Treatment of Triple-Negative Breast Cancer
For early-stage TNBC (stages II-III), neoadjuvant chemotherapy with pembrolizumab is the preferred first-line approach, using dose-dense anthracycline-taxane-carboplatin regimens, followed by surgery and continued pembrolizumab for one year total; for metastatic disease, pembrolizumab plus chemotherapy is recommended for PD-L1-positive tumors, while sequential single-agent chemotherapy is preferred for PD-L1-negative disease. 1
Early-Stage TNBC (Stages I-III)
Stage-Specific Treatment Thresholds
For tumors <5 mm (T1a): Treatment decisions should be made case-by-case, as the benefit of chemotherapy in this population is uncertain. 2
For tumors 5-10 mm (T1b): Single-agent taxane-cyclophosphamide (TC) chemotherapy is recommended. 2
For tumors >10 mm (T1c) or Stage I: Anthracycline-taxane (AC/T) chemotherapy is the standard approach. 2
For Stage II-III disease: Neoadjuvant chemotherapy is strongly preferred over adjuvant therapy to allow tumor downstaging, assessment of treatment response, and tailored post-operative management. 2, 1
Neoadjuvant Chemotherapy Regimen
The preferred neoadjuvant regimen consists of:
Dose-dense anthracycline-taxane-based chemotherapy (doxorubicin or epirubicin with cyclophosphamide, followed by taxanes) for 12-24 weeks. 2
Pembrolizumab 200 mg IV every 3 weeks should be added throughout the neoadjuvant phase, regardless of PD-L1 status, based on KEYNOTE-522 data showing improved pathological complete response (pCR) rates. 1
Carboplatin addition remains controversial: The St. Gallen panel voted against routine carboplatin use (60% against), though some panelists favor its inclusion for higher-risk disease. 2 The National Comprehensive Cancer Network includes carboplatin as part of the preferred regimen. 1
Surgical Management
Breast-conserving surgery is preferred when adequate margins (no tumor at inked margin, >2 mm for in situ disease) are achievable after neoadjuvant downstaging. 2, 1
Axillary management after neoadjuvant therapy: Completion axillary lymph node dissection is required for residual macrometastases (>2 mm) in sentinel nodes. 2 For micrometastases or isolated tumor cells, axillary radiation may be considered as an alternative, though this remains controversial pending phase III trial results. 2
Post-Neoadjuvant Adjuvant Therapy
Treatment is stratified by residual disease:
If pembrolizumab was initiated neoadjuvantly: Continue for 9 additional cycles (total 1 year of treatment) regardless of pCR status. 1
For patients with residual invasive disease after neoadjuvant chemotherapy: Capecitabine should be administered as adjuvant therapy. 2
For patients with germline BRCA1/2 mutations and residual disease: Adjuvant olaparib 300 mg PO twice daily for 1 year should be strongly considered. 1
Radiation therapy: Post-surgical radiation is mandatory after breast-conserving surgery and should be given regardless of surgical approach in most cases. 2
Important Caveats for Early-Stage Disease
Immune checkpoint inhibitors were not recommended by the 2021 St. Gallen panel for routine neoadjuvant use, pending maturation of disease-free and overall survival data. 2 However, this predates the full KEYNOTE-522 results, and current guidelines now support pembrolizumab use. 1
Anthracycline-free regimens may be considered in select low-risk patients, as carboplatin-based regimens have shown non-inferior pCR rates in some studies. 3
Metastatic TNBC
First-Line Treatment Strategy
Treatment selection is based on PD-L1 status:
For PD-L1-positive metastatic TNBC: Pembrolizumab plus chemotherapy is the preferred first-line therapy, with demonstrated improved progression-free survival (7.5 vs 5.0 months) and overall survival (25 vs 18 months in updated analysis). 2, 4, 1
For PD-L1-negative metastatic TNBC: Single-agent chemotherapy is preferred over combination regimens to minimize toxicity and preserve quality of life. 4, 1, 5
Combination chemotherapy should only be used for symptomatic visceral crisis, immediately life-threatening disease, or rapidly progressive disease requiring rapid response. 2, 4, 5
Preferred first-line chemotherapy agents:
Taxanes (paclitaxel or docetaxel) are preferred if not previously used in the adjuvant setting, with weekly paclitaxel generally favored. 4, 5
Anthracyclines (doxorubicin or epirubicin) are recommended if not previously administered. 4
Platinum agents (carboplatin or cisplatin) demonstrate particular efficacy in TNBC with potential small survival benefits, though with increased toxicity including nausea, vomiting, and anemia. 4, 5
Second-Line and Later Treatment
Treatment selection is based on germline BRCA status and prior therapy:
For patients with germline BRCA1/2 mutations: PARP inhibitors (olaparib or talazoparib) are strongly preferred over chemotherapy, with median PFS of 7.0-8.6 months versus 4.2-5.6 months with standard chemotherapy. 4, 1
For patients who have received ≥2 prior therapies: Sacituzumab govitecan is strongly recommended, with significant improvements in both progression-free survival and overall survival (overall response rate 35% vs 5% with standard chemotherapy). 4, 1
Additional chemotherapy options include eribulin (which showed overall survival benefit of 14.4 vs 9.4 months compared to capecitabine in TNBC subset), capecitabine, gemcitabine, and vinorelbine. 4, 5
Critical Treatment Principles for Metastatic Disease
Sequential single-agent chemotherapy is generally preferred over combination regimens except in visceral crisis, as combinations yield higher response rates but do not improve overall survival and increase toxicity. 4, 5
Monitor closely for immune-related adverse events when receiving checkpoint inhibitors. 4
Chemotherapy resistance develops quickly in TNBC: Third and fourth lines of therapy offer progressively declining response rates and limited benefit. 5
BRCA1/2 germline testing should be performed in all metastatic TNBC patients to identify those who may benefit from PARP inhibitors or have enhanced platinum sensitivity. 5
Important Regulatory Note
- Atezolizumab-nab-paclitaxel was initially approved by the EMA for PD-L1-positive metastatic TNBC based on IMpassion130 data, but has since been withdrawn due to negative results from the confirmatory IMpassion131 trial. 2 Pembrolizumab remains the only approved checkpoint inhibitor for this indication.