Dr Tarantino on Early-Stage HER2+ Breast Cancer Risk Stratification

“There are some pillars of oncology that have remained constant over time, and in 2025, the Tumor, Nodes, Metastasis [TNM] staging system [continues to be one of the most critical].”

Paolo Tarantino, MD, a research fellow in Medicine at Dana-Farber Cancer Institute, discussed the evolving methods for risk classification of HER2-positive breast tumors and how this classification affects treatment decision-making.

As of 2025, certain foundational principles in oncology remain essential to guiding clinical decision-making, Tarantino began. Accordingly, the Tumor, Node, Metastasis (TNM) staging system continuing to serve as a cornerstone in breast cancer assessment and prognosis, Tarantino stated, adding that primary tumor size and nodal status are still critical prognostic indicators of early-stage disease, he emphasized. Patients with small, node-negative, HER2-positive tumors generally have favorable outcomes, with current HER2-targeted treatment strategies enabling cure rates exceeding 90%, he explained. Conversely, patients presenting with larger tumors and multiple involved lymph nodes remain at a significantly higher risk of recurrence, even in cases where a pathologic complete response is achieved following neoadjuvant therapy, he said. This highlights the persistent prognostic relevance of anatomic staging, he noted.

Beyond traditional clinical staging, the biological behavior of HER2-positive tumors is influenced by their degree of HER2 dependence, Tarantino reported. Tumors with strong HER2 expression often exhibit enhanced responsiveness to HER2-directed therapies, he said. Immunologic factors are also recognized as important for informing disease management, although their integration into standard clinical algorithms remains under investigation, he continued.

Efforts to refine risk stratification have led to the development of HER2DX, a multigene assay that integrates various biologic and clinical parameters—including TNM staging, proliferation markers, luminal features, HER2 expression levels, and immune signatures, according to Tarantino. This 27-gene expression profile provides a composite risk score intended to predict recurrence risk in patients with HER2-positive breast cancer, he stated. To date, HER2DX has undergone retrospective validation, but prospective data are awaited, he added.

This assay has also been incorporated into the ongoing phase 2 CompassHER2-pCR trial (NCT04266249), and forthcoming results may determine its clinical utility, Tarantino noted. If validated, HER2DX could become analogous to Oncotype DX for HER2-negative breast cancer, offering a genomic approach to risk stratification in HER2-positive disease, he noted. However, until such tools are fully validated, TNM staging remains the primary determinant of risk and treatment planning, Tarantino concluded.