What is the recommended neoadjuvant (pre‑operative) therapy for early‑stage breast cancer based on estrogen‑receptor (ER) and progesterone‑receptor (PR) status, HER2 status, menopausal state, and any known genetic mutations such as BRCA?

Neoadjuvant Therapy for Early-Stage Breast Cancer

For early-stage breast cancer ≥2 cm or node-positive disease, neoadjuvant therapy is the preferred approach, with regimen selection determined by tumor subtype: HER2-positive tumors require dual HER2 blockade (pertuzumab + trastuzumab) with taxane-based chemotherapy; triple-negative tumors require anthracycline-taxane sequential regimens; and hormone receptor-positive/HER2-negative tumors require either chemotherapy (if high-risk features) or endocrine therapy (if low-risk, postmenopausal). 1, 2, 3

HER2-Positive Disease (≥T2 or ≥N1)

Standard Neoadjuvant Regimen

• Dual HER2 blockade with pertuzumab + trastuzumab combined with taxane-based chemotherapy is the standard of care for tumors ≥2 cm or node-positive disease. 1, 4
• The preferred chemotherapy backbone is docetaxel + carboplatin + trastuzumab + pertuzumab (TCHP), which achieved pathologic complete response (pCR) rates of 66.2% in the TRYPHAENA trial—the highest among pertuzumab-containing regimens. 1, 4
• An alternative is sequential anthracycline-based therapy (FEC or AC) followed by taxane + pertuzumab + trastuzumab, though anthracyclines must never be given concurrently with HER2-targeted agents due to severe cardiotoxicity risk. 1, 4
• The NeoSphere trial demonstrated that pertuzumab + trastuzumab + docetaxel achieved 45.8% pCR versus only 29% with trastuzumab + docetaxel alone (p=0.0063). 1

Post-Neoadjuvant Management Based on Response

• If pathologic complete response (pCR) is achieved: Continue pertuzumab + trastuzumab to complete 1 year total (18 cycles) of anti-HER2 therapy. 4, 3
• If residual invasive disease remains: Switch to trastuzumab emtansine (T-DM1) for 14 cycles, which significantly improves invasive disease-free survival (HR 0.50; 95% CI 0.39-0.64) compared to continuing trastuzumab. 1, 2, 3

Critical Pitfall to Avoid

• Do not attempt de-escalation by omitting taxanes—the KRISTINE trial showed T-DM1 + pertuzumab without chemotherapy produced significantly lower pCR (44.4% vs 55.7%) and worse 3-year event-free survival (HR 2.61) with 15 pre-surgical locoregional progressions versus zero in the chemotherapy arm. 1, 4

Triple-Negative Breast Cancer (Stage II-III)

Standard Neoadjuvant Regimen

• Sequential anthracycline-taxane regimens are the backbone, such as doxorubicin-cyclophosphamide (AC) × 4 cycles followed by taxane × 4 cycles. 2, 3
• Addition of carboplatin to taxanes increases pCR rates in triple-negative tumors, though data on long-term outcomes remain conflicting, particularly in BRCA1/2 mutation carriers. 1
• Pembrolizumab added to chemotherapy is recommended based on the KEYNOTE-522 trial showing improved outcomes. 2

Post-Neoadjuvant Management

• For residual disease after standard neoadjuvant chemotherapy: Consider adjuvant capecitabine for 6-8 cycles, which improved disease-free survival and overall survival in the CREATE-X trial (particularly in Asian patients). 1, 2
• For germline BRCA1/2 mutation carriers with residual disease: Adjuvant olaparib for 1 year is strongly endorsed (>93% of St. Gallen panelists), based on the OlympiA trial showing benefit in stage II-III HER2-negative cancers. 1, 3

Hormone Receptor-Positive/HER2-Negative Disease

Decision Algorithm: Chemotherapy vs. Endocrine Therapy

Choose neoadjuvant chemotherapy if:

• Tumor >3 cm with positive nodes 3
• Ki-67 >30% (indicates chemotherapy-responsive disease) 3
• Grade 3 histology 3
• Low or absent ER/PR expression 3
• Non-lobular histology (invasive ductal carcinoma responds better) 3

Choose neoadjuvant endocrine therapy if:

• Postmenopausal patient with ER-rich tumor (Allred score 7-8) 1
• Lobular histology or luminal A-like subtype (less responsive to chemotherapy) 1
• Patient unsuitable for or declining chemotherapy 1
• Duration: 4-8 months or until maximum response 1

Specific Endocrine Regimens by Menopausal Status

Postmenopausal patients:

• Aromatase inhibitors (anastrozole, letrozole, or exemestane) are superior to tamoxifen for neoadjuvant endocrine therapy, providing higher rates of breast-conserving surgery and objective response. 1
• The ACOSOG Z1031 trial showed response or stable disease in 60-72% of patients after 16 weeks of AI therapy. 1

Premenopausal patients:

• Neoadjuvant endocrine therapy is not routinely recommended outside clinical trials. 1
• In highly selected patients with luminal A-like tumors and no chemotherapy indication who are not candidates for optimal surgery, consider ovarian function suppression (OFS) + aromatase inhibitor. 1

Post-Neoadjuvant Adjuvant Therapy

• All hormone receptor-positive patients require adjuvant endocrine therapy (category 1 recommendation) regardless of chemotherapy use. 1
• Premenopausal: Tamoxifen 5 years ± ovarian suppression, or AI 5 years + ovarian suppression/ablation 1
• Postmenopausal: Aromatase inhibitor preferred 3

Special Considerations for BRCA Mutation Carriers

• Genetic testing is recommended for all patients meeting OlympiA trial criteria (stage II-III HER2-negative disease) to identify candidates for adjuvant olaparib. 1
• The addition of platinum compounds (carboplatin) to neoadjuvant chemotherapy in BRCA mutation carriers shows conflicting long-term outcome data. 1

Axillary Management After Neoadjuvant Therapy

• If sentinel lymph node biopsy was performed before neoadjuvant therapy and was negative: No further axillary staging needed. 1
• If sentinel lymph node biopsy before neoadjuvant therapy was positive: Level I/II axillary lymph node dissection should be performed after neoadjuvant therapy. 1
• If clinically node-positive at diagnosis with residual macrometastatic disease (>2 mm) in sentinel nodes after neoadjuvant therapy: Axillary lymph node dissection is indicated. 3

Critical Pitfalls to Avoid

• Always obtain core needle biopsy before initiating neoadjuvant therapy to document ER/PR/HER2 status and histologic grade, as 19% of patients achieve pCR making post-treatment analysis impossible. 3, 5
• Consider retesting receptor status in residual disease after neoadjuvant therapy: Changes in ER status occur in 5-25% of cases, PR status changes in 14.5-67%, and HER2 status changes less frequently but can occur, potentially impacting adjuvant treatment decisions. 6, 5, 7
• Do not use neoadjuvant therapy for low-risk ER-positive disease (≤2 cm, grade 1, node-negative) outside clinical trials, as loss of accurate pathologic staging outweighs minimal benefit. 3
• Radiation therapy planning must be based on initial (pre-treatment) staging, not post-neoadjuvant findings—initially node-positive patients with residual disease require comprehensive regional nodal irradiation regardless of response. 3
• Complete all planned chemotherapy without unnecessary breaks between preoperative and postoperative periods to maximize pCR probability. 1