Although biomarker testing is playing a greater role in the management of triple-negative breast cancer (TNBC), treatment selection still relies on relatively few validated biomarkers.
Markers for Immunotherapy
Several new therapies have been approved for TNBC in recent years, including the PD-1 inhibitor pembrolizumab (Keytruda).
In 2021, pembrolizumab was approved in combination with chemotherapy as a neoadjuvant treatment for high-risk early-stage TNBC, regardless of PD-L1 status. In updated results from the KEYNOTE-522 trial that supported the approval, neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab showed a clinically meaningful survival benefit compared with neoadjuvant chemotherapy alone in patients with high-risk early-stage TNBC.
“PD-L1 is clinically useful but imperfect,” Yara Abdou, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, told MedPage Today. “Its predictive value depends on the disease setting, assay, scoring method, tissue source, and treatment regimen.”
In the first-line metastatic setting, PD-L1 is the most clinically relevant biomarker, indicating that pembrolizumab added to chemotherapy will improve outcomes, including overall survival.
“In metastatic TNBC, there is a PD-L1 cutoff of a combined positive score (CPS) of at least 10 for use of pembrolizumab,” said Hope Rugo, MD, of the City of Hope Comprehensive Cancer Center in Duarte, California. Only about 30% to 40% of patients with metastatic TNBC will have a CPS score ≥10.
Microsatellite instability-high and mismatch repair-deficient TNBCs are very rare, and most TNBCs do not meet the tumor mutation burden-high threshold.
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 (Lynparza) is approved as an adjuvant treatment for high-risk, HER2-negative early breast cancer, and olaparib and talazoparib (Talzenna) are approved for those with advanced or metastatic disease.
“PARP inhibitors are also sometimes considered for selected patients with somatic BRCA1 or BRCA2 mutations,” Abdou said. “Although they are not specifically approved for this population, prospective data have demonstrated a signal of activity.”
HER2-low status, defined as an immunohistochemistry (IHC) score of 1+ or 2+ with a negative in situ hybridization (ISH) test, can identify patients with pretreated metastatic TNBC who might benefit from the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd; Enhertu). Approximately one-third of patients with TNBC have tumors that are IHC 1+ or IHC 2+ and ISH-negative.
“There was a small exploratory subgroup of patients with TNBC who were treated with T-DXd or standard chemotherapy in DESTINY-Breast04 and these results led to approval” in unresectable/metastatic breast cancer with HER2-low status, Rugo told MedPage Today. “But T-DXd as a treatment for metastatic TNBC is classified as ‘other recommended therapy’ due to the absence of level 1 data. T-DXd is primarily used as a treatment of choice for hormone receptor-positive and HER2-positive disease.”
Other Actionable Markers
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, Abdou said. Additionally, the role of tumor-infiltrating lymphocytes (TILs) as a predictive marker of response continues to be explored in TNBC.
“There are some ongoing studies in the early-stage setting that are triaging therapy based on the extent of TILs, with patients whose tumors have high TILs randomized or allocated to less therapy, given the association with better response to therapy and improved outcomes even without systemic therapy in this setting,” Rugo explained.
In early-stage disease, circulating tumor (ct)DNA is being used to detect molecular residual disease, estimate recurrence risk, monitor treatment response, and identify resistance prior to radiographic progression or recurrence.
The neoadjuvant, adaptively randomized phase II I-SPY 2 trial used the Signatera blood test to measure personalized ctDNA in women with high-risk early-stage breast cancer, showing that patients who had negative ctDNA at pretreatment and at the time of surgery had lower risk of metastasis, while ctDNA positivity or persistence/emerging positivity was a strong predictor of metastatic recurrence. In addition, rapid clearance of ctDNA during neoadjuvant therapy predicted pathologic complete response from immunotherapy combined with chemotherapy.
Prospective studies are now evaluating whether ctDNA can guide treatment escalation in patients with molecular residual disease. PREDICT-RD is a multicenter phase II study enrolling patients with high-risk early-stage TNBC who have residual disease after neoadjuvant therapy. The trial is evaluating whether ctDNA-positive patients can benefit from treatment escalation with datopotamab deruxtecan (Datroway), while also prospectively characterizing ctDNA clearance and its association with long-term outcomes.
“Researchers are also evaluating quantitative and spatial measurements of ADC targets such as TROP2, HER2, HER3, B7-H3, and LIV-1, together with biomarkers of payload sensitivity and resistance,” Abdou said. “Multiomic models integrating DNA, RNA, protein, digital pathology, spatial profiling, and clinical variables are particularly promising. Dynamic biomarkers measured serially during treatment may also be more informative than a single pretreatment biopsy.”
Unmet Needs
Despite this progress, 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. In addition, there is a critical unmet need for new therapies that can overcome resistance in both early- and late-stage disease.
For ADCs, which are now an approved first-line treatment option for patients with metastatic TNBC, 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.
“We also need prospective evidence showing that acting on ctDNA-detected residual disease improves outcomes rather than simply identifying patients at higher risk,” Abdou noted.
Additional knowledge gaps include the lack of standardization across PD-L1 assays, HER2-low interpretation, TIL assessment, tumor mutation burden platforms, and ctDNA technologies.
“We also need more paired tissue collected over time and greater representation of racial and ethnic minority populations in biomarker development datasets,” Abdou pointed out. “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.”
