# Cover Letter — European Journal of Surgical Oncology (EJSO)

**Date:** 13 May 2026

**To:** The Editor-in-Chief
European Journal of Surgical Oncology (EJSO)
The Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology
Elsevier Ltd, London / Oxford, UK

Dear Editor,

We are pleased to submit, for consideration as an Original Article in the European Journal of Surgical Oncology, the manuscript entitled **"Axillary management after neoadjuvant chemotherapy in node-positive breast cancer (cN+ to ypN0): an umbrella review of systematic reviews and meta-analyses (2006–2026)"**.

## Manuscript metadata

| Item | Value |
|---|---|
| Manuscript type | Original Article — Umbrella review (PRISMA 2020 / PRIOR / JBI methodology) |
| Word count (body, excl. abstract, references, tables, figures) | 4,800 |
| Abstract | 300 words, structured (Background, Methods, Results, Conclusion) |
| Figures | 3 (PRISMA flow; convergence forest plot per outcome; AMSTAR-2 heatmap) |
| Tables | 4 (included SR characteristics; AMSTAR-2 summary; per-outcome convergence; GRADE summary) |
| Supplementary files | 6 (S1 search strategy, S2 PRISMA-2020 checklist, S3 AMSTAR-2 full, S4 excluded studies, S5 extended extraction, S6 glossary) |
| References | 96 (33 included SRs + 28 guidelines/trials cited contextually) |
| Companion open repository | https://ganglio.cicatra.com |

## Originality and significance

Our umbrella review provides the first structured map of convergence and divergence among the 33 systematic reviews and meta-analyses on axillary management after neoadjuvant chemotherapy (NAC) published between 2006 and 2026. The constituent reviews — each addressing a specific intervention (SLNB, TAD, MARI, RISAS, SPIO) or outcome (ypN0, FNR, recurrence, OS/DFS, lymphedema) in isolation — leave guideline panels and bedside surgeons with a fragmented picture; this work consolidates them into a single accessible synthesis structured by intervention and by outcome.

Key findings:
- The false-negative rate of TAD converges between 2.0% and 6.5% across nine meta-analyses, well below the conventional 10% acceptability ceiling.
- The false-negative rate of SLNB alone converges between 12% and 17%, above the 10% ceiling, with consistent reduction below 10% only when ≥3 sentinel nodes are retrieved with dual tracer.
- Axillary pCR (ypN0) by molecular subtype tracks the Samiei 2021 stratification (HR−/HER2+ 60–70%, TNBC 45–55%, HR+/HER2− 15–25%), with a clear post-2018 era effect attributable to dual HER2 blockade and chemo-immunotherapy.
- Where divergence exists across reviews, it is attributable to NAC era, marker timing, and selection bias rather than to substantive methodological disagreement.

Companion deliverable: an open-source patient- and clinician-facing probability calculator at https://ganglio.cicatra.com integrates subtype-specific ypN0 estimates and AMSTAR-2-weighted recommendations.

## Why EJSO

EJSO is the journal of the European Society of Surgical Oncology and is read by the European breast-surgery community that has driven the TAD/MARI/RISAS evidence base over the past decade (e.g., Boland 2025 PMID 40009931 was published in EJSO; van Nijnatten 2015 PMID 26329781 likewise). The journal's recent thematic emphasis on de-escalation and on surgical oncology methodology aligns directly with the manuscript's scope. Submitting to EJSO ensures that European surgical-oncology readers, who are among the principal users of the underlying TAD/SPIO evidence, encounter the synthesis in a familiar venue.

## Suggested reviewers

We respectfully suggest the following reviewers, none of whom has been involved in the conduct of this work:

1. **Prof. Marjolein L. Smidt** — Maastricht University Medical Centre, the Netherlands. Senior author of MARI/RISAS. Email: m.smidt@mumc.nl.
2. **Dr Maggie Banys-Paluchowski** — University Hospital Schleswig-Holstein, Lübeck, Germany. PI of AXSANA/EUBREAST-3. Email: maggie.banys@uksh.de.
3. **Prof. Walter P. Weber** — University Hospital Basel, Switzerland. PI of TAXIS. Email: walter.weber@usb.ch.
4. **Dr Andreas Karakatsanis** — Uppsala University, Sweden. SPIO programme lead. Email: andreas.karakatsanis@surgsci.uu.se.
5. **Prof. Marjut Leidenius** — Helsinki University Hospital, Finland. Long-standing axillary-staging methodologist. Email: marjut.leidenius@hus.fi.
6. **Prof. Jean-Yves Pierga** — Institut Curie, Paris, France. Senior breast medical oncologist with surgical-oncology cross-expertise. Email: jean-yves.pierga@curie.fr.
7. **Dr Antonio Sanjuán** — Hospital Universitario Joan XXIII, Tarragona, Spain. Spanish multicentre TAD network. Email: asanjuan@grupsagessa.com.

We do not request the exclusion of any reviewer.

## Statements

- **Funding.** None.
- **Conflicts of interest.** None declared.
- **Prior submissions.** This manuscript has not been submitted, in whole or in part, to any other journal.
- **Authorship.** All four authors satisfy ICMJE criteria. Contributions detailed in the CRediT statement.
- **Ethics.** Not applicable — synthesis of published systematic reviews; no individual patient data.
- **Data availability.** Full extracted data, AMSTAR-2 scores, scripts, and companion predictor source code openly available at https://ganglio.cicatra.com (data CC-BY 4.0; predictor code MIT). PROSPERO registration ID will be added upon acceptance.
- **Reporting.** PRISMA 2020 and PRIOR adherence; PRISMA-2020 checklist supplied as Supplementary S2.

We thank you and the EJSO Editorial Office for considering the manuscript and remain at the disposal of the editors and reviewers.

Yours sincerely,

**David Duque, MD**
Corresponding author
On behalf of the authorship team:
Sergio Cervera, MD (PI); David Duque, MD; [Biostatistician — to be confirmed]; [Senior Breast Surgeon — to be confirmed]

Email: david@davidduque.com
ORCID: (to be added)
