HER2-low: rethinking sequencing with ADCs

HER2-low has reshaped treatment strategy in HR-positive disease. DESTINY-Breast06 confirms that ADCs deserve an earlier role after CDK4/6 inhibition.

The ADC turning point

HER2-low disease has emerged as one of the most significant conceptual shifts in modern breast oncology. By challenging the long-standing dichotomy of HER2-positive versus HER2-negative tumors, this biologically heterogeneous subgroup has opened a therapeutic space where antibody-drug conjugates (ADCs) are becoming central actors rather than marginal options. The publication of DESTINY-Breast06 marked the critical step: for the first time, the early integration of trastuzumab deruxtecan (T-DXd) in the post-CDK4/6 setting can be discussed not as an experimental trajectory, but as a rational and practice-changing sequence.

For more than a decade, the HR-positive/HER2-negative setting has revolved around two pillars: endocrine therapy and progressive combinations designed to delay chemotherapy. CDK4/6 inhibitors transformed first-line management, but the post-progression scenario remained crowded, empirical and fragmented. The emergence of the HER2-low phenotype and the efficacy of ADCs offer an alternative logic: instead of escalating cytotoxic pressure, clinicians can exploit targetability even in tumors that do not meet classic HER2-amplified criteria. DESTINY-Breast04 laid the groundwork by demonstrating a meaningful benefit of T-DXd in pretreated disease, but the true inflection point came with DESTINY-Breast06, which tested the strategy earlier in the metastatic course.

The relevance of DESTINY-Breast06 lies less in its statistical outcome than in its clinical consequence. By demonstrating superiority to standard chemotherapy in patients progressing after endocrine therapy and CDK4/6 inhibition, the trial validated three key ideas. First, HER2-low is not a semantic refinement of HER2-negative disease, but a therapeutically actionable biology. Second, ADCs can compete with, and in selected patients, surpass, the traditional role of chemotherapy in early post-progression lines. Third, sequencing should no longer be anchored to the late-line salvage mentality that historically limited access to innovative agents.

This is why the study functions as a paradigm shifter: it does not simply add a drug; it rewrites the order of operations. The oncologist’s question becomes less “if” and more “how early” to introduce an ADC. Equally important, the trial supports a broader cultural transition: from chemotherapy inevitability to chemotherapy selectivity. In other words, chemotherapy remains relevant, but it is no longer the gravitational center in HR-positive metastatic disease once endocrine resistance emerges.

A new logic for sequencing

Patient selection is becoming central to this shift. Not all HER2-low tumors behave uniformly, and the degree of HER2 expression, its spatial heterogeneity and the evolving role of pathology in defining low versus ultralow disease now matter in daily decision-making. DESTINY-Breast06 reinforces the idea that treatment choice should not simply follow progression, but follow biology. This requires a more proactive sequencing mindset, in which earlier ADC introduction is considered when endocrine exhaustion coexists with a targetable HER2 signal, rather than delaying for the sake of exhausting chemotherapy-based permutations. In this sense, HER2-low acts as a clinical compass: it does not dictate a single path, but it prevents oncologists from navigating in the dark once endocrine resistance has emerged.

The evolving placement of T-DXd in clinical pathways is already influencing guidelines and multidisciplinary discussions. While full algorithmic harmonization will require longer follow-up and OS confirmation, the direction of travel is unmistakable. For patients with adequate performance status and compatible comorbidities, earlier ADC use is increasingly attractive, particularly when the goal is to maintain disease control with higher precision and potentially better quality of life compared with nonspecific cytotoxic regimens.

However, acceleration comes with responsibility. ILD and pneumonitis remain the principal toxicity concerns associated with T-DXd, and the experience accumulated in prior DESTINY trials underlines the importance of early recognition, imaging vigilance and a low threshold for treatment interruption. DESTINY-Breast06 does not change this safety reality; rather, it amplifies its relevance by moving ADCs into a population that may be exposed for longer durations. Sequencing innovation must therefore be matched by toxicity literacy, shared decision-making and multidisciplinary monitoring.

The horizon is widening further. The trial also reinforces the notion that HER2 expression behaves along a spectrum, stimulating interest in emerging categories such as “HER2-ultralow.” Although still investigational, these trajectories indicate that HER2 biology may serve as a continuum of ADC eligibility rather than a binary classifier. As additional ADCs and payload technologies enter development, the logic first crystallized in DESTINY-Breast06 is likely to expand, not contract.

In summary, the significance of the past year in metastatic breast cancer is not the arrival of yet another agent, but the consolidation of a sequencing revolution. DESTINY-Breast06 gives oncologists permission, and evidence, to rethink therapeutic order, narrowing the space of chemotherapy in favor of a precision-guided approach that capitalizes on HER2-directed payload delivery. The shift is both conceptual and practical: HER2-low disease is now a targetable entity, and ADCs have moved from option to strategy.

The post-CDK4/6 era is no longer defined by chemotherapy inevitability. With DESTINY-Breast06, HER2-low disease becomes a pivotal therapeutic category and T-DXd earns an earlier and clearer role. The update of 2025 can be summarized in one line: sequencing has changed, and oncology must adapt to it.

Sources and further reading
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