Emerging Roles of Biomarkers in HER2-Positive Breast Cancer
Key Points
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Biomarkers such as circulating tumor DNA (ctDNA) and tumor-infiltrating lymphocytes (TILs) show promise in guiding HER2-positive breast cancer, but are not yet ready for routine clinical decision-making.
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Trastuzumab deruxtecan (T-DXd) and tucatinib continue to move earlier in treatment, with HER2CLIMB-05 supporting tucatinib in first-line maintenance.
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A growing pipeline of new antibody-drug conjugates (ADCs) and cellular therapies may address unmet needs after progression on current HER2-directed agents.
At the 2025 San Antonio Breast Cancer Symposium (SABCS 2025), increasing attention was placed on how biomarkers and novel HER2-directed therapies may shape treatment decisions in the coming years. In a discussion with Yash Agrawal, MD, of UNC School of Medicine, and Madison Canning, MD, of Emory School of Medicine, they focused on whether emerging data on ctDNA, TILs, and HER2 heterogeneity are ready to meaningfully guide clinical care.
Although enthusiasm around biomarker-driven escalation and de-escalation strategies is high, most approaches are not yet ready for routine clinical use, Dr. Agrawal said.
Among the more promising advances were results from the CompassHER2 pCR trial, which evaluated TILs alongside HER2DX, a 27-gene expression assay. Results showed a pathologic complete response rate of 64% in patients with early-stage HER2-positive, ER-negative breast cancer. Unlike prior retrospective analyses, ongoing prospective trials are now assessing whether HER2DX can meaningfully tailor neoadjuvant and adjuvant treatment intensity.
The conversation also addressed the expanding role of established HER2-directed therapies. Agents such as T-DXd and tucatinib, which have reshaped outcomes in metastatic disease, are now being studied earlier in the treatment course. Data from HER2CLIMB-05 demonstrated a benefit for tucatinib-based maintenance in the first-line setting, regardless of hormone receptor status. Being able to use these treatments earlier allows clinicians the opportunity to control the disease longer and improve survival outcomes, Dr. Agrawal said.
While earlier use of highly effective therapies raises concerns about exhausting future options, Dr. Agrawal emphasized that the pipeline remains robust. Novel ADCs and emerging cellular therapies, including chimeric antigen receptor T-cell approaches, may offer new opportunities for patients who progress after T-DXd or tucatinib. As these agents advance in clinical trials, they may help define the next generation of treatment strategies in HER2-positive breast cancer.