What is the recommended first-line treatment for a patient with locally advanced breast cancer?

Neoadjuvant Chemotherapy for Locally Advanced Breast Cancer

Systemic therapy, specifically neoadjuvant chemotherapy, should be the initial treatment for locally advanced breast cancer, not surgery or radiotherapy. 1

Primary Treatment Approach

Neoadjuvant systemic therapy is the standard first-line treatment for all patients with locally advanced breast cancer (stage IIIA, IIIB, IIIC), with the specific regimen determined by tumor biology. 1, 2

• Systemic therapy must be initiated before any surgical intervention or radiotherapy 1
• Surgery or radiotherapy as initial treatment is contraindicated in locally advanced disease 1
• A combined treatment modality based on multidisciplinary approach (systemic therapy, surgery, and radiotherapy) is required after initial systemic therapy 1

Pre-Treatment Requirements

Before initiating neoadjuvant therapy, several critical steps must be completed:

• Obtain a core biopsy for histology and biomarker analysis (ER, PR, HER2, proliferation/grade) to guide treatment decisions 1, 2
• Complete full staging workup including chest and abdominal imaging (preferably CT) and bone imaging to rule out metastatic disease 1
• Refer patient to both a breast surgeon and radiation oncologist before starting chemotherapy 2

Treatment Selection by Tumor Subtype

Triple-Negative Breast Cancer

• Anthracycline-and-taxane-based chemotherapy is the recommended initial treatment 1
• Administer at least six cycles over 4-6 months 2
• The backbone regimen includes anthracyclines and taxanes given either sequentially or concurrently 1, 3

HER2-Positive Disease

• Concurrent taxane and anti-HER2 therapy (trastuzumab) is required as it increases pathological complete response rates 1
• Anthracycline-based chemotherapy should be incorporated but administered sequentially with anti-HER2 therapy, never concurrently due to cardiac toxicity risk 1, 2
• Patients should receive preoperative systemic therapy incorporating trastuzumab for at least 9 weeks 1
• A pertuzumab-containing regimen may be administered preoperatively to patients with T2 or N1, HER2-positive disease 1

Hormone Receptor-Positive/HER2-Negative Disease

• Options include anthracycline-and-taxane-based chemotherapy or endocrine therapy 1
• Choose chemotherapy over endocrine therapy if the tumor demonstrates aggressive features: high grade, high Ki67, or if rapid response is needed 1
• For postmenopausal women receiving endocrine therapy, an aromatase inhibitor is preferred 1
• Endocrine therapy duration should be at least 6 months or until maximum response is achieved 2

Standard Chemotherapy Regimens

The specific regimens recommended include:

• Anthracycline and taxane-based regimens administered either sequentially or in combination 1, 3
• Several chemotherapy regimens with activity in the preoperative setting are those recommended in the adjuvant setting 1
• Administration of all chemotherapy prior to surgery is preferred 1

Post-Neoadjuvant Therapy Management

Surgical Approach for Responders

• Following clinical response to preoperative chemotherapy, local therapy consists of either total mastectomy with level I/II axillary dissection or lumpectomy with level I/II axillary dissection 1
• Breast-conserving surgery may be possible in carefully selected patients with good response 1
• For inflammatory breast cancer, mastectomy with axillary dissection is recommended in almost all cases, even with good response 1
• Axillary staging following preoperative systemic therapy may include sentinel node biopsy or level I/II dissection 1

Radiation Therapy

• Chest wall (or breast) and supraclavicular node irradiation is required due to sufficient risk for local recurrence 1
• If internal mammary lymph nodes are involved, they should be irradiated 1
• Loco-regional radiotherapy is required even when pathological complete response is achieved 1

Adjuvant Systemic Therapy

• Complete planned chemotherapy regimen if not completed preoperatively 1
• Complete up to one year of trastuzumab therapy if HER2-positive (category 1) 1
• Trastuzumab may be administered concurrently with radiation therapy and endocrine therapy 1
• Add endocrine therapy if ER-positive and/or PR-positive (sequential chemotherapy followed by endocrine therapy) 1

Management of Non-Responders

• Patients with disease progression during preoperative chemotherapy should be considered for palliative breast irradiation to enhance local control 1
• If locally advanced breast cancer remains inoperable after systemic therapy and radiation, 'palliative' mastectomy should not be performed unless surgery is likely to result in overall improvement in quality of life 1
• Consider additional systemic chemotherapy and/or preoperative radiation 1

Critical Pitfalls to Avoid

• Do not perform surgery or radiotherapy as initial treatment - systemic therapy must come first 1
• Do not administer concomitant anthracycline and trastuzumab outside clinical trials due to cardiac toxicity 1, 2
• Do not use neoadjuvant endocrine therapy in patients who are candidates for chemotherapy unless specific contraindications exist 1
• Do not delay surgery beyond 2-4 weeks after completion of neoadjuvant chemotherapy to allow adequate response assessment 2
• Accurate assessment of in-breast tumor or regional lymph node response to preoperative chemotherapy is difficult and should include physical examination and imaging studies that were abnormal at initial staging 1

Survival Outcomes

• Neoadjuvant and adjuvant therapy demonstrate equivalent survival outcomes - neoadjuvant treatment is not an inferior alternative 2, 4
• Patients achieving pathological complete response have significantly improved long-term outcomes 2, 3
• The probability of 5-year survival is substantially higher in those with complete response compared to partial response 5