefit (HR 0.63,95% CI 0.48-0.82, P<0.001) with continuation of immunotherapy. 2, 4