What is the treatment for a patient with stage 4 triple negative breast cancer?

Treatment of Stage 4 Triple-Negative Breast Cancer

For stage 4 triple-negative breast cancer, first-line treatment should be pembrolizumab plus chemotherapy for PD-L1-positive disease (CPS ≥10), PARP inhibitors for germline BRCA1/2 mutations, or single-agent chemotherapy for PD-L1-negative disease without BRCA mutations. 1, 2

Immediate Testing Requirements

Before initiating treatment, all patients with stage 4 TNBC require:

• PD-L1 testing using an FDA-approved assay to determine eligibility for immunotherapy 1, 2
• Germline BRCA1/2 mutation testing to identify candidates for PARP inhibitors 1
• Re-biopsy of metastatic lesions when feasible to confirm triple-negative status, as tumor biology may change from primary to metastatic disease 3

First-Line Treatment Algorithm

For PD-L1-Positive Disease (CPS ≥10)

Pembrolizumab plus chemotherapy is the preferred first-line regimen, providing significant survival benefit with median OS of 23.0 versus 16.1 months (HR 0.73; P=0.0093). 3, 2 The FDA-approved regimen is pembrolizumab combined with chemotherapy for locally recurrent unresectable or metastatic TNBC with PD-L1 expression (CPS ≥10). 2

Alternatively, atezolizumab plus albumin-bound paclitaxel demonstrated improved PFS (7.5 vs 5 months; HR 0.62) and OS (25 vs 15.5 months; HR 0.62) in PD-L1-positive tumors with ≥1% tumor-infiltrating immune cells. 1

Critical monitoring requirement: Patients receiving checkpoint inhibitors must be monitored closely for immune-related adverse events affecting any organ system. 3

For Germline BRCA1/2-Mutated Disease

PARP inhibitors (olaparib or talazoparib) are preferred over chemotherapy in the first-through third-line setting. 1, 3

• Olaparib (FDA-approved, category 1): Median PFS 7.0 months vs 4.2 months with chemotherapy (HR 0.58; P<0.001) 1
• Talazoparib (FDA-approved, category 1): Median PFS 8.6 months vs 5.6 months with chemotherapy (HR 0.54; P<0.001) 1

Platinum agents (cisplatin or carboplatin) are preferred alternatives if PARP inhibitors are unavailable or contraindicated. The TNT trial demonstrated carboplatin superiority over docetaxel in BRCA-mutated patients (ORR 68.0% vs 33.3%; P=0.03). 1

For PD-L1-Negative, BRCA Wild-Type Disease

Single-agent chemotherapy is preferred to minimize toxicity. 3 Combination chemotherapy should be reserved only for symptomatic or immediately life-threatening disease where rapid response is critical. 3

Preferred first-line chemotherapy options (if not previously used in adjuvant setting):

• Taxanes (paclitaxel or docetaxel) 3
• Anthracyclines if not previously administered 3
• Weekly paclitaxel 80 mg/m² IV on days 1,8,15 plus carboplatin AUC 2 IV on days 1,8,15, cycled every 28 days 4

Critical pitfall to avoid: When using weekly paclitaxel, use carboplatin AUC 2 weekly instead of AUC 6 every 3 weeks to avoid excessive toxicity. 4

Second-Line and Beyond

After ≥2 Prior Therapies

Sacituzumab govitecan is strongly recommended, demonstrating dramatic superiority over standard chemotherapy with significant improvements in both PFS and OS. 4, 3

Alternative Second-Line Options

• Platinum agents (if not previously used) 1
• Capecitabine 1
• Eribulin 1
• Gemcitabine 1

For heavily pretreated HR-positive disease misclassified as TNBC: Single-agent abemaciclib showed median PFS of 6 months and median OS of 22.3 months in the MONARCH 1 trial. 5

Duration of Treatment

Continue chemotherapy until disease progression or limiting toxicities. 3 For HER2-targeted therapy in any breast cancer subtype with germline BRCA1/2 mutations, continue until progression or unacceptable toxicity. 1

Common Pitfalls to Avoid

• Do not rely on triple-negative status alone without confirmatory testing for PD-L1 and BRCA mutations, as these determine optimal first-line therapy 1, 3
• Do not use combination chemotherapy routinely in first-line for PD-L1-negative disease; reserve for symptomatic/life-threatening presentations 3
• Do not assume somatic BRCA mutations confer the same platinum benefit as germline mutations; the TNT trial showed benefit only in germline BRCA carriers 1
• Do not use bevacizumab routinely, as it improves PFS but not OS, limiting its recommendation 3
• Monitor closely for peripheral neuropathy with paclitaxel; reduce dose by 20% or hold for grade ≥3 neuropathy 4