Why is PD-L1 (Programmed Death-Ligand 1) testing not required in non-metastatic breast cancer, but is used to guide immunotherapy decisions in metastatic disease?

PD-L1 Testing in Breast Cancer: Non-Metastatic vs Metastatic Disease

PD-L1 testing is not required in non-metastatic breast cancer because immunotherapy benefit in the neoadjuvant setting is independent of PD-L1 status, whereas in metastatic disease, PD-L1 expression is a mandatory predictive biomarker that determines eligibility for immune checkpoint inhibitor therapy and correlates with survival benefit. 1

Non-Metastatic (Early-Stage) Breast Cancer

Neoadjuvant Setting

• For high-risk early-stage triple-negative breast cancer (TNBC), pembrolizumab combined with neoadjuvant chemotherapy is standard of care regardless of PD-L1 status. 1
• PD-L1 testing is not required in the neoadjuvant setting because clinical benefit is independent of PD-L1 expression. 1
• The treatment decision is based on disease stage and triple-negative status, not biomarker selection. 1

Key Distinction

The fundamental difference is that neoadjuvant immunotherapy trials demonstrated efficacy across all PD-L1 expression levels, eliminating the need for biomarker-driven patient selection in this curative-intent setting. 1

Metastatic Breast Cancer

Mandatory PD-L1 Testing

Patients with locally recurrent unresectable or metastatic hormone receptor-negative and HER2-negative breast cancer who are candidates for immune checkpoint inhibitor therapy must undergo PD-L1 testing with an FDA-approved test. 2

Specific Testing Requirements

For Pembrolizumab Plus Chemotherapy

• Use the 22C3 companion assay to calculate Combined Positive Score (CPS). 2
• The CPS is calculated as: (number of PD-L1 staining tumor cells + lymphocytes + macrophages) ÷ (total viable tumor cells) × 100. 2
• Treatment eligibility requires CPS ≥10. 2
• At this cutoff, pembrolizumab-chemotherapy improved median PFS from 5.6 to 9.7 months (HR 0.65, P=0.0012). 2

For Atezolizumab Plus Nab-Paclitaxel

• Use the SP142 assay to assess PD-L1 expression on immune cells. 2
• Treatment eligibility requires ≥1% PD-L1 expression on immune cells. 2, 1
• At this cutoff, atezolizumab provided PFS benefit of 7.5 vs 5.0 months (HR 0.62, P<0.001) and OS benefit of 25 vs 15.1 months. 2, 1

Critical Assay-Specific Requirements

The specific assay used in the trial supporting each agent must be obtained—different antibodies and scoring systems are not interchangeable. 2

• The 22C3 assay evaluates tumor cells, lymphocytes, and macrophages. 2
• The SP142 assay evaluates immune cells in tumor and stroma. 2
• Using the wrong assay may incorrectly classify patients as eligible or ineligible for therapy. 2

Why PD-L1 Predicts Benefit in Metastatic Disease

Survival Correlation

In the KEYNOTE-355 trial, patients with PD-L1 CPS ≥10 had significantly improved outcomes, while those with CPS <10 did not meet statistical significance thresholds. 2

Biomarker Imperfection

PD-L1 is not a perfect biomarker—less than half of biomarker-selected patients benefit from treatment, and some responses occur in biomarker-negative cohorts. 3

• In KEYNOTE-119 (pembrolizumab monotherapy), there was no OS benefit even in PD-L1-positive patients (HR 0.78, P=0.057 for CPS ≥10). 2
• This demonstrates that PD-L1 testing is most predictive when immunotherapy is combined with chemotherapy in the first-line metastatic setting. 2

Tissue Sampling Considerations

Primary vs Metastatic Tissue

Considerable discordance exists between PD-L1 status in primary and metastatic breast cancer, emphasizing the importance of appropriate tissue sampling. 4

• Pooled PD-L1 positivity is higher in primary tumors compared to metastases when assessed in immune cells (51.2% vs 37.1%, P<0.001). 4
• PD-L1 positivity is lowest in bone metastases (12%) and highest in lymph nodes (60%). 4
• Repeating PD-L1 testing on metastatic tissue should be considered if primary tumor was negative, particularly for lung, pleura, and liver metastases where negative-to-positive conversion has been documented. 5

Post-Treatment Changes

Primary tumors show higher PD-L1 expression than matched metastatic tumors, and post-neoadjuvant chemotherapy tumors show lower PD-L1 expression compared to pre-treatment tumors. 5

Non-Triple-Negative Breast Cancer

Immunotherapy should not be used in routine clinical practice for hormone receptor-positive or HER2-positive breast cancer outside clinical trials. 1

• This applies to both metastatic and non-metastatic settings. 1
• PD-L1 testing is therefore not indicated for these subtypes in routine practice. 1

Timing Restrictions for Metastatic Immunotherapy

Immunotherapy is only indicated for metastatic disease if disease developed de novo or at least 12 months after completion of (neo)adjuvant chemotherapy. 2, 1

• This restriction applies regardless of PD-L1 status. 2
• Patients with earlier recurrence should receive standard chemotherapy without immunotherapy. 2