The therapeutic landscape for HER2-positive breast cancer has changed dramatically: a subtype once linked to poor outcomes is now frequently curable in early-stage disease. Right‑sizing treatment means tailoring intensity to clinical stage, tumour biology, treatment response, expected toxicity and patient preferences. The Review presents a conceptual framework that links clinical stage and risk to choices about de‑escalation, standard neoadjuvant backbones and post‑neoadjuvant escalation for residual disease.
For patients with low‑risk tumours, the emphasis is on sparing therapy where safe. For those with stage II–III disease, the focus is on optimizing neoadjuvant chemotherapy backbones to maximize response while balancing toxicity. Patients with residual disease after neoadjuvant therapy represent a high‑risk group for whom escalation of HER2‑directed therapy in the post‑neoadjuvant setting is recommended under current paradigms.
Neoadjuvant HER2‑targeted combinations have yielded variable pathological complete response (pCR) rates depending on the regimen and patient selection. The Review summarizes pCR outcomes with contemporary neoadjuvant HER2‑targeted regimens and frames decision making around who might safely undergo de‑escalated approaches versus who should receive intensified therapy.
Post‑neoadjuvant treatment is risk‑adapted: patients achieving pCR generally continue with standard adjuvant HER2‑directed therapy, whereas those with residual invasive disease are candidates for escalation. The arrival of more active agents in earlier lines both provides opportunities to improve cure rates and complicates choice of optimal escalation regimens.
The antibody–drug conjugate trastuzumab deruxtecan (T‑DXd) has been moved rapidly into earlier lines of therapy. Its roles now include the first‑line metastatic setting, adjuvant treatment of high‑risk residual disease and use within neoadjuvant regimens. This rapid expansion presents clear clinical opportunities to improve outcomes across the disease continuum.
However, moving T‑DXd into curative‑intent settings raises key unanswered questions. The Review highlights evidence gaps around optimal treatment duration, best sequencing with other HER2‑targeted agents, and strategies for retreatment if disease relapses after prior exposure to T‑DXd. These uncertainties affect both clinical trial design and everyday practice decisions.
For metastatic HER2‑positive disease, first‑line and maintenance strategies are increasingly complex. Traditional paradigms used sequential HER2‑directed agents, but newer options require rethinking induction and maintenance phases.
One current consideration is integrating trastuzumab–pertuzumab maintenance after induction therapy versus using other maintenance approaches. The Review discusses potential intensification strategies such as adding CDK4/6 inhibitors (for example, palbociclib) or small molecule tyrosine‑kinase inhibitors (for example, tucatinib) into maintenance regimens. Another emerging model is continuous first‑line therapy with T‑DXd plus pertuzumab, but the optimal duration of such regimens and how they should be sequenced with subsequent lines remain uncertain.
The authors propose a treatment algorithm for advanced‑stage HER2‑positive, hormone‑receptor‑positive disease that balances induction efficacy, tolerability and downstream sequencing, although full algorithm details are contained in the full Review.
Biomarker development is central to implementing right‑sized therapy. The Review describes multiple biomarker modalities that are approaching clinical utility:
Quantitative measures of HER2 expression, which may refine which patients derive greatest benefit from specific HER2‑directed agents.
Intrinsic molecular subtyping of tumours to inform likely chemotherapy sensitivity and benefit from HER2‑targeted combinations.
Dynamic imaging‑based response metrics used during neoadjuvant therapy to guide escalation or de‑escalation decisions.
Circulating tumour DNA (ctDNA) assays for monitoring response and detecting minimal residual disease or early recurrence.
Several of these markers show promising potential for clinical implementation and may soon influence decisions on escalation, de‑escalation, sequencing and retreatment.
While therapeutic options have expanded, the Review emphasizes persistent evidence gaps. Key unknowns include optimal sequencing of highly active agents, criteria for retreatment after prior exposure (notably after T‑DXd), and appropriate treatment durations for new first‑line combinations. These uncertainties complicate decisions about intensifying therapy for high‑risk early‑stage patients and about maintenance strategies in the metastatic setting.
The authors call attention to the need for prospective data to define when treatment can be safely de‑escalated, which neoadjuvant backbones are optimal for different risk groups, and how to integrate biomarkers into routine practice. The Review also includes visual summaries—a conceptual framework for early‑stage selection, pCR rate comparisons for neoadjuvant regimens, a proposed advanced‑stage algorithm and a biomarker development pathway—intended to synthesize current evidence and guide future research.
Overall, the clinical imperative is to individualize therapy—to deliver enough treatment to maximize cure or control while minimizing unnecessary toxicity—using expanding HER2‑targeted options and emerging biomarkers to guide those choices. The full Review provides detailed data, figures and references to support these concepts; the excerpted source here notes that full access requires subscription.