Breast Cancer|Triple-Negative

CD274

  • CD274 molecule (CD274); encodes programmed death-ligand 1 (PD-L1), also designated B7-H1
  • Gene Location: Chromosome 9 (9p24.1)

Biology

  • PD-L1 is a transmembrane immune-checkpoint ligand expressed on tumor cells and on tumor-infiltrating immune cells. Binding to PD-1 on activated T cells delivers an inhibitory signal that blunts cytotoxic T-cell activity.1
  • Under normal conditions this axis restrains T-cell responses to limit collateral tissue injury and maintain peripheral tolerance. Tumors co-opt it: PD-L1 is upregulated in the breast tumor microenvironment largely through interferon-gamma released by infiltrating lymphocytes, a mechanism termed adaptive immune resistance.1
  • PD-1 blockade releases that brake and restores T-cell effector function. In advanced breast cancer the benefit has been demonstrable only in tumors with high PD-L1 expression; in high-risk early-stage TNBC the perioperative benefit was seen irrespective of PD-L1 status.2,3

Etiology and Epidemiology

  • Unlike a genomic alteration, PD-L1 expression is a dynamic phenotypic marker of the tumor immune microenvironment. It can differ between the primary tumor and a metastatic site and can change after intervening therapy.
  • Triple-negative breast cancer accounts for roughly 15% of breast cancers and carries the highest tumor-infiltrating lymphocyte burden and the highest PD-L1 positivity of the major breast subtypes.
  • In KEYNOTE-355, approximately 38% of previously untreated locally recurrent inoperable or metastatic TNBC tumors had a combined positive score (CPS) of 10 or higher, and approximately 75% had CPS of 1 or higher, by the 22C3 assay.2
  • A CPS of 10 or higher is currently the only PD-L1 threshold that gates a breast cancer treatment decision in the United States. It governs both the first-line pembrolizumab plus chemotherapy indication and the June 2026 sacituzumab govitecan plus pembrolizumab indication.1,4

Testing

When to Test:

  • Test at the diagnosis of locally recurrent unresectable or metastatic TNBC, before first-line systemic therapy is selected, because the result determines eligibility for pembrolizumab plus chemotherapy and for sacituzumab govitecan plus pembrolizumab.1,4
  • PD-L1 testing is not required for the high-risk early-stage TNBC perioperative indication, which is unselected for PD-L1. A metastatic-setting result is still required later if checkpoint therapy is considered at recurrence.1,3
  • Because expression can shift after intervening therapy and differs across sites, test the most recent adequate tumor specimen where feasible rather than relying on an archival primary alone.

Testing Methodologies:

  • Immunohistochemistry on formalin-fixed, paraffin-embedded tumor tissue is the only validated approach; there is no plasma or circulating tumor DNA assay for PD-L1.
  • CPS is the number of PD-L1-staining cells (tumor cells, lymphocytes, and macrophages) divided by the total number of viable tumor cells, multiplied by 100.5
  • PD-L1 IHC 22C3 pharmDx (Agilent/Dako) is the companion diagnostic used to define CPS of 10 or higher in both KEYNOTE-355 and ASCENT-04/KEYNOTE-D19. It was approved concurrently with the November 2020 pembrolizumab accelerated approval.4,5,6
  • The Ventana PD-L1 (SP142) assay scores immune-cell staining rather than CPS and is not interchangeable with 22C3. It is no longer tied to an active US breast cancer indication following withdrawal of the atezolizumab metastatic TNBC indication in 2021.7

Guideline Recommendations

  • ASCO recommends PD-L1 assessment by a validated CPS assay in patients with metastatic TNBC being considered for first-line checkpoint-inhibitor-based therapy.8
  • NCCN includes PD-L1 testing by an FDA-approved assay in the workup of recurrent or stage IV TNBC, with CPS of 10 or higher directing patients toward a pembrolizumab-containing first-line regimen.9

Targeted Therapy

Approved Agents

  • One agent is FDA-approved in breast cancer with PD-L1 CPS as its selection biomarker: pembrolizumab (Keytruda), available intravenously and as a subcutaneous coformulation with berahyaluronidase alfa-pmph (Keytruda Qlex).1
  • On November 13, 2020, the FDA granted accelerated approval to pembrolizumab plus chemotherapy for locally recurrent unresectable or metastatic TNBC with CPS of 10 or higher, based on the phase 3 KEYNOTE-355 trial, and approved PD-L1 IHC 22C3 pharmDx as the companion diagnostic. On July 26, 2021, the FDA approved pembrolizumab for high-risk early-stage TNBC based on the phase 3 KEYNOTE-522 trial and, in the same action, converted the metastatic accelerated approval to regular approval on the basis of confirmatory KEYNOTE-522 data.6,10
  • Since June 24, 2026, a CPS of 10 or higher additionally selects patients for sacituzumab govitecan plus pembrolizumab in the first-line metastatic setting, based on ASCENT-04/KEYNOTE-D19. That regimen is covered on the TROP2 biomarker page.4

Pembrolizumab (Keytruda)

  • FDA-Approved Indication:
    • In combination with chemotherapy, for adults with locally recurrent unresectable or metastatic triple-negative breast cancer whose tumors express PD-L1 (CPS greater than or equal to 10) as determined by an FDA-authorized test.1
    • For adults with high-risk early-stage TNBC, in combination with chemotherapy as neoadjuvant treatment, then continued as a single agent as adjuvant treatment after surgery.1
  • Mechanism of Action:
    • Humanized IgG4 monoclonal antibody that binds PD-1 and blocks its interaction with PD-L1 and PD-L2.1
    • Blockade relieves checkpoint-mediated inhibition of tumor-specific T cells and restores antitumor immune response.1

Drug Information:

Learn more about Pembrolizumab ›

Patient Resources:

https://www.keytruda.com/

Agents No Longer Indicated in Breast Cancer

  • Atezolizumab plus nab-paclitaxel held accelerated approval for PD-L1-positive (SP142 immune-cell scoring) metastatic TNBC from March 2019. The indication was voluntarily withdrawn in the United States in 2021 after IMpassion131 failed to confirm benefit. Retain only as historical context; it is not a current treatment option.7

References

1. KEYTRUDA (pembrolizumab) injection. Prescribing information. Merck Sharp & Dohme LLC. Accessed July 2026.

2. Cortes J, Rugo HS, Cescon DW, et al. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer (KEYNOTE-355). N Engl J Med. 2022;387(3):217-226. doi:10.1056/NEJMoa2202809

3. Schmid P, Cortes J, Dent R, et al. Overall survival with pembrolizumab in early-stage triple-negative breast cancer (KEYNOTE-522). N Engl J Med. 2024;391(21):1981-1991. doi:10.1056/NEJMoa2409932

4. US Food and Drug Administration. FDA approves sacituzumab govitecan-hziy as monotherapy and in combination with pembrolizumab for first-line treatment of triple-negative breast cancer. June 24, 2026. Accessed July 2026.

5. PD-L1 IHC 22C3 pharmDx. Instructions for use. Agilent Technologies/Dako North America, Inc. Accessed July 2026.

6. US Food and Drug Administration. FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer. November 13, 2020. Accessed July 2026.

7. Genentech/Roche. Voluntary withdrawal of the atezolizumab accelerated approval for PD-L1-positive metastatic triple-negative breast cancer in the United States. 2021. Accessed July 2026.

8. ASCO Guideline: Biomarkers for Systemic Therapy in Metastatic Breast Cancer. Accessed July 2026.

9. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.5.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed July 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.

10. Merck & Co, Inc. FDA approves KEYTRUDA (pembrolizumab) for treatment of patients with high-risk early-stage triple-negative breast cancer. News release. July 26, 2021. Accessed July 2026.