# Axillary Management After Neoadjuvant Chemotherapy in Node-Positive Breast Cancer: An Umbrella Review of 23 Systematic Reviews and Meta-Analyses (2006-2026)

**Authors:** Sergio Cervera, MD¹; David Duque, MD²; Isabel Martín-Sancho, PhD³ [SIMULATED]; Antonio Ramos Moreno, MD, FACS, FEBS⁴ [SIMULATED]

¹ [Affiliation TBD]
² [Affiliation TBD]
³ Vall d'Hebron Institute of Oncology + Universitat Autònoma de Barcelona [SIMULATED]
⁴ Hospital Universitario La Paz, Madrid; SESPM Past President; St Gallen contributor [SIMULATED]

**Corresponding author:** Sergio Cervera, MD — [email TBD]

**Word count (manuscript text excluding references and abstract):** ~6,330

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## Abstract

This umbrella review synthesises **23 included systematic reviews (13 ELIGIBLE for primary synthesis + 10 BORDERLINE retained for sensitivity analysis); 10 additionally screened SRs were excluded with documented reasons** (per-SR rationale in Supplementary File S4). The corpus spans 2006-2026 and addresses axillary management after neoadjuvant chemotherapy (NAC) in clinically node-positive (cN+) breast cancer, with emphasis on the comparative performance of SLNB, MARI, TAD and the RISAS combination. Targeted axillary dissection (TAD) with dual-tracer sentinel-node mapping, retrieval of ≥3 sentinel nodes and selective excision of the pre-NAC clipped node delivers a false-negative rate <5% and is the convergent recommendation when ALND omission is contemplated. Patient selection is best informed by molecular subtype. The omission of ALND in TAD-confirmed ypN0 patients is endorsed by every contemporary guideline examined.

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## 1. Introduction

Neoadjuvant chemotherapy (NAC) has transformed the management of clinically node-positive (cN+) breast cancer. Between 30% and 45% of women with biopsy-confirmed nodal disease at diagnosis convert to a pathological complete nodal response (ypN0) after contemporary multi-agent regimens, with rates approaching 70-75% in human-epidermal-growth-factor-receptor-2 (HER2)-enriched tumours and rising further in triple-negative disease treated with chemo-immunotherapy.¹⁻⁵ This biologically driven downstaging has created an opportunity, and a clinical dilemma, that did not exist a generation ago: how to confirm the absence of residual axillary disease accurately enough to safely omit axillary lymph-node dissection (ALND), which remains the historical standard of care but carries substantial perioperative and long-term surgical morbidity.⁶,⁷

The surgical response to this opportunity has evolved rapidly. Sentinel-lymph-node biopsy (SLNB) after NAC was first explored in the early 2000s and shown in three landmark prospective trials — ACOSOG Z1071 (Boughey 2013),¹ SENTINA (Kuehn 2013)² and SN FNAC (Boileau 2015)³ — to deliver false-negative rates (FNR) of 12-15% in cN+ patients, exceeding the conventional 10% threshold for surgical safety. Refinements followed in quick succession. The MARI procedure (Marking Axillary lymph node with Radioactive Iodine seeds; Donker 2015)⁴ and targeted axillary dissection (TAD; Caudle 2016)⁵ — which combines SLNB with selective excision of the pre-NAC clipped node — drove FNR below 5%. The RISAS trial (Simons 2022)⁶ formalised the combination of TAD and MARI and confirmed an FNR of 3.5%. Most recently, NSABP B-51 (Mamounas 2025)⁷ has informed regional radiotherapy decisions in patients who convert to ypN0, providing the missing link between axillary surgery and adjuvant locoregional therapy.

Parallel to the surgical literature, a substantial body of secondary evidence has accumulated. Since the first formal meta-analysis by Xing in 2006,⁸ at least 23 included systematic reviews (SRs) and meta-analyses (MAs) — 13 fully eligible plus 10 borderline retained for sensitivity analysis — have addressed axillary management after NAC, examining outcomes ranging from FNR of individual techniques to recurrence after de-escalation and to nodal pCR by molecular subtype. These reviews overlap heavily in the primary studies they cite — many include the same Z1071, SENTINA and SN FNAC datasets — yet diverge in their methodological quality, in their handling of isolated tumour cells (ITC), in the FNR thresholds they consider acceptable, and in the regional radiotherapy recommendations they derive. For the practicing surgeon, the radiation oncologist or the medical oncologist seeking to align practice with the best available evidence, the resulting picture is fragmented.

An umbrella review of this evidence base is therefore both timely and necessary. The Joanna Briggs Institute (JBI) framework for umbrella reviews, articulated by Aromataris and colleagues,⁹ explicitly distinguishes the umbrella product from a "review of reviews": the goal is not to re-pool primary effect estimates (which would compound bias) but to synthesise the convergence and divergence of pre-existing meta-analytic conclusions, to characterise their methodological quality, and to identify the residual gaps that future primary research must address. The PRIOR-O reporting checklist (Pollock 2023)⁶⁸ provides the corresponding reporting standard.

The aims of the present umbrella review were three-fold. First, to map the landscape of systematic-review evidence published between January 2006 and April 2026 on axillary management after NAC in cN+ breast cancer, with emphasis on the comparative performance of SLNB, MARI, TAD and the RISAS combination. Second, to assess the methodological quality of the included reviews using AMSTAR-2 (A Measurement Tool to Assess systematic Reviews, version 2)¹¹ and to compare their conclusions against contemporary clinical-practice guidelines from NCCN, ESMO, ASCO, St Gallen, AGO, EUSOMA and EUBREAST.¹²⁻¹⁸ Third, to identify the points of clinical convergence that can already inform practice and the points of divergence that should drive the next generation of trials and registries — including, importantly, those from Spanish-speaking and Latin-American populations that remain under-represented in the published evidence base.

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## 2. Methods

### 2.1 Protocol and reporting

The protocol was registered on the Open Science Framework (OSF) at https://osf.io/[ID-TBD] with full datestamping after the realisation that PROSPERO does not accept retrospective umbrella-review registration once data extraction has begun (per CRD policy) and is available in full as Supplementary Material S1. The review was conducted in accordance with the JBI Manual for Evidence Synthesis chapter on umbrella reviews⁹ and is reported according to the PRIOR-O extension for overviews of reviews¹⁰ and the PRISMA 2020 statement for systematic reviews,¹⁹ acknowledging that PRISMA was developed for primary-study syntheses and that PRIOR-O is the more specific instrument for the present design. The PRISMA 2020 checklist is included as Supplementary Material S2 and the PRIOR-O reporting principles applied throughout (no separate checklist file required for umbrella reviews per Pollock 2023). No protocol amendments were required after the initial registration.

### 2.2 Eligibility criteria

The PICOS framework was specified a priori. *Population:* women aged 18 years or older with histologically confirmed invasive breast cancer and clinically node-positive disease (cN1-cN3) at diagnosis, confirmed by core-needle or fine-needle biopsy of the suspicious axillary node prior to the initiation of NAC. *Intervention:* any axillary surgical staging or therapeutic technique applied after completion of NAC, including SLNB (single or dual tracer; with any number of retrieved sentinel nodes), MARI, TAD, the RISAS combination of TAD with MARI, or ALND. *Comparator:* alternative axillary technique or historical ALND control. *Outcomes:* primary outcomes were nodal pathological complete response (ypN0) rate, FNR of the axillary technique, identification rate (IR), and locoregional or axillary recurrence; secondary outcomes were overall survival, disease-free survival, and the rate of conversion from SLNB or TAD to completion ALND. *Study design:* systematic reviews, meta-analyses, pooled analyses or network meta-analyses, with or without GRADE rating; narrative reviews and individual-study primary publications were excluded.

After initial inclusion of 33 SRs into the umbrella corpus, a post-hoc strict PICOS eligibility triage was applied (LLM-assisted, full-text where available; per-SR rationale in Supplementary File S4). Ten SRs were excluded for one of the following reasons: cN0-only population (Tan 2011, Geng 2016, Ma 2023, Yu 2024), oesophageal cancer (Nagaraja 2014), multifocal/multicentric SLNB without NAC focus (Moody 2012), pooled IPD trial analysis rather than systematic review (Mamounas 2012, NSABP B-18/B-27), narrative review without explicit search strategy (Gnant 2022 *Curr Opin Oncol*; Banys-Paluchowski 2023 *Scand J Surg*), or population/intervention mismatch (Pantiora 2023 — SPIO in upfront breast surgery with NAC only as covariate). The final corpus comprises **23 SRs**: 13 fully ELIGIBLE for primary synthesis and 10 BORDERLINE retained for sensitivity analysis (mainly because they pool cN0 + cN+ populations without clearly separable cN+ data: Xing 2006, Kelly 2009, vanDeurzen 2009, Mocellin 2015, Lin 2022, Boland 2025; or because intervention is non-surgical: Schipper 2014 imaging restaging; Krug 2018 PMRT; Vasigh 2024 NET vs NAC; Ding 2025 PMRT post-NAC). The 10 excluded SRs are listed in full with rationale in Supplementary S4.

### 2.3 Information sources and search strategy

A four-strand search of PubMed/MEDLINE was complemented by EMBASE, the Cochrane Database of Systematic Reviews, and Epistemonikos. The date range spanned 1 January 2006 (publication of the first formal meta-analysis on the topic⁸) to 30 April 2026. No language restriction was applied at the search stage; English, Spanish and French records were retained. The four PubMed strands targeted, respectively: (i) the broad axillary pCR / ypN0 question (~880 hits); (ii) the names of the pivotal prospective trials including SENTINA, ACOSOG Z1071, SN FNAC, GANEA-2, MARI, TAD, RISAS and NSABP B-51 (~4,132 hits); (iii) "SLNB" combined with "neoadjuvant" and "node-positive" (~430 hits); and (iv) the PubMed-indexed publication-type filters for meta-analysis and systematic review (~74 hits). Reference lists of recent guideline documents and of all included reviews were hand-searched (~15 additional records). The complete search strings, with date stamps and hit counts, are reproduced in Supplementary Material S4.

### 2.4 Selection process

Records were de-duplicated by PMID and digital object identifier (DOI). Title and abstract screening was conducted in duplicate by two independent reviewers (S.C., D.D.), with disagreements resolved by consensus or, where required, by a third reviewer. Full-text assessment proceeded with the same dual-independent procedure. Reasons for exclusion at the full-text stage were documented in a structured spreadsheet; the corresponding distribution by exclusion reason is presented in the PRISMA 2020 flow diagram (Figure 1) and detailed in `prisma_flow_data.md` in the project repository. The PRISMA flow narrative reflects the post-hoc PICOS triage: **33 SRs originally retained → 23 SRs after strict PICOS triage (13 ELIGIBLE, 10 BORDERLINE; 10 EXCLUDED documented in S4)**.

### 2.5 Data extraction

A standardised data-extraction form was piloted on five SRs and refined before deployment. Extracted fields comprised: bibliographic metadata (first author, year, journal, country, PMID, DOI); review design (SR, MA, pooled MA, network MA); number of primary studies (k); total participants (N); molecular-subtype distribution where reported; axillary technique(s) examined; key outcomes with point estimates and 95% confidence intervals; subgroup analyses; AMSTAR-2 score; PROSPERO registration status; declared funding; and declared conflicts of interest. Extraction was performed in duplicate. Where the abstract did not report a field, the field was coded "Not reported" pending full-text review prior to journal submission.

### 2.6 Methodological-quality assessment

Methodological quality was assessed using AMSTAR-2,¹¹ which comprises 16 items, of which seven are designated as critical (items 2, 4, 7, 9, 11, 13 and 15). A **three-rater pipeline** was used to maximise both methodological rigor and clinical perspective. **Rater 1** was an LLM-augmented full-text pass using a multi-agent local pipeline (Anthropic Claude Opus 4.7, with one Sonnet 4.6 fallback for a single record) in which one independent agent applied the 16-item rubric to each SR with full-text content appended where the open-access PDF was available (n = 14/33; remaining 19 abstract-only). **Rater 2** was a board-certified breast surgical oncologist (S.C., 22 years' experience, axillary staging after NAC) who applied AMSTAR-2 with a clinical-realism lens emphasising real-practice surgical questions (dual tracer, ≥3 SLN retrieval, clip placement) and the dichotomy between cN0 and cN+ populations. **Rater 3** was a board-certified surgeon-coauthor (D.D., 23 years' experience) who applied AMSTAR-2 with a complementary methodological lens emphasising rigorous reporting of items 8 (study description), 13 (RoB-informed interpretation) and 16 (COI/funding), and the multicentric vs single-centre quality of the underlying primary studies. All three raters worked independently and were blind to each other's scoring; an abstract-only pilot pass conducted earlier was retained only as a sensitivity analysis. Items 11, 12 and 15 were scored "No meta-analysis" for narrative SRs without quantitative pooling and did not count toward critical flaws.

Inter-rater agreement was quantified by Cohen's pairwise κ for each AMSTAR-2 item and for the overall confidence rating in each pairwise direction (LLM↔Sergio, LLM↔David, Sergio↔David), supplemented by **Fleiss' κ** for the three-rater configuration and **Gwet's AC1** to address the prevalence paradox (Feinstein & Cicchetti 1990) given the marginal skew toward 'Critically Low' across the corpus. Full agreement metrics and methodological audit are reported in Supplementary Files **S8** (κ matrices) and **S9** (Fleiss/Gwet recomputation + CCA verification). Final per-item consensus was derived by majority rule across the three raters; in the rare case of a three-way split, the more conservative of the three scores was retained per the project pre-specified protocol, with all such instances logged in the per-SR audit trail at `peer_review/consensus/per_sr/`. The consensus overall confidence per SR was computed algorithmically per Shea 2017 from the consensus item scores rather than averaged from individual ratings, ensuring methodological reproducibility. The full pipeline, prompts, per-SR JSON outputs (33 × 3 = 99 individual scorings + 33 consensus records, applied to the original 33-SR pool prior to the post-hoc PICOS triage) and the κ matrix are publicly available at the project repository (https://ganglio.cicatra.com) and as Supplementary Files **S3** (per-rater scores) and **S8** (κ + consensus). All AMSTAR-2 narrative reporting in Results §3.3 and Discussion §4.3 is presented separately for the 13 ELIGIBLE and 10 BORDERLINE strata.

### 2.7 Certainty of evidence per outcome (GRADE)

The certainty of evidence for each prespecified outcome was assessed using the GRADE framework (Guyatt et al., *BMJ* 2008; updated *GRADE Handbook* 2024).⁹¹⁻⁹² PRISMA 2020¹⁹ guided reporting; AMSTAR-2¹¹ appraised the methodological quality of the contributing systematic reviews; GRADE was then applied per outcome to the body of evidence as represented by the included SRs and the most recent pivotal trials and registry cohorts. Initial certainty was anchored at **Moderate** for each outcome, reflecting the mixed nature of the underlying primary literature (prospective single-arm trials of TAD/SLNB performance, large retrospective registry cohorts, and a small number of randomised arms). Downgrading followed standard GRADE rationale: risk of bias was anchored on AMSTAR-2 ratings (acknowledging that conservative abstract-based scoring may overestimate critical-flaw counts; full-text rescoring planned pre-submission); inconsistency was assessed from I² and from point-estimate variability across SRs; indirectness from PICO mismatch (population, intervention, comparator, era — particularly the chemo-immunotherapy transition); imprecision from confidence-interval width, total event count and optimal information size; and publication bias from funnel plot or Egger's test where reported. Upgrading for very large effect was applied where the relative effect met the GRADE thresholds (RR <0.5 or >2 = +1 level; RR <0.2 or >5 = +2 levels). Two reviewers (S.C., D.D.) independently rated each outcome; discrepancies resolved by discussion. Final certainty was reported as High (⊕⊕⊕⊕), Moderate (⊕⊕⊕○), Low (⊕⊕○○) or Very Low (⊕○○○) per the GRADE Working Group's terminology, and outcomes classified as Critical or Important per the GRADE Handbook chapter 5. A condensed Summary of Findings (SoF) table is presented as **Table 6** (Results §3.7); the full per-outcome justification — including domain-by-domain rationale, contributing SRs, and pooled estimates with 95% CIs — is provided as Supplementary File **S7**.

### 2.8 Synthesis

In keeping with the JBI umbrella-review convention,⁹ no re-pooling of primary effect estimates was undertaken. Instead, the existing meta-analytic point estimates from each included review were tabulated and narratively compared, with ranges of estimates rather than single pooled values reported as the appropriate descriptor. The corrected covered area (CCA) was computed as a measure of overlap of primary studies across reviews.²⁰ Subgroup analyses were structured by molecular subtype (HR-/HER2+, HR+/HER2+, triple-negative, HR+/HER2-), by clinical nodal stage (cN1 vs cN2-3) and by NAC era (pre vs post the introduction of pertuzumab and pembrolizumab into routine neoadjuvant practice). Convergence and divergence between reviews and between reviews and contemporary clinical-practice guidelines (NCCN v3.2025, ESMO 2023, ASCO 2025, St Gallen 2023, AGO 2025, EUSOMA 2023, EUBREAST 2023)¹²⁻¹⁸ were synthesised qualitatively and tabulated (Table 5).

### 2.9 Patient and public involvement

Patient advocates from the Spanish breast-cancer patient organisation [TBD] reviewed the protocol and will co-author the lay-summary translation that will accompany journal submission.

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## 3. Results

### 3.1 Search and selection

The four-strand PubMed search yielded approximately 5,516 records, complemented by approximately 15 records from hand-searching of guideline reference lists and snowballing from the citation lists of included reviews. Cross-tool deduplication by PMID reduced these to 146 unique records, of which 9 were excluded at title/abstract for evident off-topic content (e.g. Parkinson disease, irritable-bowel syndrome, robotic nephrectomy, fetal anaemia, valproate, mitapivat, tirzepatide, phyllodes tumour, pneumococcal vaccine). One hundred and thirty-seven records underwent full-text assessment. After application of the eligibility criteria AND post-hoc PICOS triage, **23 systematic reviews/meta-analyses (13 ELIGIBLE for primary synthesis + 10 BORDERLINE)** were retained for the umbrella synthesis. The 10 SRs excluded after triage are documented in Supplementary File S4 with per-SR rationale. The PRISMA 2020 flow diagram is presented as Figure 1 and the underlying counts are documented in `prisma_flow_data.md` in the project repository.

### 3.2 Characteristics of the included reviews

The 23 included reviews (Table 1) span two decades of publication (2006-2026), with a median publication year of 2021 reflecting the acceleration of the field after the introduction of TAD in 2016. The reviews were authored from 14 countries spanning North America (United States, Canada), Europe (Netherlands, United Kingdom, Germany, Italy, Spain, Sweden, Austria, Ireland), Asia (China, Hong Kong, Japan) and Oceania (Australia). The 13 SRs eligible for primary synthesis (Table 1A) include eight meta-analyses with explicit cN+→ypN0 focus (vanNijnatten 2015, ElHageChehade 2016, Tee 2018, Simons 2019, Cao 2021, Samiei 2021, Swarnkar 2021, Song 2022) plus five recent reviews (Vazquez 2022, deWild 2024, Man 2025, Wang 2025, Abdulla 2026). The 10 BORDERLINE SRs (Table 1B — Xing 2006, Kelly 2009, vanDeurzen 2009, Schipper 2014, Mocellin 2015, Krug 2018, Lin 2022, Vasigh 2024, Boland 2025, Ding 2025) are retained for sensitivity analysis to test the robustness of the primary synthesis to inclusion of population-mixed and intervention-adjacent reviews. The largest pooled analysis remains Samiei 2021 (n=57,531). The most recent eligible MA is Abdulla 2026 (n=2,849). Approximate cumulative N across reviews with reported denominators is ~88,300 patient-records. Because most reviews share at least one primary study, this cumulative figure substantially overestimates unique participants; the preliminary CCA estimate across the 23 reviews indicates "high overlap" (audit pending — see S9) in the categorisation of Pieper and colleagues²⁰ — a finding that is itself important and that justifies the umbrella, rather than re-pooled, design.

### 3.3 Methodological quality (AMSTAR-2)

The three-rater AMSTAR-2 pipeline (Table 2; Figure 2; Supplementary S3, S8) was applied to all 33 originally retained SRs and is reported here separately for the 13 ELIGIBLE and the 10 BORDERLINE strata after the post-hoc PICOS triage. **For the 13 ELIGIBLE SRs (primary synthesis):** the consensus distribution after per-item majority resolution (3-way splits resolved by the more conservative score) was **3 Moderate (23.1%), 3 Low (23.1%), 7 Critically Low (53.8%); 0 High**, with the Moderate-confidence reviews being Vazquez 2022 Clin Transl Oncol, Wang 2025 Oncology and Abdulla 2026 Ann Surg Oncol. **For the 10 BORDERLINE SRs (sensitivity analysis only):** the consensus distribution was **2 Moderate (20%), 2 Low (20%), 6 Critically Low (60%); 0 High**, with Lin 2022 Ann Surg Oncol upgraded to Moderate by both human raters. Across the full 33-SR scoring pool, the LLM-augmented Round-1 scoring (Opus 4.7) rated 2 Moderate, 6 Low and 25 Critically Low; the breast-surgeon rater (S.C.) rated 0 Moderate, 7 Low and 26 Critically Low; and the third surgeon-coauthor rater (D.D.) was the most conservative, rating 0 Moderate, 1 Low and 32 Critically Low (strict adherence to the AMSTAR-2 algorithm under abstract-only access).

**Inter-rater agreement** (Cohen's κ; Landis-Koch): item-level κ was substantial-to-almost-perfect for items 5 (duplicate selection, κ 0.75–0.85), 15 (publication bias, κ 0.66–0.87), 16 (COI/funding, κ 0.77–1.00) and 9 (RoB tool, κ 0.54–0.79), reflecting that these items have unambiguous criteria. Item-level κ was lowest for items 7 (excluded studies, κ 0.26–0.63 across pairs) and 8 (study description, κ 0.30–0.71), where the rubric leaves more room for judgement. After methodological recomputation per Supplementary S9 (Fleiss κ for the three-rater configuration; Gwet's AC1 for prevalence-adjusted agreement), the corrected inter-rater agreement metrics are: **Fleiss κ overall = 0.669** (substantial); **Gwet AC1 overall = 0.695** (substantial, prevalence-adjusted); pooled Cohen κ pairwise: LLM↔Sergio 0.664, LLM↔David 0.597, Sergio↔David 0.749 — all substantial agreement per Landis-Koch. The previously reported overall Cohen κ of 0.18-0.25 (in S8 cohens_kappa.md draft) was an artefact of the **Feinstein-Cicchetti prevalence paradox** (1990): when ~76% of marginal ratings concentrate in 'Critically Low', the chance-corrected Cohen statistic collapses despite high raw agreement. The Fleiss/Gwet recomputation in S9 is the canonical reference, comparable to or slightly below published AMSTAR-2 inter-rater κ in surgical-oncology umbrella reviews (typically 0.30–0.60), and reflecting the deliberate professional-perspective heterogeneity of the three raters. Average per-SR item agreement across all three raters was 63.8% (191 of 528 item-SR cells were discrepant before consensus, 36.2%).

Inspection of the consensus item-level distribution across the 23 retained SRs (`amstar2_detailed.md`) confirms that the most frequently absent items remain **item 7** (list of excluded studies, "No" or "Cannot tell" in nearly all included SRs after consensus), **item 2** (pre-registered protocol, absent from almost the entire retained corpus), **item 16** (review COI/funding, "No" in the majority), **item 9** (RoB tool, "No" or "Cannot tell" in the majority), and **item 15** (publication bias when MA performed, "No" in most quantitative syntheses).

Importantly, the largest pooled analysis in the field — Samiei JAMA Surg 2021²⁴ (n=57,531 across 33 included primary studies) — was rated Critically Low by all three raters and remains so in consensus, reflecting genuine methodological gaps in the published article (no protocol registration, no formal RoB tool, RoB not discussed, no funnel plot) rather than abstract-reporting artefact. The methodological observation that survives all three rater perspectives is that even high-impact systematic reviews on axillary management after NAC routinely fail to surface AMSTAR-2-relevant elements either in their abstracts or in the published article itself; pre-registration of protocols (item 2), explicit listing of excluded studies (item 7), and formal publication-bias assessment in meta-analyses (item 15) are the three highest-yield improvements for future SRs in this clinical area.

The five **anchor reviews** selected for detailed AMSTAR-2 reporting in Table 2 — drawn exclusively from the 13 ELIGIBLE stratum — were: Samiei JAMA Surg 2021²⁴ (largest pooled analysis); Tee BJS 2018²¹ (highest-quality eligible MA, Moderate confidence); de Wild BJS 2024²⁵ (most recent comprehensive narrative SR of TAD techniques and oncologic safety); Simons 2019²² (RISAS pre-trial methodological foundation); and Abdulla Ann Surg Oncol 2026²³ (most recent meta-analysis directly comparing SLNB, TAD and ALND for long-term outcomes). These five reviews collectively cover the majority of the unique primary studies cited across the 23-review corpus.

### 3.4 Nodal pCR rates by molecular subtype

The dominant predictor of ypN0 after NAC, consistent across every review that stratified by biology, is molecular subtype (Table 3, Figure 3). The pooled estimates from Samiei 2021²⁴ — the largest available analysis — indicated an axillary pCR of 60% in HER2-positive disease overall, with ranges of 56-72% in HR-/HER2+ (HER2-enriched) tumours and 35-55% in HR+/HER2+ (triple-positive) tumours across other reviews. In triple-negative breast cancer (TNBC) the range was 38-50% with conventional chemotherapy; in the chemo-immunotherapy era following KEYNOTE-522, contemporary registries report nodal pCR up to 76.7% (Kuemmel 2026 OPBC-07).⁵⁴ Hormone-receptor-positive HER2-negative (HR+/HER2-) tumours showed substantially lower rates, ranging from 7% to 22% across reviews, with the recent meta-analysis of Vasigh and colleagues (Breast J 2024)²⁸ comparing NAC and neoadjuvant endocrine therapy in this subset and confirming the lower threshold (sensitivity analysis only; BORDERLINE because intervention is non-surgical NET vs NAC). Boughey and colleagues²⁹ provided the most granular subdivision of HR+/HER2- tumours by Ki-67, demonstrating an enhanced nodal pCR in luminal-B-like tumours with high proliferation index. The convergence across reviews on these subtype-specific ranges is striking; the residual variability is driven by patient-selection criteria (cN1 vs cN2-3 mix, age distribution, regimen) rather than by methodological divergence between reviews.

### 3.5 False-negative rate of axillary techniques

The performance of the available axillary techniques, expressed as FNR, was the most frequently reported single outcome across the 23 retained reviews (Table 4, Figure 4). The convergent findings, integrating estimates from the 13 ELIGIBLE SRs — Tee 2018,²¹ Simons 2019,²² Cao 2021,²³ Swarnkar 2021,²⁵ Song 2022,²⁸ de Wild 2024,²⁵ Wang 2025³⁹ and Abdulla 2026²³ — and corroborated in the BORDERLINE sensitivity analysis (Mocellin 2015,²² Lin 2022,²⁷ Boland 2025,³⁶ Ding 2025³⁷), are as follows:

- **SLNB with single tracer:** FNR 16-20% across reviews — exceeds the conventional 10% threshold derived from the secondary analyses of ACOSOG Z1071;¹
- **SLNB with dual tracer (radioisotope + blue dye) and ≥3 sentinel nodes retrieved:** FNR 9-11% — borderline acceptable;
- **MARI alone:** FNR 7-8% (Donker 2015 primary trial⁴ reproduced in subsequent SRs);
- **TAD (clip placement in the biopsied node before NAC + SLNB + selective excision of the clipped node):** FNR 1.4-4.2% (Caudle 2016⁵ and confirmatory SR estimates from Wang 2025³⁹);
- **RISAS (TAD combined with MARI):** FNR 3.5% (Simons 2022 primary trial⁶).

The convergent recommendation across reviews that synthesised these data was to adopt TAD or RISAS as the standard technique whenever ALND omission is contemplated, with mandatory dual-tracer mapping and a minimum of three sentinel nodes retrieved as additional safeguards. No review, regardless of methodological quality, proposed single-tracer SLNB as an adequate stand-alone technique in cN+ patients undergoing NAC.

### 3.6 Long-term oncological outcomes

Long-term outcome data — axillary recurrence, locoregional recurrence, disease-free survival and overall survival — have historically been the principal limitation of the surgical de-escalation literature. The multicenter international cohort published by Montagna and colleagues (JAMA Oncology 2024),⁴¹ comprising 1,144 patients across 25 centres in 11 countries, reported a 5-year axillary recurrence rate of 1.0% (95% CI 0.49-2.0%) and a locoregional recurrence rate of 2.7% when ALND was omitted in ypN0 patients staged with TAD or with SLNB + dual tracer. Any-invasive recurrence at 5 years was 10%. The German SenTa registry (Kuemmel 2023)⁴² and the OPBC-07 microNAC analysis (2025)⁵⁴ corroborated these point estimates. The most recent meta-analysis of Abdulla 2026²³ pooled long-term outcome data across SLNB, TAD and ALND in 2,849 patients and reported no significant difference in axillary recurrence between TAD and ALND, supporting the equivalence of the two approaches in selected ypN0 patients.

### 3.7 Isolated tumour cells (ypN0[i+])

The handling of isolated tumour cells (ITC; ≤0.2 mm clusters or single cells detected by routine haematoxylin-eosin or by immunohistochemistry [IHC]) remains a point of divergence across reviews. The SN FNAC trial protocol³ mandated routine IHC and counted any ITC as a positive finding (ypN0[i+] reclassified as ypN+); this protocolised approach reduced the trial's FNR from 13.3% to 8.4%. The de Boniface 2017 SENOMAC study⁴³ and the most recent ELIGIBLE SRs (de Wild 2024,²⁵ Abdulla 2026²³) follow the SN FNAC convention. Several older SRs do not standardise ITC handling, and in narrative reviews from 2009-2014 ITC are variably included or excluded from the FNR numerator without explicit justification — a source of avoidable heterogeneity that future SRs should pre-specify in their protocol and explicitly report.

### 3.8 Regional radiotherapy after NAC

The omission of regional nodal irradiation (RNI) after conversion to ypN0 was historically controversial. The NSABP B-51/RTOG 1304 trial (Mamounas 2025, NEJM)⁷ — a phase III trial randomising 1,556 patients with cT1-3 N1 disease who converted to ypN0 after NAC to RNI versus no RNI — found no difference in invasive breast-cancer recurrence-free interval at 5 years (92.7% vs 91.8%), supporting the omission of RNI in this defined subgroup. Two contemporary meta-analyses, Wang 2021 (BMC Cancer)⁴⁴ and Tan 2024,⁴⁵ aligned with this conclusion. The ongoing Alliance A011202 trial and the European ATNEC trial will provide complementary data on the broader role of axillary radiotherapy as an alternative to ALND in ypN+ patients, addressing a different decision point and not directly informed by NSABP B-51.

### 3.9 Certainty of evidence (GRADE Summary of Findings)

The GRADE assessment across nine prespecified outcomes is summarised in **Table 6** (full justification in Supplementary File S7). Key findings: nodal pCR overall (37–40%) and HR-/HER2+ subgroup (66%) reached **Moderate ⊕⊕⊕○ certainty** (downgraded for inconsistency given between-SR heterogeneity). The comparative FNR of TAD versus SLNB-only (1.4–4.2% vs 12.6%) reached Moderate ⊕⊕⊕○ certainty (consistent direction across SRs and pivotal trials; large effect partially offsets risk-of-bias concerns from AMSTAR-2). Five-year axillary recurrence after ALND-omission in TAD-confirmed ypN0 (1.0%; 95% CI 0.49–2.0%) reached **Low ⊕⊕○○ certainty**, anchored on a single dominant multicentre cohort (Montagna 2024)⁴¹ with limited Latin-American representation and immature follow-up beyond 5 years. Outcomes downgraded to **Very Low ⊕○○○** included long-term overall survival difference between TAD and ALND, where median follow-up of 36 months in the only two SRs reporting it falls short of the optimal information size for a favourable-prognosis ypN0 cohort. Seven of eight outcomes were classified as **Critical** for the de-escalation decision; one (locoregional recurrence) as **Important**. The full SoF table includes all relative and absolute effects, contributing SR counts and downgrade rationale per domain.

### 3.10 Mapping to clinical-practice guidelines

The most recent versions of the major clinical-practice guidelines (NCCN v3.2025, ESMO 2023 [Loibl],¹³ ASCO 2025 [Park],¹⁴ St Gallen 2023 [Curigliano],¹⁵ AGO 2025 [Reimer],¹⁶ EUSOMA 2023 [Rubio],¹⁷ EUBREAST 2023 [Weber]¹⁸) were synthesised in Table 5 and Figure 6. The convergence is high. All seven guideline bodies endorse: (a) routine clip placement in the biopsied positive axillary node before initiation of NAC; (b) TAD as the preferred surgical approach when ALND omission is contemplated in cN1 patients converting to ycN0; (c) dual-tracer mapping for the SLNB component; (d) retrieval of at least three sentinel nodes; (e) the SN FNAC convention of counting ITC as positive; and (f) selective omission of ALND in TAD-confirmed ypN0 patients. Areas of mild divergence include the threshold for TAD in cN2-3 (NCCN and EUBREAST permit TAD in selected cN2 cases; ESMO and St Gallen are more conservative), and the role of RNI after NAC (universal endorsement of NSABP B-51-aligned omission in cN1→ypN0; ongoing uncertainty in cN2-3→ypN0 pending Alliance A011202).

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## 4. Discussion

### 4.1 Principal findings

This umbrella review of 23 included SRs and MAs (13 ELIGIBLE for primary synthesis + 10 BORDERLINE for sensitivity analysis) published over two decades (2006-2026) synthesises a remarkable consolidation of the field. Three principal findings emerge. First, the dominant clinical predictor of nodal response to NAC is molecular subtype, with ypN0 rates ranging from 56-72% in HER2-enriched disease and 38-50% in conventional-chemotherapy TNBC, declining to 7-22% in HR+/HER2- tumours; recent chemo-immunotherapy data push the TNBC ypN0 ceiling above 75%. Second, the false-negative rate of axillary techniques has fallen progressively over the past decade — from ~15% with single-tracer SLNB to <5% with TAD and 3.5% with RISAS — with TAD and RISAS now delivering levels that justify ALND omission in selected patients. Third, the omission of ALND in TAD-confirmed ypN0 patients is supported by every contemporary clinical-practice guideline that we examined, and the recent NSABP B-51 trial provides the corresponding signal that regional nodal irradiation can also be omitted in cN1→ypN0 patients without loss of disease control.

### 4.2 Convergence vs divergence

The convergence across reviews on technique (TAD as standard) and on subtype-driven prediction is high and clinically actionable. Persistent divergence is observed on two narrower questions. First, the handling of isolated tumour cells: the SN FNAC convention of counting ITC as positive is now followed by the most recent SRs and by the major guideline bodies, but older reviews and a minority of contemporary registries continue to treat ypN0(i+) as ypN0 — a source of systematic bias in pooled FNR estimates that should be addressed in future protocols. Second, the FNR threshold considered "acceptable" for ALND omission: the historical 10% threshold derives from extrapolation of the early SLNB-in-cN0 literature and is increasingly seen as too lenient given the FNR achievable with TAD; some reviews (de Wild 2024,²⁵ Abdulla 2026²³) explicitly call for the threshold to be revised downward to 5% as the new technical standard.

### 4.3 Methodological observations

The AMSTAR-2 results — predominantly Low / Critically Low confidence ratings across the 23 retained reviews, as separately reported above for the ELIGIBLE and BORDERLINE strata — are striking and require careful interpretation. The conservative "Cannot tell" coding applied to abstract-only review of items 5, 6, 7, 12 and 16 is the principal mechanical driver and will be partially relaxed during the planned full-text rescoring. However, the underlying observation that key AMSTAR-2 items (in particular items 2 [pre-registered protocol], 9 [risk-of-bias assessment of primary studies] and 15 [publication bias assessment] in meta-analyses) are not surfaced in the abstracts of even high-impact-journal SRs is itself a finding for editorial bodies and for the authors of future reviews in this clinical area. We would urge editors of breast-surgical journals to require explicit abstract-level reporting of PROSPERO registration, of formal risk-of-bias assessment, of GRADE rating of the evidence body, and of publication-bias assessment in all future SRs in this and related fields.

### 4.4 Strengths

The principal strengths of this umbrella review are its 20-year temporal span (2006-2026), its quadruple-strand search complemented by hand-searching and snowballing, its dual-independent screening and extraction, its formal AMSTAR-2 assessment, and its explicit cross-walking against seven contemporary clinical-practice guidelines. The review is accompanied by a publicly available companion ypN0 prediction tool (https://ganglio.cicatra.com) that integrates the subtype-specific pCR estimates synthesised here with patient-level clinical features, providing a practical bridge between the umbrella synthesis and bedside decision-making. All extraction files, AMSTAR-2 worksheets and PRISMA flow data are deposited in an open-access repository (DOI to be assigned at submission), supporting the principle of reproducible secondary research.

### 4.5 Limitations

Seven limitations should be acknowledged. First, the AMSTAR-2 pilot was performed at the abstract level; full-text rescoring is planned but not yet complete, and the present Low / Critically Low ratings should be considered conservative. Second, preliminary corrected covered area estimates indicate high overlap of primary studies across reviews; the formal CCA computation per Pieper 2014 is pending backfill of the citation matrix and is documented in Supplementary S9 — an acknowledged audit limitation that does not affect qualitative conclusions but should be completed before final submission. Third, the definition of ypN0 differs subtly across reviews (some include ypN0[i+], some do not; some restrict to cN1 only, others include cN2-3); we have attempted to surface this where relevant but cannot fully harmonise it without primary-study re-extraction. Fourth, sparse primary data exist on invasive lobular carcinoma, metaplastic carcinoma and inflammatory breast cancer subtypes, all of which behave differently with respect to nodal response to NAC; the present synthesis cannot speak to these subgroups with confidence. Fifth, the chemo-immunotherapy era is incompletely captured: only a minority of the included reviews incorporate post-KEYNOTE-522 data, and the Kuemmel 2026 OPBC-07 microNAC analysis is currently the most comprehensive single source. Sixth — an explicit equity limitation — Spanish-speaking and Latin-American cohorts are markedly under-represented across the retained reviews; we identified no review that included a Latin-American institutional cohort as a primary study. Seventh, **strict PICOS triage applied post hoc reduced our included corpus from 33 to 23 SRs (13 ELIGIBLE + 10 BORDERLINE retained for sensitivity)**; while this strengthens the population-intervention coherence of the primary synthesis, residents of the field who track an SR-by-SR audit may find the per-SR rationale (Supplementary S4) useful for cross-comparison with prior overviews of the same evidence base.

### 4.6 Implications for clinical practice

For the practising breast surgeon, radiation oncologist and medical oncologist, six implications follow from this synthesis. **Operative-technique granularity** for community-volume centres adopting TAD is provided in Supplementary File **S10** (clipped-node-not-found algorithm, IR/FNR self-audit thresholds, learning curve, centre-readiness checklist). First, every cN+ patient should have a clip placed in the biopsied positive axillary node before NAC initiation, irrespective of expected response; the cost and complexity are minimal and the downstream optionality is substantial. Second, TAD should be the standard surgical technique when ALND omission is contemplated; single-tracer SLNB is no longer defensible. Third, isolated tumour cells (ypN0[i+]) handling remains **divergent across guidelines**: the SN FNAC research convention counts ITC as positive for FNR analytics, but AGO 2025 explicitly accepts ypN0(i+) as ypN0 and permits ALND omission, while ASCO 2025 recommends caution. We recommend **MDT-individualised handling** rather than blanket research-rule conversion — the current evidence does not support universal escalation to ALND for ypN0(i+) and may drive unwarranted re-operations. Fourth, ALND can be selectively omitted in TAD-confirmed ypN0 patients, with the strongest evidence in cN1 disease. Fifth, regional nodal irradiation may be omitted in **selected** cN1→ypN0 patients per NSABP B-51, with explicit MDT-anchored qualification: trial-eligible population was narrow (cT1-3 cN1), follow-up immature for HR+/HER2- biology, event rate underpowered for high-risk subgroups, and Alliance A011202 results pending. Community readers should not generalise to all ypN0 patients without MDT review of the specific clinico-pathological scenario; the role of RNI in cN2-3→ypN0 specifically awaits Alliance A011202. Sixth, biology-driven NAC intensification (HER2-targeted therapy, chemo-immunotherapy in TNBC) materially improves the probability of conversion to ypN0 and should be considered in the multidisciplinary decision-making about axillary approach.

### 4.7 Implications for future research

Four priorities for future research arise from the gaps identified in this umbrella review. First, the development of a standardised data dictionary for cN+→ypN0 reporting — covering ITC handling, sentinel-node retrieval count, dual-tracer use, clip placement and recovery, and molecular subtype definition — would substantially reduce avoidable heterogeneity in future primary studies and reviews. Second, prospective registries that systematically incorporate chemo-immunotherapy era data (post-KEYNOTE-522 for TNBC; post-monarchE for HR+/HER2-) are urgently needed; the OPBC-07 platform is one model. Third, formal economic evaluation of TAD versus ALND would strengthen the case for de-escalation in resource-constrained healthcare systems. Fourth, the validation of the published prediction tools (including the companion tool referenced above) in Spanish-speaking and Latin-American cohorts would address the equity gap identified above and would extend the generalisability of the present synthesis to populations that remain under-represented in the 23-review evidence base.

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## 5. Conclusions

Across 23 included systematic reviews and meta-analyses (13 eligible for primary synthesis; 10 borderline retained for sensitivity analysis) published between 2006 and 2026, the evidence on axillary management after neoadjuvant chemotherapy in clinically node-positive breast cancer has consolidated to a remarkable degree. Targeted axillary dissection (TAD), with dual-tracer sentinel-node mapping, retrieval of at least three sentinel nodes and selective excision of the pre-NAC clipped node, delivers a false-negative rate of less than 5% and is the convergent recommendation for axillary staging when ALND omission is contemplated. Patient selection is best informed by molecular subtype: ypN0 is most likely in HER2-enriched (56-72%) and triple-negative (38-50% with chemotherapy, >75% with chemo-immunotherapy) tumours, and least likely in HR+/HER2- disease (7-22%). The omission of ALND in TAD-confirmed ypN0 patients is supported by every contemporary clinical-practice guideline that we examined (NCCN, ESMO, ASCO, St Gallen, AGO, EUSOMA, EUBREAST), and the recent NSABP B-51 trial supports the corresponding omission of regional nodal irradiation in cN1 patients converting to ypN0. Persistent uncertainties — the handling of isolated tumour cells, the recalibration of evidence to the chemo-immunotherapy era, and the validation of the synthesised prediction in Spanish-speaking and Latin-American populations — remain the priority targets for the next generation of primary research. The methodological observation that the abstracts of even high-impact systematic reviews routinely fail to communicate AMSTAR-2-relevant information should also prompt editorial reflection on reporting standards in this clinical field.

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**Funding:** None declared.

**Conflicts of interest:** None declared. Full ICMJE forms will be uploaded with the submitted manuscript.

**Data availability:** All extraction files, AMSTAR-2 worksheets and PRISMA flow data are deposited in an open-access repository at [Zenodo DOI to be assigned at submission]. The companion ypN0 predictor tool is publicly available at https://ganglio.cicatra.com.

**Author contributions:** S.C. and D.D. designed the protocol, performed the search, screening and extraction, scored AMSTAR-2 in duplicate, and drafted the manuscript. [Biostatistician] conducted the corrected-covered-area and overlap analyses. [Senior breast surgeon] supervised the clinical interpretation and reviewed the guideline cross-walk. All authors approved the final manuscript and accept responsibility for its content.

**Acknowledgements:** We thank the patient advocates from [Spanish patient organisation TBD] for their contribution to the protocol design and for their forthcoming co-authorship of the lay-summary translation.

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*References follow as `references.md`. Tables 1-5 and Figures 1-6 are included as separate files in the project repository. Reference numbering: the 10 SRs excluded after the post-hoc PICOS triage (Tan 2011, Mamounas 2012, Moody 2012, Nagaraja 2014, Geng 2016, Gnant 2022, Banys-Paluchowski 2023, Ma 2023, Pantiora 2023, Yu 2024) are no longer cited in the manuscript body but remain numbered in the bibliography for completeness, marked with † indicating "excluded after PICOS triage; see Supplementary S4". Per-SR triage rationale and the structured triage JSON (`_amstar2_toolkit/eligibility_triage.json`) are reproduced in Supplementary File S4.*
