From prognosis to precision: interpreting HER2DX assay in early HER2-positive breast cancer

The management of early breast cancer (EBC) has evolved substantially over the past two decades, shifting from uniform treatment strategies based primarily on conventional clinicopathological factors to more personalized approaches guided by biological risk stratification (1). In hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative disease, multigene assays such as Oncotype DX (a 21-gene recurrence score assay) have been integrated into routine clinical practice, where the recurrence score is used to guide decisions regarding adjuvant chemotherapy (2,3). This paradigm illustrates how genomic assays can refine prognosis beyond anatomical staging and significantly influence treatment selection.

However, HER2-positive EBC presents a distinct challenge. Despite dramatic improvements in outcomes with HER2-targeted therapies, substantial heterogeneity in prognosis and treatment response persists within this subgroup. HER2DX was developed to address this unmet clinical requirement. By integrating the expression of 27 genes representing immune infiltration, luminal differentiation, tumor proliferation, and HER2 amplicon activity, together with tumor size and nodal status, HER2DX generates complementary outputs that quantify recurrence risk, estimate the likelihood of pathological complete response (pCR), and measure HER2 mRNA expression.

An individual patient-level meta-analysis integrating data from 11 clinical trials encompassing 2,518 patients with HER2-positive EBC represents the most comprehensive evaluation of HER2DX to date (4). By pooling heterogeneous study populations and treatment settings, investigators can robustly assess the independent contribution of HER2DX across a wide range of clinically relevant scenarios, including variations in stage, HR status, treatment strategies, and pathological response categories. Importantly, HER2DX consistently stratifies event-free survival beyond traditional clinicopathological variables and pCR status.

A particularly notable finding was the ability of HER2DX to provide additional prognostic discrimination within patient groups often considered uniformly favorable, including those achieving pCR after neoadjuvant therapy and those undergoing upfront surgery. These findings underscore that achieving a pCR or presenting with early-stage disease does not equate to biological homogeneity. In this regard, meta-analyses have made important advances in translating the intrinsic biological diversity of HER2-positive breast cancer into clinically meaningful risk categories.

Nevertheless, the prognostic value of a biomarker should not be confused with its clinical utility. While the present findings firmly establish HER2DX as a robust prognostic biomarker, they do not demonstrate its predictive utility, that is, whether adjusting treatment intensity based on HER2DX scores leads to improved patient outcomes. This distinction is particularly relevant in the current therapeutic landscape. Recent perioperative trials, including DESTINY-Breast05 and DESTINY-Breast11, suggest that trastuzumab deruxtecan may soon assume a central role in treatment strategies for HER2-positive EBC (5,6). However, these pivotal trials did not incorporate HER2DX-based risk-stratified analyses, leaving unresolved how optimally to deploy highly potent antibody-drug conjugates across biologically distinct risk groups.

In an era of rapidly expanding therapeutic options, the clinical appeal of HER2DX lies not in its ability to dictate specific regimens but in its potential to inform nuanced decisions about treatment escalation and de-escalation. Like other genomic assays, HER2DX is expensive and methodologically complex, underscoring the importance of judicious patient selection rather than universal application. Its greatest value is likely to emerge in patients for whom prognosis estimation and treatment selection remain uncertain when relying solely on conventional clinicopathological factors that lie at the boundary between overtreatment and undertreatment.

Following the successful integration of Oncotype DX into the management of HR-positive, HER2-negative disease, HER2DX may represent a parallel advancement in HER2-positive EBC. Moreover, the current development of subtype-specific genomic tools in other breast cancer subgroups suggests a broader shift toward precision frameworks tailored to biological contexts rather than one-size-fits-all approaches (7). Ultimately, the critical questions are whether HER2DX can refine prognostic stratification and whether treatment strategies guided by HER2DX can deliver clinically meaningful improvements in patient outcomes. Addressing these questions requires prospective, biomarker-driven trials that move beyond risk prediction to true therapeutic optimization.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0119/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0119/coif). K.Y. reports fees for participating in a speaker’s bureau and/or acting in a consulting/advisory role from Pfizer, Eisai, AstraZeneca, Eli Lilly, Takeda, Chugai, MSD, FujiFilm Pharma, Bayer, Asteras, Boehringer Ingelheim, Daiichi-Sankyo, PDR Pharma, and Sanofi; and institutional research funding from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Daiichi-Sankyo, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono Pharmaceutical, Seattle Genetics, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, Sanofi, and Haihe. The other authors have no conflicts of interest to declare.

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