What are the treatment options for a patient with stage 4 (metastatic) breast cancer, specifically triple-negative breast cancer, using immunotherapy such as pembrolizumab (anti-PD-1 antibody)?

Immunotherapy for Stage 4 Breast Cancer

For patients with stage 4 triple-negative breast cancer (TNBC) who are PD-L1 positive, pembrolizumab combined with chemotherapy is the standard first-line treatment, improving overall survival from 16.1 to 23.0 months (HR 0.73, P=0.0093). 1, 2

Treatment Algorithm Based on Tumor Subtype and Biomarker Status

Triple-Negative Breast Cancer (TNBC)

PD-L1 Testing is Mandatory:

• All patients with metastatic TNBC must undergo PD-L1 testing using an FDA-approved assay before initiating treatment 1, 2
• For pembrolizumab eligibility, use the 22C3 assay with a Combined Positive Score (CPS) ≥10 cutoff 1
• For atezolizumab eligibility, use the SP142 assay with ≥1% immune cell staining cutoff 1
• Critical pitfall: These assays are NOT interchangeable—you must use the specific companion diagnostic matched to your chosen immunotherapy agent 2

First-Line Treatment for PD-L1-Positive Disease (CPS ≥10):

• Pembrolizumab plus chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin) is the preferred regimen, providing median PFS improvement from 5.6 to 9.7 months (HR 0.65, P=0.0012) 1
• Alternative: Atezolizumab plus nab-paclitaxel (NOT regular paclitaxel) improves PFS from 5.0 to 7.5 months (HR 0.62) and OS from 15.1 to 25 months 1, 2
• Critical caveat: The IMpassion131 trial showed atezolizumab with regular paclitaxel does NOT work—you must use nab-paclitaxel specifically 1

First-Line Treatment for PD-L1-Negative Disease:

• Single-agent chemotherapy is preferred over combination regimens to minimize toxicity 1, 3
• Taxanes (paclitaxel or docetaxel) are preferred if not previously used in the adjuvant setting 3
• Combination chemotherapy should be reserved only for visceral crisis or rapidly progressive disease requiring immediate response 2, 3

Timing Restriction—Critical Pitfall:

• Immunotherapy is ONLY indicated if metastatic disease developed de novo OR at least 12 months after completion of (neo)adjuvant chemotherapy 2
• Do NOT initiate immunotherapy if disease recurred within 12 months of completing adjuvant treatment—this is an exclusion criterion 2

BRCA Mutation Considerations:

• All patients with TNBC should undergo germline BRCA1/2 mutation testing 3, 4
• For BRCA-mutated patients, PARP inhibitors (olaparib or talazoparib) are preferred over chemotherapy in first-through third-line settings, with median PFS of 7.0 vs 4.2 months (HR 0.58, P<0.001) 3
• The choice between immunotherapy and PARP inhibitors for first-line treatment in PD-L1-positive, BRCA-mutated patients remains debated, though immunotherapy plus chemotherapy is generally prioritized first-line 2

Non-Triple-Negative Breast Cancer (HR+/HER2- and HER2+)

Immunotherapy should NOT be used in routine clinical practice for any other biological subtype of breast cancer outside clinical trials. 2

• For HR+/HER2- metastatic breast cancer, endocrine therapy with CDK4/6 inhibitors remains the standard first-line approach 1
• For HER2+ metastatic breast cancer, HER2-targeted therapy combinations (trastuzumab, pertuzumab, chemotherapy) remain standard 1
• Pembrolizumab has shown objective responses in PD-L1-positive, trastuzumab-resistant HER2+ disease in early trials, but this remains investigational 2

Immune-Related Adverse Events—Critical Monitoring

Common immune-related toxicities requiring vigilance:

• Thyroid disease occurs in 23% of patients receiving atezolizumab 1
• Approximately 10% experience other immune-related adverse events affecting any organ system 1
• Treatment discontinuation rates: 16% with atezolizumab vs 8% with placebo 1
• Treatment-related mortality: 0.7% with atezolizumab (3/451 patients) 1

Contraindication consideration:

• The risks of checkpoint inhibitor therapy must be carefully weighed in patients with a history of autoimmune disease 1

Second-Line and Beyond for TNBC

After progression on first-line therapy:

• For patients who received ≥2 prior therapies for metastatic disease, sacituzumab govitecan is strongly recommended, with ORR 35% vs 5% and median PFS 5.6 vs 1.7 months (HR 0.41) 3, 4
• Platinum agents (carboplatin or cisplatin) are appropriate if not previously used, particularly for BRCA-mutated patients 3
• Alternative single-agent chemotherapy options include capecitabine, eribulin, and gemcitabine 3

FDA-Approved Indications

Pembrolizumab is FDA-approved for:

• High-risk early-stage TNBC in combination with neoadjuvant chemotherapy, then continued as adjuvant monotherapy after surgery (regardless of PD-L1 status) 5
• Locally recurrent unresectable or metastatic TNBC in combination with chemotherapy for tumors expressing PD-L1 (CPS ≥10) 5