PD-L1 in Triple-Negative Breast Cancer

PD-L1 (programmed death-ligand 1) is a protein that some cancers use to hide from the immune system. In triple-negative breast cancer (TNBC), testing for PD-L1 helps determine whether a type of immunotherapy called a checkpoint inhibitor is likely to help. Triple-negative breast cancer is the breast cancer subtype most likely to respond to immunotherapy, and PD-L1 is the main test used to identify who is eligible for it when the cancer is advanced. This article explains what PD-L1 testing measures in triple-negative breast cancer, how the result is reported, and, importantly, why the result matters when the cancer is advanced but not when it is early-stage. For a broader look at PD-L1 across all cancers, see our overview of PD-L1 testing in cancer.

What the test looks for

PD-L1 is a protein found on the surface of some cancer cells and on immune cells within a tumor. Its normal job is to act as a brake on the immune system: when PD-L1 binds to a partner protein called PD-1 on immune cells called T cells, it sends a signal telling those T cells to stand down. Many cancers take advantage of this by making large amounts of PD-L1, which disguises them from the immune system. A group of drugs called immune checkpoint inhibitors, such as pembrolizumab (Keytruda), work by blocking this brake so the immune system can attack the cancer.

Triple-negative breast cancer is defined by the absence of three receptors that drive most other breast cancers: the estrogen receptor, the progesterone receptor, and HER2. You can read more about the first two in our article on the estrogen receptor and progesterone receptor in breast cancer. Because triple-negative breast cancers cannot be treated with hormone-blocking or HER2-targeted therapy, other approaches are needed. These cancers also tend to contain more immune cells and more PD-L1 than other breast cancers, which is why they are the breast cancer subtype most likely to respond to immunotherapy. PD-L1 testing measures how much of this protein is present, which helps predict who will benefit from a checkpoint inhibitor.

When PD-L1 testing matters: early-stage versus advanced disease

The single most important thing to understand about PD-L1 in triple-negative breast cancer is that the result matters in advanced disease but not in early-stage disease. Whether your PD-L1 result affects your treatment depends on the stage of your cancer.

In advanced disease (triple-negative breast cancer that is locally advanced and cannot be removed with surgery, or that has spread to other parts of the body), PD-L1 determines eligibility for immunotherapy. Pembrolizumab combined with chemotherapy is a first-line treatment, but only for patients whose tumor is PD-L1-positive at the required level. In this setting, the PD-L1 result directly decides whether immunotherapy is an option.

In early-stage disease (a larger or node-positive triple-negative breast cancer that is still confined to the breast and nearby lymph nodes), the situation is different. For these higher-risk early-stage cancers, pembrolizumab is added to chemotherapy before surgery and continued after surgery, and it is given regardless of the PD-L1 result. Eligibility here is based on the stage of the cancer, not on PD-L1. This means a person with early-stage triple-negative breast cancer may receive immunotherapy even if their PD-L1 result is negative, and PD-L1 testing is often not required to make that decision.

How the test is performed

PD-L1 testing in triple-negative breast cancer is performed using immunohistochemistry (IHC), a laboratory technique in which a specially designed antibody is applied to a thin slice of tumor tissue on a glass slide. Cells that carry PD-L1 stain brown, and a pathologist examines the slide to measure how much PD-L1 is present. The test is done on tissue from a biopsy or a surgical specimen. For triple-negative breast cancer, the specific antibody used is the 22C3 assay, which is the version paired with pembrolizumab.

How the result is reported

PD-L1 in triple-negative breast cancer is reported using the Combined Positive Score, or CPS. The CPS counts the number of PD-L1-positive cells of all types (both cancer cells and nearby immune cells), divides that by the total number of cancer cells, and multiplies by 100. A CPS of 10 means that for every 100 cancer cells counted, there are 10 PD-L1-positive cells of any type. A report might read something like “PD-L1 CPS: 12 (22C3),” often with a note saying whether the result is positive or negative relative to the treatment threshold.

For advanced triple-negative breast cancer, a CPS of approximately 10 or higher is the threshold used to identify eligibility for pembrolizumab. This is a specific cut-off tied to the drug and the assay rather than a general “normal” value, so the exact number matters. Your report should state which assay was used, because the score is only meaningful in the context of that assay.

What your result means

Because these articles exist to help you read your own report, it helps to know what each possible result means.

CPS 10 or higher (PD-L1-positive). In advanced triple-negative breast cancer, this result means the cancer is eligible for pembrolizumab combined with chemotherapy as a first-line treatment. A positive result does not guarantee that immunotherapy will work, but it identifies the group most likely to benefit.
CPS less than 10 (PD-L1-negative or low). In advanced triple-negative breast cancer, this result means the cancer does not qualify for pembrolizumab based on PD-L1. Other treatments are used instead, and which ones depend on your other results, such as chemotherapy, targeted drugs called PARP inhibitors if a BRCA mutation is present, and newer antibody-based treatments. Your oncologist will explain the options.
Early-stage cancer, any CPS. If your cancer is early-stage, the CPS threshold above does not apply, because immunotherapy in that setting is decided by the stage of the cancer rather than by PD-L1.

One further point is worth knowing: a biopsy samples only part of a tumor, and PD-L1 can vary between different areas of the same cancer and between the original tumor and a site where it has spread. When a result falls close to the threshold, your team may take this into account or consider testing another sample.

Why the assay used matters

Different checkpoint inhibitor drugs were developed with different PD-L1 tests, and the results are not interchangeable. In triple-negative breast cancer, the 22C3 assay with CPS scoring is the test paired with pembrolizumab. A different test, called the SP142 assay, which uses a separate scoring system, was paired with another checkpoint inhibitor, atezolizumab (Tecentriq). Atezolizumab was previously approved for PD-L1-positive metastatic triple-negative breast cancer, but its approval for this use was withdrawn in the United States. The practical point for patients is that the assay must match the drug being considered: a result from the SP142 assay cannot be used to decide eligibility for pembrolizumab, and it is reasonable to confirm which assay was performed.

PD-L1 is not an inherited result

PD-L1 measured by immunohistochemistry reflects the behavior of the cancer and the immune cells around it. It is not an inherited (germline) finding. A high or low PD-L1 result does not indicate a genetic predisposition to cancer, cannot be passed on to family members, and does not call for testing of relatives. This is different from biomarkers such as BRCA1 and BRCA2, where a result can reflect an inherited mutation with implications for family members.

What happens next

PD-L1 is one part of a larger treatment plan for triple-negative breast cancer, and what happens next depends on the stage of the cancer and the result. If your cancer is advanced and the CPS is 10 or higher, your oncologist will discuss pembrolizumab combined with chemotherapy. If your cancer is advanced and the CPS is below 10, your team will focus on other treatments, guided by your other results, including BRCA testing. If your cancer is early-stage, the decision about immunotherapy is based on stage rather than PD-L1, so a negative result does not by itself rule out pembrolizumab. In all cases, PD-L1 is interpreted alongside the rest of your pathology results and your overall health, and your oncologist will explain how it fits into your specific plan.

Questions to ask your doctor

Is my triple-negative breast cancer considered early-stage or advanced, and does my PD-L1 result affect my treatment?
What is my PD-L1 CPS, and which assay was used to measure it?
Does my result make me eligible for pembrolizumab, or is immunotherapy being considered based on my stage?
If my PD-L1 is below the threshold, what other treatment options do I have?
Has my cancer been tested for a BRCA mutation, and could I be a candidate for a PARP inhibitor?
If my result is close to the threshold, would testing another sample change the plan?
What side effects should I expect from immunotherapy, and how are they managed?
If my cancer progresses, will PD-L1 be tested again?
Are there clinical trials I should know about based on my results?