Biomarkers in Triple-Negative Breast Cancer: Progress and Unmet Needs
Despite advancements in biomarker testing for triple-negative breast cancer, more research is needed to improve treatment outcomes and address existing knowledge gaps
The management of triple-negative breast cancer (TNBC) has seen significant progress in recent years, with biomarker testing playing a crucial role in treatment selection. However, the current arsenal of validated biomarkers is limited, and more research is needed to improve outcomes for patients with this aggressive form of breast cancer.
Markers for Immunotherapy
Several new therapies have been approved for TNBC, including the PD-1 inhibitor pembrolizumab, which has shown clinically meaningful survival benefits in combination with chemotherapy. The PD-L1 biomarker is currently the most clinically relevant marker in the first-line metastatic setting, indicating that pembrolizumab added to chemotherapy will improve outcomes. However, according to Yara Abdou, MD, PD-L1 is "clinically useful but imperfect," and its predictive value depends on various factors, including disease setting, assay, scoring method, tissue source, and treatment regimen.
Markers for Targeted Therapy
Other available treatment options for TNBC are indicated through testing for germline BRCA1/2 mutations or HER2 expression, as well as somatic mutations in BRCA1/2 and HER2. For patients with germline BRCA mutations, the PARP inhibitor olaparib is approved as an adjuvant treatment for high-risk, HER2-negative early breast cancer. HER2-low status can also identify patients with pretreated metastatic TNBC who might benefit from the antibody-drug conjugate trastuzumab deruxtecan.
Other Actionable Markers and Unmet Needs
There are other rare actionable alterations in patients with TNBC, such as NTRK fusions, which could provide access to tumor-agnostic therapies or prompt inclusion in clinical trials. Additionally, the role of tumor-infiltrating lymphocytes (TILs) as a predictive marker of response continues to be explored in TNBC. Despite progress in biomarker development, there remains a need for biomarkers that can better determine who will benefit from immunotherapy and when other treatments should be escalated or safely de-escalated. The table below summarizes some of the key biomarkers and their corresponding treatments:
| Biomarker | Treatment | Patient Population |
|---|---|---|
| PD-L1 | Pembrolizumab + chemotherapy | First-line metastatic TNBC |
| Germline BRCA1/2 mutations | Olaparib | High-risk, HER2-negative early breast cancer |
| HER2-low status | Trastuzumab deruxtecan | Pretreated metastatic TNBC |
| NTRK fusions | Tumor-agnostic therapies | Rare TNBC cases |
| TILs | Immunotherapy | Early-stage TNBC |
The lack of standardization across PD-L1 assays, HER2-low interpretation, TIL assessment, tumor mutation burden platforms, and ctDNA technologies is a significant knowledge gap that needs to be addressed. Furthermore, more research is needed to fully understand the optimal target expression thresholds, the importance of intratumoral heterogeneity, and the mechanisms of cross resistance between agents carrying similar payloads. Ultimately, future biomarkers must demonstrate not only prognostic association but true clinical utility, meaning that using the biomarker to select or modify treatment improves patient outcomes.
