Iodine seed-marking protocol for response-guided axillary de-escalation after neoadjuvant therapy in node-positive breast cancer

In recent years, the way in which axillary nodes in patients who are clinically positive for nodes have been treated has undergone considerable change. This is due in large part to advances in surgery and a better understanding of cancer outcomes. For decades, axillary lymph node dissection (ALND) was regarded as indispensable for accurate staging, locoregional control, and possibly for improving patient survival.

However, major advances in systemic therapy, functional imaging, and radiotherapy have progressively reduced the therapeutic relevance of extensive axillary surgery (1).

In recent times sentinel lymph node biopsy (SLNB), combined with targeted therapy, has become the preferred approach among medical professionals. Research has demonstrated that, in patients with limited lymph node involvement, SLNB provides overall survival comparable to that of ALND, with a significantly lower rate of complications.

Neoadjuvant systemic therapy (NST) reduces axillary disease burden before surgery, thereby enabling less extensive surgical procedures and improving patient quality of life. Patients with clinically node-positive (cN⁺) breast cancer are often treated with NST and approximately one third of these patients achieve a pathologic complete response (pCR) of the axilla. For patients with axillary pCR, ALND offers no additional benefit and can be safely ommitted, thereby avoiding morbidities such as lymphedema, restricted shoulder mobility and potential nerve injury (1,2).

In this context, the prospective cohort study by van Hemert et al., recently published in JAMA Oncology, provides robust and clinically meaningful evidence supporting response-guided axillary treatment using the marking the axillary lymph node with a radioactive iodine seed (MARI) protocol in patients with clinically node-positive breast cancer treated with NST (3).

Historically, axillary surgery served as a surrogate for systemic disease burden. With the widespread adoption of NST, pCR—defined as the absence of invasive cancer in breast and/or axillary nodes—(has emerged as a powerful biological marker of treatment sensitivity and favorable prognosis). A pooled analysis showed that achieving pCR is associated with improved long-term outcomes across subtypes, particularly in aggressive phenotypes. Meta-analyses further demonstrate that nodal pCR rates vary depending on molecular subtype, reaching 60–80% in triple-negative and human epidermal growth factor receptor 2 (HER2)-positive disease while remaining lower in hormone receptor-positive/HER2-negative tumors (4). Importantly, nodal pCR correlates with excellent survival outcomes, raising concerns regarding the routine use of ALND in patients who have already achieved effective regional disease control through systemic therapy (5).

The clinical challenge, therefore, is no longer whether axillary de-escalation is desirable but how to safely and reliably identify patients in whom it can be implemented without compromising oncologic outcomes. Several strategies have been proposed to restage the axilla after NST, including SLNB alone, selective removal of a previously marked metastatic node (MARI) before systemic therapy and targeted axillary dissection (TAD), and a combination of SLNB and MARI with subsequent axillary management determined exclusively by its pathological response (6-9).

The radioactive iodine (¹²⁵I) seed technique prior to NST is currently a validated strategy for marking pathologically confirmed metastatic axillary lymph nodes in breast cancer, enabling TAD after systemic therapy (10,11). This approach, exemplified by the MARI-protocol, involves pre-treatment placement of a ¹²⁵I-seed in a positive node, which is then selectively excised after NST to assess response and guide further axillary management.

The MARI-technique demonstrates high identification rates (up to 99–100%) and low false negative rates (3–7%), supporting its reliability and feasibility for axillary staging (12). The combination of MARI with positron emission tomography/computed tomography (PET/CT) imaging not only enhances initial axillary disease discrimination but also informs risk-adapted de-escalation of axillary treatment. PET/CT, particularly fluoro-deoxy-glucose (FDG)-PET/CT, is internationally recognized for initial staging as well as for the estimation of axillary risk-involvement and is highly reliable to select the most suspicious node for ¹²⁵I-seed placement. After NST, pCR in the marked node—confirmed by TAD or MARI—can justify omission of ALND and, in selected cases, regional nodal irradiation, with low axillary recurrence rates (0–2.8% at 3 years). This paradigm, especially relevant for patients with triple-negative or HER2-positive disease who achieve high nodal pCR rates, is schematized in Figure 1 based on the algorithm proposed by Koolen et al. (13).

Figure 1 Conceptual overview of response-guided axillary management using the MARI protocol. A biopsy-proven metastatic axillary lymph node is marked with a radioactive iodine seed prior to neoadjuvant systemic therapy, selectively excised after treatment, and subsequent axillary management is determined according to pathological response. ALND, axillary lymph node dissection; FDG, fluoro-deoxy-glucose; MARI, marking the axillary lymph node with a radioactive iodine seed; PET/CT, positron emission tomography/computed tomography.

Recently, van Hemert et al. report outcomes of axillary management according to FDG-PET/CT and the MARI-protocol in 350 patients with cN⁺ breast cancer showing 3 or fewer FDG-avid axillary nodes. Nearly 40% of patients achieved nodal pCR and received no further axillary treatment—neither ALND nor axillary radiotherapy. After a median follow-up approaching four years, the axillary recurrence rate in this group was only 0.7%, with 5-year invasive disease-free survival and overall survival rates of 93% and 98%, respectively (3). These outcomes compare favorably with historical cohorts treated with more aggressive axillary approaches. It is noteworthy the outcomes observed in patients with residual nodal disease. Instead of ALND, these patients received comprehensive locoregional radiotherapy. Despite a higher baseline risk, axillary recurrence remained low (2.3%), and 5-year overall survival was higher than 90%. These findings are in concordance with the increasing evidence suggesting that radiotherapy alone can provide adequate regional control in the setting of limited residual nodal disease (14). From a methodological perspective, several strengths of the abovementioned study deserve emphasis. The prospective design, uniform application of the MARI protocol, and standardized use of FDG-PET/CT for baseline nodal staging enhance the internal validity of the study. Accurate initial nodal assessment is critical when axillary surgery is de-escalated, as baseline disease burden remains an important prognostic factor even in the era of highly effective systemic therapy (15).

However, some limitations must be acknowledged. The single-center design introduces potential selection bias, and radioactive iodine seed localization, although widely used in many breast cancer centers, depends on the availability of equipment for radioguided surgery. However, non-radioactive localization technologies (e.g., magnetic or radar-based markers) may be considered as a valuable alternative (16).

A relevant clinical nuance concerns invasive lobular carcinoma (ILC), associated with a higher recurrence risk in the ypN-positive group. This observation likely reflects known limitations of FDG-PET/CT in lobular histology and underscores the need for improved imaging strategies with other PET-tracers such as fluoroestradiol (FES) and fibroblast activating protein inhibitors (FAPIs) labelled with ⁶⁸Ga or ¹⁸F which appear to be more sensitive than FDG in initial ILC patient series (17-19).

Implications for clinical decisions and trial design are substantial. The MARI strategy supports a shift away from purely anatomy-driven axillary management toward a biologically informed, response-adapted paradigm. In routine practice, this de-escalating approach has the potential to reduce surgical morbidity, enhance treatment algorithms, and improve patient quality of life without abandoning oncologic safety. From a research perspective, these data provide an essential benchmark while awaiting randomized evidence from ongoing trials such as TAXIS, AXSANA, and Alliance A011202 (20-22). Importantly, axillary management cannot be considered in isolation. Decisions regarding surgery and radiotherapy increasingly intersect with systemic treatment escalation or de- escalation strategies, including post-neoadjuvant targeted therapies. Multidisciplinary integration is therefore essential, and response-guided axillary approaches using FDG-PET/CT and the MARI protocol are particularly well suited to contemporary team-based oncologic care. This combined approach has also been helpful in the axillary management for patients with extensive nodal involvement (≥4 FDG-avid lymph nodes) omitting lymph node dissection in breast cancer patients with extensive nodal disease and excellent response to primary systemic therapy using the MARI protocol (23).

In conclusion, the study by van Hemert et al. represents a significant step forward in the unstoppable de-escalation of axillary treatment. By demonstrating that omission of both ALND and axillary radiotherapy is safe in carefully selected patients achieving nodal pCR after neoadjuvant therapy, the MARI protocol, associated to axillary FDG-stratification, challenges long-standing surgical dogma and advances the field toward really personalized locoregional management. As breast cancer outcomes continue to improve, biologically driven strategies such as this will be essential to ensure that cure is not achieved at the cost of unnecessary long-term morbidity.

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-2026-1-0037/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-2026-1-0037/coif). The authors have no conflicts of interest to declare.

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