What is the efficacy of programmed cell death ligand 1 (PD-L1) blockers, such as atezolizumab (atezolizumab) and pembrolizumab (pembrolizumab), in treating breast cancer with liver metastases?

PD-L1 Blockers in Breast Cancer with Liver Metastases

For metastatic triple-negative breast cancer (TNBC) with liver metastases and PD-L1 positivity, immune checkpoint inhibitors combined with chemotherapy demonstrate significant survival benefits and should be offered as first-line therapy, with pembrolizumab plus chemotherapy preferred for patients with CPS ≥10 or atezolizumab plus nab-paclitaxel for those with PD-L1 ≥1% on immune cells. 1, 2

Efficacy in PD-L1-Positive Metastatic TNBC

Pembrolizumab-Based Therapy

• Pembrolizumab plus chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin) improves progression-free survival from 5.6 to 9.7 months (HR 0.65, P=0.0012) in patients with PD-L1 CPS ≥10 1, 2
• The benefit is specifically limited to patients with CPS ≥10 using the FDA-approved 22C3 companion diagnostic assay 1, 2
• Grade 3-4 adverse events occur in approximately 68% of patients, comparable to chemotherapy alone (67%), with immune-mediated adverse events in 26% of patients 1

Atezolizumab-Based Therapy

• Atezolizumab plus nab-paclitaxel improves both progression-free survival (7.5 vs 5.0 months, HR 0.62, P<0.0001) and overall survival (25 vs 15.5 months, HR 0.62) in PD-L1-positive patients 1, 2
• The overall survival benefit represents a 7-month improvement, which is clinically meaningful for mortality reduction 1, 2
• PD-L1 positivity is defined as ≥1% tumor-infiltrating immune cells using the SP142 antibody assay 1
• Treatment discontinuation due to adverse events occurs in 16% with atezolizumab versus 8% with placebo, with thyroid disease in 23% and other immune-related events in 10% 1

Critical Requirements for Treatment Selection

Mandatory PD-L1 Testing

• All patients with metastatic hormone receptor-negative/HER2-negative breast cancer must undergo PD-L1 testing with the specific FDA-approved companion diagnostic before initiating checkpoint inhibitor therapy 1, 2
• The assays are not interchangeable: use 22C3 for pembrolizumab decisions and SP142 for atezolizumab decisions 1, 2
• The 22C3 assay calculates a Combined Positive Score (tumor cells, lymphocytes, macrophages), while SP142 evaluates immune cells in tumor and stroma 1, 2

Timing Restrictions

• Immunotherapy is only indicated if metastatic disease developed de novo or ≥12 months after completing (neo)adjuvant chemotherapy 2
• For patients relapsing within 12 months of adjuvant therapy, standard chemotherapy without immunotherapy is recommended 1

Chemotherapy Partner Selection

Critical Caveat: Taxane Type Matters

• Atezolizumab must be paired specifically with nab-paclitaxel, NOT standard paclitaxel 1
• The IMpassion131 trial demonstrated that atezolizumab plus paclitaxel failed to improve PFS in PD-L1-positive patients (6.0 vs 5.7 months, HR 0.82, P=0.20) 1
• Pembrolizumab can be combined with nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin based on patient factors 1

Efficacy in Non-TNBC Subtypes

Hormone Receptor-Positive/HER2-Negative Disease

• Immunotherapy should NOT be used in routine clinical practice for hormone receptor-positive breast cancer outside clinical trials 2
• Current evidence does not support PD-L1 blockade in this population regardless of metastatic site 2

HER2-Positive Disease

• Pembrolizumab plus trastuzumab shows objective responses only in PD-L1-positive, trastuzumab-resistant HER2-positive disease, but remains investigational 2
• This is not standard practice for liver metastases in HER2-positive breast cancer 2

Safety Considerations for Liver Metastases

Immune-Related Adverse Events

• Treatment-related deaths occurred in 0.7% (3/451) of atezolizumab-treated patients in IMpassion130 1
• One treatment-related death occurred in the pembrolizumab arm of KEYNOTE-355 1
• Patients with autoimmune disease history require individualized risk-benefit assessment before adding checkpoint inhibitors 1
• Grade 3-4 immune-related adverse events occur in 5% of pembrolizumab-treated patients versus 0% with chemotherapy alone 1

Algorithm for Treatment Selection

Step 1: Confirm triple-negative (hormone receptor-negative/HER2-negative) metastatic breast cancer with liver metastases 1, 2

Step 2: Verify timing—disease must be de novo metastatic OR recurred ≥12 months after completing adjuvant therapy 2

Step 3: Obtain PD-L1 testing with appropriate FDA-approved assay 1, 2

Step 4: If PD-L1 CPS ≥10 (22C3 assay): Offer pembrolizumab plus chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin) 1, 2

Step 5: If PD-L1 ≥1% immune cells (SP142 assay): Offer atezolizumab plus nab-paclitaxel specifically 1, 2

Step 6: If PD-L1-negative: Offer single-agent chemotherapy without immunotherapy 1

Step 7: For visceral crisis or immediately life-threatening disease, combination chemotherapy may be considered regardless of PD-L1 status 1

Common Pitfalls to Avoid

• Do not use atezolizumab with standard paclitaxel—this combination lacks efficacy based on IMpassion131 1
• Do not assume PD-L1 assays are interchangeable—each drug requires its specific companion diagnostic 1, 2
• Do not use immunotherapy in patients who relapsed <12 months after adjuvant therapy—this population was excluded from pivotal trials 2
• Do not use pembrolizumab monotherapy in the first-line metastatic setting—KEYNOTE-119 showed no OS benefit with monotherapy versus chemotherapy 1
• Do not apply these recommendations to hormone receptor-positive or HER2-positive breast cancer—evidence supports use only in TNBC 2