What is the relevance of testing for Programmed Death-Ligand 1 (PD-L1) in a patient with a history of breast cancer, now presenting with metastatic triple negative breast cancer (TNBC)?

PD-L1 Testing in Metastatic Triple-Negative Breast Cancer

Yes, PD-L1 testing is absolutely essential in metastatic triple-negative breast cancer because it determines eligibility for immune checkpoint inhibitor therapy, which provides a clinically meaningful 7-month overall survival benefit in PD-L1-positive patients. 1

Mandatory Testing Requirement

Patients with metastatic TNBC who are candidates for first-line systemic therapy must undergo PD-L1 testing with an FDA-approved companion diagnostic assay before treatment initiation. 1 This is a strong recommendation based on intermediate-quality evidence from multiple phase III randomized controlled trials. 1

The testing requirement exists because:

• Pembrolizumab plus chemotherapy improves progression-free survival from 5.6 to 9.7 months (HR 0.65, P=0.0012) in patients with PD-L1 combined positive score (CPS) ≥10 using the 22C3 assay 1, 2
• Atezolizumab plus nab-paclitaxel improves overall survival from 15.1 to 25 months (7-month absolute benefit) in patients with ≥1% PD-L1 expression on immune cells using the SP142 assay 1, 2, 3

Critical Assay-Specific Requirements

The specific companion diagnostic assay validated in the clinical trial for each drug must be used—different PD-L1 assays are NOT interchangeable. 1, 2

For Pembrolizumab:

• Use the 22C3 pharmDx assay on the Dako Autostainer Link 48 platform 1, 4
• Score using Combined Positive Score (CPS): number of PD-L1-positive cells (tumor cells, lymphocytes, macrophages) divided by total viable tumor cells, multiplied by 100 1, 2
• Treatment threshold: CPS ≥10 1, 2

For Atezolizumab:

• Use the VENTANA PD-L1 SP142 assay on the BenchMark Ultra platform 1, 5
• Score using Immune Cell (IC) score: percentage of tumor area occupied by PD-L1-positive immune cells (lymphocytes, dendritic cells, macrophages, granulocytes) 1, 5
• Treatment threshold: IC ≥1% 1, 5

The SP263 and 22-C3 assays, while widely used in other tumor types, failed to reproduce SP142 clinical validity in the IMpassion-130 trial context and should not be substituted for atezolizumab treatment decisions. 1 However, recent data demonstrate that SP263 on the Ventana platform shows excellent interobserver agreement with 22C3 for CPS scoring (ICC 0.972) and can be used interchangeably with 22C3 for pembrolizumab decisions. 4

Impact on Mortality and Quality of Life

The survival benefit is substantial and clinically meaningful:

• Overall survival improvement: 25 months versus 15.1 months with atezolizumab plus nab-paclitaxel in PD-L1-positive disease (7-month absolute benefit) 2, 3
• Progression-free survival improvement: 9.7 months versus 5.6 months with pembrolizumab plus chemotherapy in CPS ≥10 disease 1, 2
• 2-year overall survival: PD-L1-positive patients have significantly better outcomes (OR 2.47,95% CI 1.30-4.69, P=0.006) 6

Treatment Eligibility Restrictions

Immunotherapy is only indicated if metastatic disease developed de novo OR at least 12 months after completion of (neo)adjuvant chemotherapy. 2, 7 Patients who recur within 12 months of completing adjuvant therapy were excluded from the pivotal trials and should not receive checkpoint inhibitors. 2

Common Pitfalls to Avoid

Do not delay PD-L1 testing until after starting chemotherapy—testing should occur at the time of metastatic diagnosis to avoid missing the window for first-line immunotherapy, which is where the survival benefit is demonstrated. 1, 7

Do not use archival tissue from the primary tumor without consideration—while acceptable, a metastatic biopsy is preferred to confirm diagnosis and reassess all biomarkers (ER, PR, HER2, PD-L1) as discordance occurs in 10-40% of cases. 1

Do not assume PD-L1 positivity based on high tumor-infiltrating lymphocytes—while high TILs are prognostic in TNBC, PD-L1 expression and TIL levels are not perfectly correlated, and PD-L1 expression can actually attenuate the positive prognostic impact of high TILs. 8

Do not use checkpoint inhibitor monotherapy in later lines—immunotherapy must be combined with chemotherapy in the first-line setting, as monotherapy response rates are low (5-10%) in pretreated patients. 2

Do not pair atezolizumab with standard paclitaxel—the IMpassion131 trial showed no PFS benefit with atezolizumab plus paclitaxel (6.0 vs 5.7 months, HR 0.82, P=0.20), so atezolizumab must be specifically paired with nab-paclitaxel. 3

Practical Implementation

For patients with newly diagnosed metastatic TNBC:

1. Obtain metastatic biopsy to confirm TNBC diagnosis and assess PD-L1 status 1, 7
2. Order the appropriate companion diagnostic: 22C3 for pembrolizumab or SP142 for atezolizumab based on institutional availability and drug access 1, 2
3. Ensure pathologist training and certification in PD-L1 scoring, as interobserver variability exists despite good overall reproducibility (ICC 0.939 for 22C3, 0.972 for SP263) 4
4. Verify timing eligibility: confirm disease developed de novo or ≥12 months after completing adjuvant therapy 2
5. If PD-L1-positive: initiate pembrolizumab plus chemotherapy (CPS ≥10) or atezolizumab plus nab-paclitaxel (IC ≥1%) 1, 2
6. If PD-L1-negative: proceed with chemotherapy alone or consider PARP inhibitor if germline BRCA1/2 mutation present 7

The testing is cost-effective given the magnitude of survival benefit (7-month OS improvement) and the ability to spare PD-L1-negative patients from unnecessary immunotherapy toxicity and cost. 3, 6