What is the best treatment approach for a 64-year-old female with breast cancer, specifically T2 (tumor size >2cm but ≤5cm) N1 (metastasis in 1-3 axillary lymph nodes) triple negative (estrogen receptor negative, progesterone receptor negative, and human epidermal growth factor receptor 2 negative)?

Treatment of T2N1 Triple-Negative Breast Cancer in a 64-Year-Old Female

This patient requires neoadjuvant chemotherapy with sequential anthracycline-taxane regimen (AC or EC × 4 cycles followed by taxane × 4 cycles), followed by definitive surgery with axillary staging, then radiation therapy to the chest wall and regional nodes. 1, 2

Initial Treatment: Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy is the preferred first-line approach for this T2N1 triple-negative presentation, as it provides effective systemic therapy, allows tumor downstaging to improve surgical options, and enables response-based treatment tailoring. 2

Specific Chemotherapy Regimen

• The standard regimen is AC (doxorubicin/cyclophosphamide) or EC (epirubicin/cyclophosphamide) for 4 cycles followed by a taxane (paclitaxel or docetaxel) for 4 cycles, with total duration of 12-24 weeks. 1, 2

• Sequential administration of anthracyclines followed by taxanes is superior to concurrent administration and reduces toxicity while maintaining efficacy. 2

• Fluorouracil (5-FU) should be omitted from anthracycline-based regimens as it adds toxicity without improving efficacy; therefore AC or EC (not FAC or FEC) are the preferred anthracycline backbones. 2

• Anthracycline- and taxane-based chemotherapy is specifically recommended as initial treatment for triple-negative locally advanced breast cancer. 1

Important Monitoring During Neoadjuvant Therapy

• Patients should be closely observed during neoadjuvant chemotherapy, and if there is any evidence of tumor progression, the chemotherapeutic regimen should be modified or surgery performed immediately to avoid losing the opportunity for potentially effective treatment. 3

• Regular cardiac assessments are recommended before, during, and following anthracycline therapy. 2

Surgical Management After Neoadjuvant Therapy

For T2N1 disease after response to neoadjuvant therapy, surgical options include:

• Breast-conserving surgery (lumpectomy) with axillary staging if adequate tumor response allows, as triple-negative breast cancer characteristically shrinks toward its center and has an expanding growth pattern without extensive intraductal spread. 1, 3

• Mastectomy with axillary dissection if lumpectomy is not feasible or if progressive disease is confirmed, with or without breast reconstruction. 1, 2

• Sentinel node biopsy and axillary assessment must be performed with utmost caution, as the regional recurrence rate is higher in triple-negative breast cancer than in other subtypes. 3

Radiation Therapy

Radiation therapy decisions must be based on pre-chemotherapy tumor characteristics, not post-neoadjuvant pathology. 2, 4

Specific Radiation Recommendations

• Radiation therapy is recommended to the chest wall (if mastectomy) or whole breast (if lumpectomy) and supraclavicular lymph nodes. 1, 2

• Strong consideration should be given to including the internal mammary lymph nodes in the radiation therapy field. 2

• Hypofractionated schedules are recommended: moderate (15-16 fractions of 2.5-2.67 Gy per fraction) or ultra-hypofractionated regimens. 2

• Post-mastectomy radiation therapy is recommended for T2 tumors with node-positive disease. 1, 2

Adjuvant Systemic Therapy Considerations

For triple-negative breast cancer, there is no role for endocrine therapy as these tumors lack hormone receptor expression. 1

If Residual Disease After Neoadjuvant Therapy

• Patients with triple-negative metastatic breast cancer who have received at least two prior therapies should be offered treatment with sacituzumab govitecan. 1

• Patients with germline BRCA mutations previously treated with chemotherapy may be offered a PARP inhibitor rather than additional chemotherapy. 1

Critical Sequencing and Pitfalls to Avoid

• Never base radiation therapy planning on post-chemotherapy staging alone - radiation decisions must be based on pre-chemotherapy tumor characteristics (T2N1 in this case). 2, 4

• Never delay surgery if tumor progression occurs during neoadjuvant chemotherapy - immediate surgical intervention is required to preserve treatment efficacy. 3

• Never perform sentinel node biopsy after neoadjuvant chemotherapy outside of clinical trials, as accuracy is compromised; full axillary dissection is preferred in this setting. 1

• Chemotherapy regimens should not be specifically tailored to triple-negative subtype beyond the standard anthracycline-taxane approach, as there is absence of evidence proving differential efficacies for subtype-specific modifications. 1

Expected Outcomes

• Neoadjuvant chemotherapy with anthracycline-taxane regimens produces pathological complete response (pCR) rates higher than 20% in patients with triple-negative breast cancer. 3

• After 3 years, a pCR is associated with good outcomes, whereas a non-pCR sometimes results in distant recurrence, even when residual tumor is minimal. 3

• The local recurrence rate after breast-conserving therapy is not higher in triple-negative breast cancer compared to other subtypes when adequate margins are achieved. 3