What are the different Neoadjuvant Chemotherapy (NACT) regimens for patients with Triple Negative Breast Cancer (TNBC) and Hormone Positive Breast Cancer, including specific trial names and designs, and what are the typical inclusion and exclusion criteria for these regimens?

Neoadjuvant Chemotherapy Regimens for TNBC and Hormone Positive Breast Cancer

Triple-Negative Breast Cancer (TNBC)

Standard Regimen for Stage II-III TNBC: KEYNOTE-522 Protocol

For stage II-III TNBC, the preferred regimen is pembrolizumab combined with carboplatin and paclitaxel, followed by pembrolizumab with anthracycline and cyclophosphamide, then continued as adjuvant pembrolizumab for up to one year regardless of pathologic response. 1, 2

Trial Design:

• KEYNOTE-522: Randomized, double-blind, placebo-controlled Phase 3 trial 2, 3
• Patients received 4 cycles of paclitaxel 80 mg/m² weekly + carboplatin AUC 5 or 6 every 3 weeks + pembrolizumab 200 mg every 3 weeks, followed by 4 cycles of doxorubicin/epirubicin + cyclophosphamide + pembrolizumab, then adjuvant pembrolizumab for 9 additional cycles 2, 4
• Primary endpoints: pathologic complete response (pCR) and event-free survival 5
• Results: pCR rate 64.8% with pembrolizumab-chemotherapy versus 51.2% with chemotherapy alone; event-free survival HR 0.63 (95% CI 0.48-0.82, P<0.001) 4, 3

Inclusion Criteria:

• Previously untreated stage II (cT2 cN0 or higher) or stage III TNBC 1, 2
• ECOG performance status 0-1 2
• Adequate organ function 2
• No contraindications to pembrolizumab or chemotherapy 2

Exclusion Criteria:

• Prior systemic therapy for breast cancer 2
• Active autoimmune disease requiring systemic therapy 2
• Known HIV, hepatitis B, or hepatitis C infection 2
• Pregnancy or breastfeeding 2

Limitations:

• Median follow-up only 30 months at primary analysis 5
• Long-term toxicity data for pembrolizumab in this setting still maturing 1
• Increased toxicity with carboplatin addition (neutropenia, thrombocytopenia) 6, 7

Alternative Regimen: Dose-Dense AC-T

Dose-dense doxorubicin/cyclophosphamide followed by paclitaxel every 2 weeks with G-CSF support is a preferred alternative regimen. 1, 2

Trial Design:

• Multiple trials including CALGB 9741 demonstrated superiority of dose-dense scheduling 2
• Regimen: AC (doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m²) every 2 weeks × 4 cycles, followed by paclitaxel 175 mg/m² every 2 weeks × 4 cycles with G-CSF support 2, 8
• Alternative: AC every 2 weeks × 4, then weekly paclitaxel 80 mg/m² × 12 weeks 1, 2

Inclusion Criteria:

• Stage I (T1c) to stage III TNBC 1
• Adequate cardiac function (LVEF within normal limits) 1, 3
• Adequate bone marrow, hepatic, and renal function 8

Exclusion Criteria:

• Baseline LVEF below institutional normal 1
• Cumulative prior anthracycline exposure approaching maximum (>240 mg/m² doxorubicin equivalent) 4
• Severe hepatic impairment 8

Limitations:

• No direct comparison with pembrolizumab-containing regimens 1
• Higher rates of febrile neutropenia requiring G-CSF support 2
• Cardiac toxicity risk with anthracyclines 1, 3

Carboplatin-Containing Regimens Without Immunotherapy

For patients ineligible for pembrolizumab, carboplatin may be added to anthracycline-taxane backbone, particularly in node-positive disease or germline BRCA1/2 mutation carriers. 1

Trial Design:

• GeparSixto: Randomized Phase 2 trial adding carboplatin AUC 1.5 weekly to dose-dense paclitaxel + non-pegylated liposomal doxorubicin 9, 7
• pCR rate increased from 37% to 53% with carboplatin addition (p=0.005) 7
• CALGB 40603: 2×2 factorial design adding carboplatin and/or bevacizumab to dose-dense AC-T 7
• Carboplatin increased pCR from 41% to 54% (p=0.0018) 7

Inclusion Criteria:

• Stage II-III TNBC 1, 9
• Particularly beneficial in germline BRCA1/2 mutation carriers 1, 9
• Node-positive disease 1, 4

Exclusion Criteria:

• Creatinine clearance <50 mL/min 4
• Baseline thrombocytopenia or neutropenia 4
• Hearing impairment or peripheral neuropathy grade ≥2 4

Limitations:

• Increased hematologic toxicity (thrombocytopenia, neutropenia) 6, 7
• No demonstrated overall survival benefit in unselected populations 7
• Potential impact on fertility in young women 1

Stage-Specific Recommendations

Stage I TNBC:

• T1a (≤5 mm): Chemotherapy case-by-case basis 1
• T1b (6-10 mm): TC (docetaxel + cyclophosphamide) or AC/EC 1
• T1c (11-20 mm): AC/T with consideration of carboplatin and pembrolizumab for higher-risk features 1, 2

Stage II TNBC:

• AC/T chemotherapy with consideration of pembrolizumab for cT2 cN0 1
• Neoadjuvant therapy preferred over adjuvant 1

Stage III TNBC:

• AC/T chemotherapy with pembrolizumab 1
• Neoadjuvant therapy strongly preferred 1

Post-Neoadjuvant Therapy Based on Response

For patients with residual disease after neoadjuvant chemotherapy:

Germline BRCA1/2 wild-type:

• Capecitabine 1,250 mg/m² PO twice daily on days 1-14 of 21-day cycles for 6-8 cycles 1, 2
• Based on CREATE-X trial showing improved disease-free survival (HR 0.70, p=0.01) and overall survival (HR 0.59, p=0.01) 2

Germline BRCA1/2 mutation carriers:

• Olaparib 300 mg PO twice daily for 1 year 1
• Based on OlympiA trial for high-risk features (≥pT2 or ≥pN1, or residual disease after neoadjuvant therapy) 1

Pembrolizumab recipients:

• Continue adjuvant pembrolizumab for 9 courses regardless of pathologic response 1, 2, 3

---

Hormone Receptor-Positive/HER2-Negative Breast Cancer

Neoadjuvant Chemotherapy Approach

For HR-positive/HER2-negative breast cancer requiring neoadjuvant therapy, sequential anthracycline and taxane-based regimens are standard, though neoadjuvant endocrine therapy is preferred in postmenopausal patients with low-risk features. 1

Standard Chemotherapy Regimen:

• AC (doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m²) every 3 weeks × 4 cycles, followed by paclitaxel 175 mg/m² every 3 weeks × 4 cycles 1, 8
• Alternative: Dose-dense AC every 2 weeks × 4, then paclitaxel every 2 weeks × 4 with G-CSF 1
• Alternative: TC (docetaxel 75 mg/m² + cyclophosphamide 600 mg/m²) every 3 weeks × 4-6 cycles for lower-risk disease 10

Inclusion Criteria for Neoadjuvant Chemotherapy:

• Locally advanced or large operable tumors (>2 cm) requiring tumor reduction for breast-conserving surgery 1
• High-risk features: grade 3, high Ki67 (>20%), node-positive, luminal B subtype 1
• Low or absent hormone receptor expression despite ER-positivity 1

Exclusion Criteria:

• Postmenopausal patients with strongly ER/PR-positive (≥10%), low-grade, low Ki67 tumors (better suited for neoadjuvant endocrine therapy) 1
• Baseline LVEF below normal if anthracyclines planned 1

Limitations:

• Lower pCR rates compared to TNBC (10-20% vs. 40-60%) 1, 6
• pCR less predictive of long-term outcomes in HR-positive disease 1
• Chemotherapy-induced amenorrhea may confound endocrine therapy benefits 1

Neoadjuvant Endocrine Therapy

For postmenopausal patients with ER-positive/HER2-negative cancers requiring neoadjuvant therapy but not candidates for chemotherapy, aromatase inhibitors for 4-8 months or until maximum response is preferred. 1

Trial Design:

• IMPACT trial: Compared anastrozole vs. tamoxifen vs. combination in postmenopausal women 1
• No significant difference in clinical response rate between AI and tamoxifen 1
• Duration: 4-8 months or until maximum response 1

Inclusion Criteria:

• Postmenopausal status 1
• ER and PR ≥10% 1
• Low grade, invasive lobular histology, low Ki67 1
• Not candidates for chemotherapy or chemotherapy unlikely to provide benefit 1
• Breast-conserving surgery not possible or suboptimal cosmesis 1

Exclusion Criteria:

• Premenopausal status (limited data, investigational) 1
• High-grade, high Ki67, luminal B features 1
• Rapidly progressive disease requiring urgent surgery 1

Limitations:

• Limited data in premenopausal patients 1
• Lower response rates than chemotherapy in chemotherapy-sensitive tumors 1
• Longer treatment duration (4-8 months vs. 12-18 weeks for chemotherapy) 1

Adjuvant Chemotherapy After Surgery (TAC Regimen)

For adjuvant treatment of node-positive HR-positive breast cancer, paclitaxel 175 mg/m² every 3 weeks × 4 cycles administered sequentially after doxorubicin 50 mg/m² + cyclophosphamide 500 mg/m² every 3 weeks × 4 cycles is standard. 8

Trial Design:

• CALGB 9344/Intergroup: Phase 3 factorial trial in 3,170 node-positive patients 8
• Patients randomized to AC × 4 cycles followed by paclitaxel 175 mg/m² × 4 cycles vs. AC alone 8
• Primary endpoints: disease-free survival and overall survival 8
• Results: 22% reduction in disease recurrence (HR 0.78,95% CI 0.67-0.91, p=0.0022) and 26% reduction in death (HR 0.74,95% CI 0.60-0.92, p=0.0065) with paclitaxel addition 8
• Median follow-up: 30.1 months 8

Inclusion Criteria:

• Node-positive breast cancer (any number of positive nodes) 8
• Adequate organ function 8
• ECOG performance status 0-1 8

Exclusion Criteria:

• Prior chemotherapy for breast cancer 8
• Baseline cardiac dysfunction 8
• Pregnancy or lactation 8

Limitations:

• Subset analysis showed smaller benefit in ER-positive tumors (HR 0.92 for disease-free survival) compared to ER-negative tumors 8
• Increasing doxorubicin dose beyond 60 mg/m² provided no additional benefit 8
• Relatively short median follow-up at primary analysis 8

---

Critical Implementation Principles Across All Regimens

Premedication Requirements:

• Dexamethasone 20 mg PO 12 and 6 hours before paclitaxel (reduce to 10 mg in AIDS-related Kaposi's sarcoma) 8
• Diphenhydramine 50 mg IV 30-60 minutes before paclitaxel 8
• H2-blocker (cimetidine 300 mg or ranitidine 50 mg IV) 30-60 minutes before paclitaxel 8

Baseline Assessments:

• Core biopsy confirming invasive disease with ER/PR/HER2 status 2
• Germline BRCA1/2 testing for all TNBC patients 2, 3
• Baseline LVEF measurement if anthracyclines planned 1, 3
• Referral to breast surgeon and radiation oncologist before initiating therapy 2

Treatment Initiation Timing:

• Begin neoadjuvant therapy within 2-4 weeks of diagnosis completion 2, 3
• Avoid unnecessary delays that may compromise outcomes 3

Dose Modifications:

• Do not repeat chemotherapy until neutrophils ≥1,500 cells/mm³ and platelets ≥100,000 cells/mm³ (solid tumors) 8
• Reduce dose by 20% for severe neutropenia (<500 cells/mm³ for ≥1 week) or severe peripheral neuropathy 8
• Hepatic impairment requires dose reduction based on transaminase and bilirubin levels 8

Common Pitfalls to Avoid:

• Do not use anthracycline-free regimens as standard unless contraindicated 3
• Do not split chemotherapy between neoadjuvant and adjuvant phases—complete all planned chemotherapy preoperatively 1
• Do not omit G-CSF support with dose-dense regimens 2, 4
• Do not exceed cumulative doxorubicin dose of 240 mg/m² 4
• Perform completion axillary dissection if residual macrometastases (>2 mm) found in sentinel nodes after neoadjuvant therapy 1, 2