What is the role of neoadjuvant therapy in early stage breast cancer?

Neoadjuvant Therapy in Early Stage Breast Cancer

For patients with stage II or III breast cancer, neoadjuvant systemic therapy is the preferred approach, particularly for HER2-positive and triple-negative subtypes, as it provides effective systemic therapy, improves surgical options in the breast and axilla, and allows tailoring of adjuvant treatment based on tumor response. 1

Primary Indications and Benefits

Neoadjuvant therapy should be strongly considered for:

• Stage II-III breast cancer, especially HER2-positive or triple-negative disease 1
• Inflammatory breast cancer or inoperable locally advanced tumors requiring downstaging 1
• Patients where breast-conserving surgery is not initially feasible or would result in suboptimal cosmetic outcomes 1
• Any patient who would receive adjuvant chemotherapy, as neoadjuvant therapy provides equivalent survival with the added benefit of in vivo assessment of treatment response 1, 2

The key advantages include downstaging tumors to enable breast conservation, providing early information on tumor biology and response, and allowing risk stratification based on pathologic complete response (pCR) to optimize post-neoadjuvant treatment 1.

Subtype-Specific Neoadjuvant Regimens

HER2-Positive Breast Cancer

For stage II-III HER2-positive disease, neoadjuvant chemotherapy combined with dual HER2 blockade (trastuzumab and pertuzumab) is strongly endorsed. 1

• Preferred chemotherapy backbone: Taxane-based chemotherapy with either anthracycline-based or carboplatin-based regimens 1
• Anthracycline-free alternatives (carboplatin with taxanes) show similar outcomes to anthracycline-containing regimens while improving cardiac safety 1
• Dual HER2 blockade yields higher pCR rates compared to trastuzumab alone and lower risks of recurrence 1

Critical caveat: Concomitant anthracycline and trastuzumab should only occur in clinical trials due to cardiac toxicity concerns 2

Triple-Negative Breast Cancer (TNBC)

Neoadjuvant therapy is the standard approach for stage II-III TNBC. 1

• Preferred regimen: Dose-dense anthracycline- and taxane-based chemotherapy 1
• Carboplatin addition: Panelists remain divided; a majority (60%) voted against routine carboplatin use in 2021, though some favor its inclusion particularly for node-positive disease 1
• Immune checkpoint inhibitors: The 2021 St. Gallen panel did not recommend adding immune checkpoint inhibitors as neoadjuvant therapy 1

Important note: While the IMpassion031 trial showed improved pCR rates with atezolizumab plus chemotherapy (58% vs 41%, p=0.0044) 3, this was not yet incorporated into the 2021 St. Gallen guidelines. Clinical judgment should consider emerging evidence.

Hormone Receptor-Positive/HER2-Negative Disease

Neoadjuvant chemotherapy can effectively downstage HR-positive/HER2-negative cancers for surgical purposes, though pCR rates are uncommon (<10%). 1

• For low-grade and/or low-genomic risk tumors: Neoadjuvant endocrine therapy is favored over chemotherapy 1
• Duration of neoadjuvant endocrine therapy: At least 6 months, or continue until maximum response is achieved 1
• Genomic assays on core biopsies are endorsed as a strategy for choosing between chemotherapy or endocrine therapy 1
• A short-term decline in Ki67 during initial neoadjuvant endocrine therapy identifies patients with endocrine-sensitive tumors unlikely to benefit from chemotherapy 1

Post-Neoadjuvant Treatment Strategies

Post-neoadjuvant therapy should be customized by the extent of residual cancer following preoperative treatment. 1

For HER2-Positive Disease:

• Patients achieving pCR: Continue anti-HER2 therapy to complete 1 year total duration 1
• Patients with residual disease: Switch to trastuzumab emtansine (T-DM1) for 14 courses 1
• Pertuzumab addition to trastuzumab in post-neoadjuvant setting need not be routinely considered for clinically node-negative tumors at baseline that achieve pCR 1

For Triple-Negative Disease:

• Patients with residual invasive cancer after neoadjuvant therapy: Capecitabine is recommended 1

Axillary Management After Neoadjuvant Therapy

The majority of the St. Gallen panel (73%) voted that axillary lymph node dissection should be indicated following neoadjuvant chemotherapy when there is any residual macrometastatic cancer (>2 mm) in the sentinel node biopsy, or in just one of three sentinel nodes. 1

• Patients with clinically positive axillary lymph nodes after neoadjuvant therapy require axillary node dissection 1
• For lower sentinel node tumor burdens (micrometastasis or isolated tumor cells in one of three sentinel nodes), many panelists felt axillary radiation could be an alternative to axillary dissection, though others urged caution 1

Regional Radiation Therapy Considerations

In patients who received neoadjuvant systemic therapy, the indications and target volumes for regional radiation therapy can be individualized based on initial tumor stage and tumor response. 1

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

Common Pitfalls to Avoid

• Do not assume neoadjuvant therapy is inferior to adjuvant therapy: Meta-analyses demonstrate equivalent survival outcomes 4, 2
• Do not use neoadjuvant endocrine therapy in patients who are candidates for chemotherapy unless specific contraindications exist or the tumor has low-risk features 1
• Do not routinely offer neoadjuvant therapy to patients with T1a or T1bN0 TNBC 2
• Ensure multidisciplinary evaluation before initiating neoadjuvant therapy, including referral to breast surgeon and radiation oncologist 2
• Obtain core biopsy confirmation of invasive cancer and predictive markers (ER/PR, HER2 status, grade) before starting treatment 2