Residual disease after neoadjuvant therapy in HER2-positive breast cancer: biology, burden, or both?

Since the advent of human epidermal growth factor receptor 2 (HER2)-targeted therapies, the prognosis for this once-dismal breast cancer subtype has been continuously improving (1-4). The use of these therapies in the neoadjuvant setting has allowed clinicians to test tumor biology in vivo, yielding dramatically improved outcomes in patients whose tumors achieve pathologic complete response (pCR) and leading to more personalized adjuvant care for those whose tumors do not (5). Additionally, this approach offers a unique platform for translational research to be conducted given these in vivo alterations of the tumor and its microenvironment which can be studied before and after therapeutic pressure (6,7).

For patients with residual disease (RD) after neoadjuvant therapy, the pooled outcomes are associated with higher risk of recurrence, but the clinical picture is heterogeneous (8,9). While some patients with RD experience long-term survival that is indistinguishable from those who achieved pCR, others face rapid recurrence. Distinguishing these HER2-positive tumors with an indolent course from those which are more aggressive remains a major unmet clinical need (4,10-12).

In this vein, Fernandez-Martinez et al. presented a large-scale pooled analysis of four major neoadjuvant trials (CALGB 40601, NeoALTTO, NSABP B-41, and PAMELA) aiming to elucidate the ‘black box’ of RD biology (13). Their findings highlight the phenotypic drift in the epithelial makeup that occurs after neoadjuvant therapy. Most notably, they identify that the HER2-enriched subtype often undergoes a phenotypic switch towards more normal-like or luminal-like profiles in the residual bulk tumor. This highlights that these tumors, though residual, are likely ‘good actors’ in the long-term scope. This more favorable tumor biology is associated with longer-term event-free-survival.

The authors also describe a critical shift in prognostic value: while intrinsic tumor biology predicts outcomes at baseline, immune biology becomes the dominant prognosticator in RD. Specifically, an ‘immune-switch’ to an IgG/B-cell enriched phenotype appears to confer a survival advantage. Immune switch is defined as a transcriptomic shift characterized by elevated adaptive immune signatures including B-cell, CD8⁺ T-cell, and natural killer (NK) cell infiltration. This switch suggests that an active adaptive immune microenvironment may keep residual epithelial cells in check, promoting a state of tumor dormancy.

However, the interpretation of this phenotypic drift requires caution. The shift towards normal-like is quite difficult to interpret and raises a fundamental question: does this represent true biological reprogramming or rather is it a bioinformatic artifact from low tumor purity? As assessed via the PUREE package in the original study, normal-like samples demonstrated significantly lower RNA-sequencing-based tumor purity. We hypothesize that in the setting of a partial response, sampling of the tumor bed often captures a high ratio of normal breast stroma and scar tissue relative to viable tumor cells. Therefore, rather than intrinsically favorable biology, the normal-like signature may simply be a genomic proxy for a low residual cancer burden (RCB). If this is the case, the association with improved EFS is not due to a molecular switch, but simply confirms the well-established dogma that ‘less cancer is better’. Disentangling molecular evolution from low cellularity remains a challenge that future transcriptomic studies must address.

This challenge is compounded by the inherent limitations of bulk RNA sequencing. Because this method pools the entirety of the sampled tumor and outputs an average transcriptomic profile, it is highly susceptible to stromal contamination and sampling variability. Furthermore, it leads to a loss of granularity regarding intra-tumor heterogeneity, potentially diluting the signal of rare, resistant subclonal populations which may eventually drive recurrence.

This focus on “in-breast” residual biology also highlights a significant clinical limitation: the omission of residual nodal status. In HER2-positive breast cancer, long-term survival is heavily driven by nodal status. A patient with a Normal-like breast tumor subtype and a negative axilla has a fundamentally different prognosis from a patient with residual axillary disease. Grouping all patients with in-breast RD without controlling for nodal status obscures the survival data, making it less conclusive. Subsetting patients by residual nodal status would have strengthened the argument that tumor biology rather than tumor burden is the primary driver of outcomes. Moving forward, a critical hypothesis to test is whether the prognostic value of an IgG/B-cell-high signature is maintained within node-positive strata, or if the sheer burden of residual axillary disease overrides the favorable immune biology of the primary tumor bed.

Perhaps the most clinically relevant finding of this study is that, in contrast to the HER2-enriched subtype, the Basal-like subset stagnated and retained its aggressive phenotype following neoadjuvant HER2-targeted therapy. This finding reinforces the concept that these tumors are truly biologically distinct bad actors, relying less on HER2-driven pathways, and thus likely evading HER2-targeted therapies. This aligns with prior intrinsic subtype analyses, such as the CALGB 40601 trial (14), which demonstrated that Basal-like tumors exhibit significantly lower pCR rates to dual HER2 blockade alone and rely more heavily on the inclusion of cytotoxic chemotherapy to achieve optimal responses. It is unfortunate that the pooled nature of this study did not allow for granular evaluation of the chemotherapy backbone; one might hypothesize that it is this specific subtype that may derive the most benefit from classic cytotoxic therapy when compared to the HER2-enriched subset which may derive more benefit from a dual-HER2-targing approach, as in the chemotherapy-sparing PAMELA protocol. This would have been an interesting, hypothesis-generating subgroup analysis and could have offered rationale for de-escalating cytotoxic chemotherapy in certain subtypes of HER2-positive breast cancer while favoring its use in other subtypes.

Finally, since these trials were conducted, the therapeutic landscape for RD in HER2-positive disease now includes adjuvant T-DM1 [KATHERINE trial (15)] and potentially trastuzumab deruxtecan (T-DXd) for high-risk patients [DESTINY-Breast05 (16)]. While the authors of this study acknowledge this limitation, the findings of B-cell enrichment are highly relevant in the antibody-drug conjugate (ADC) era, given that these agents rely on immune engagement in addition to their payload delivery (17,18). However, it is crucial to acknowledge that in the KATHERINE trial, the benefit of adjuvant T-DM1 was observed broadly across clinical and biomarker subgroups. Therefore, while it is plausible that the patients most likely to derive a significant survival advantage from these ADCs are those with the high IgG/B-cell phenotype identified in this study, the use of these biomarkers for patient selection remains strictly hypothesis-generating and requires rigorous prospective validation.

In conclusion, Fernandez-Martinez et al. begin to pull the curtain of the phenotypic pressures exerted on HER2-positive tumors undergoing neoadjuvant targeted therapy. Their work aligns with current interest in elucidating mechanisms for RD in those patients whose tumors do not achieve pCR and the need to better stratify these patients. However, to truly understand the biological shifts in phenotypes, we must make sure to approach these data carefully, ensuring that we disentangle biological evolution from low tumor burden. Additionally, we must not forget to take into consideration the known clinical prognosticators in this tumor subtype, notably the RD burden within the lymph nodes. Until we can truly parse these elements out, our most robust tool remains the microscope, which can evaluate RCB scores within the breast and the axilla. Ultimately, optimal risk stratification in HER2-positive RD will require a multi-dimensional approach that integrates intrinsic subtype, immune biology, and precise measures of residual burden, particularly nodal status.

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-2026-1-0110/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0110/coif). K.T. reports receiving support from US National Institutes of Health (grant Nos. R01CA287731, R01CA250412, and R37CA248018), as well as US Department of Defense BCRP (grant Nos. W81XWH-19-1-0674 and HT9425-24-1-0762), unrelated to this work. Roswell Park Comprehensive Cancer Center was supported by US National Institute of Health Cancer Center Support Grant No. P30CA016056, also unrelated to this work. The other author has no conflicts of interest to declare.

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