What is the current treatment for a patient with stage III Triple Negative Breast Cancer (TNBC)?

Treatment of Stage III Triple-Negative Breast Cancer

For stage III TNBC, neoadjuvant chemotherapy with pembrolizumab combined with carboplatin, taxanes, anthracyclines, and cyclophosphamide is the current standard of care, followed by surgery, completion of adjuvant pembrolizumab for one year, and radiation therapy. 1, 2

Neoadjuvant Systemic Therapy (Preferred Approach)

Neoadjuvant therapy is strongly preferred over upfront surgery for stage III TNBC because it allows tumor downstaging, provides prognostic information through pathologic response assessment, and enables tailoring of post-surgical treatment. 3, 1

Standard Neoadjuvant Regimen (KEYNOTE-522 Protocol)

The preferred regimen includes: 1, 2, 4

• Pembrolizumab (immune checkpoint inhibitor) concurrent with chemotherapy throughout the neoadjuvant phase
• Carboplatin plus paclitaxel (taxane phase)
• Followed by anthracycline (doxorubicin or epirubicin) plus cyclophosphamide
• The benefit from pembrolizumab is independent of PD-L1 status 1, 4

Alternative Neoadjuvant Regimens

If the pembrolizumab-based regimen is not feasible: 3, 2

• Dose-dense anthracycline-taxane chemotherapy remains an acceptable standard
• Sequential regimens: AC (doxorubicin/cyclophosphamide) or EC (epirubicin/cyclophosphamide) followed by paclitaxel every 2 weeks (dose-dense) 2
• AC followed by weekly paclitaxel or docetaxel every 3 weeks are also acceptable 2

Important caveat: The St. Gallen 2021 panel did not recommend routine addition of immune checkpoint inhibitors as neoadjuvant therapy at that time, and panelists remained divided on carboplatin addition. 3 However, the more recent KEYNOTE-522 data has shifted practice toward pembrolizumab-based regimens as the new standard. 1, 2

Surgical Management

After completion of neoadjuvant chemotherapy: 1, 2

• Lumpectomy with level I/II axillary dissection if adequate margins can be achieved and tumor has responded sufficiently
• Total mastectomy with level I/II axillary lymph node dissection if lumpectomy is not feasible or for larger residual tumors 3
• Delayed breast reconstruction may be more appropriate than immediate reconstruction given the high likelihood of requiring post-mastectomy radiation 1

Axillary Management After Neoadjuvant Therapy

Critical pitfall to avoid: Axillary management must be based on both pre-treatment and post-treatment nodal status. 3, 2

• If residual macrometastases (>2 mm) are found in sentinel nodes after neoadjuvant therapy, completion axillary lymph node dissection is required 3, 2
• Patients with clinically positive axillary nodes after neoadjuvant therapy require axillary node dissection 3
• Patients who convert from clinically N1 to clinically N0 after neoadjuvant treatment may be candidates for sentinel node biopsy if at least three sentinel nodes can be identified and resected 3

Post-Surgical Adjuvant Therapy

Completion of Immunotherapy

Continue adjuvant pembrolizumab to complete the full one-year treatment course, regardless of whether pathologic complete response (pCR) was achieved. 1, 2, 4 This recommendation applies to all patients who started pembrolizumab in the neoadjuvant phase.

Additional Adjuvant Therapy Based on Residual Disease

For patients with residual invasive disease after neoadjuvant chemotherapy: 1, 2, 4

• Capecitabine 1,250 mg/m² PO twice daily on days 1-14 of 21-day cycles for 6-8 cycles if germline BRCA1/2 wild-type 1, 2
• This improves recurrence-free survival (HR 0.53) and overall survival (HR 0.55) in TNBC with residual disease 2

For patients with germline BRCA1/2 mutations: 1, 2, 4

• Adjuvant olaparib for 1 year after completion of chemotherapy and surgery, particularly if residual disease is present 1, 2
• This applies to patients with ≥pT2 or ≥pN1 disease 2

Genetic Testing Requirement

All patients with stage III TNBC should undergo germline BRCA1/2 mutation testing at diagnosis to guide adjuvant therapy decisions. 1, 2, 4 Consider PALB2 assessment as well. 1

Radiation Therapy

Radiation therapy is mandatory for stage III TNBC and should be based on pre-chemotherapy characteristics. 3

Post-Mastectomy Radiation Therapy (PMRT)

For stage III disease: 3

• Chest wall radiation is required
• Supraclavicular lymph node radiation is required
• Internal mammary lymph node radiation should be strongly considered 3

Radiation After Breast-Conserving Surgery

• Whole breast radiation is standard 1
• Boost radiation is favored for TNBC subtype given its high-grade nature 3

Regional Nodal Radiation Individualization

For patients who received neoadjuvant therapy, regional radiation volumes can be individualized: 3

• Highest-risk group (clinically N+ at baseline with residual nodal involvement after neoadjuvant treatment, or clinically N+ at baseline with no residual tumor but not intermediate risk): RT to level 1-3 axillary nodes (excluding surgically removed areas), supraclavicular nodes, and internal mammary nodes 3
• Intermediate-risk group (clinically N1 at baseline with no residual tumor in lymph nodes; without ALND; without lymphovascular invasion or extranodal extension): exclusive level 1-2 axillary RT 3
• Lowest-risk group (clinically node negative at baseline with no residual tumor in lymph nodes): no regional field radiation required 3

Important note: Even patients achieving pCR who initially presented with clinically positive axillary nodes should receive regional nodal irradiation. 3

Treatment Timeline and Coordination

Critical pitfall to avoid: Delaying neoadjuvant therapy beyond 2-4 weeks after diagnosis completion should be avoided. 2 Deliver all planned chemotherapy without unnecessary breaks between neoadjuvant and adjuvant phases to maximize probability of achieving pCR. 2

The treatment sequence is: 1, 2

1. Core biopsy confirmation with ER/PR/HER2 status
2. Referral to breast surgeon and radiation oncologist before initiating neoadjuvant therapy
3. Neoadjuvant chemotherapy with pembrolizumab (approximately 4-6 months)
4. Surgery
5. Adjuvant pembrolizumab completion (to total 1 year)
6. Additional adjuvant therapy based on pathologic response (capecitabine if residual disease and BRCA wild-type, or olaparib if BRCA-mutated)
7. Radiation therapy (can be given concurrently with pembrolizumab and endocrine therapy if applicable)

Prognostic Considerations

Pathologic complete response (pCR) is the strongest prognostic indicator and serves as a surrogate for survival outcomes. 1, 5, 6 Patients achieving pCR have significantly better long-term outcomes, while those with residual disease require treatment intensification with capecitabine or olaparib as outlined above. 1, 2