# PROSPERO Protocol — Umbrella Review

## 1. Review title
Axillary management after neoadjuvant chemotherapy in node-positive breast cancer (cN+ → ypN0): an umbrella review of systematic reviews and meta-analyses (2006–2026).

## 2. Anticipated start and completion dates
- **Anticipated start:** 2026-06-01
- **Anticipated completion:** 2026-12-01

## 3. Stage of review at registration
Preliminary searches and pilot data extraction completed. A pilot search executed in the source repository identified 33 systematic reviews and meta-analyses, 22 prospective/randomized clinical trials, and 28 clinical practice guideline documents (totalling 292 references after deduplication) that are candidates for the umbrella review. Pilot AMSTAR-2 calibration on three seminal reviews (Samiei 2021 PMID 33881478; Swarnkar 2021 PMID 33810544; de Wild 2024 PMID 38531689) has been performed by two reviewers with substantial inter-rater agreement.

## 4. Named contact
**David Duque, MD** — Corresponding author and data lead. Email: david@davidduque.com

## 5. Organisational affiliation
Independent academic project. The review is conducted as a non-commercial, investigator-initiated synthesis with no institutional sponsorship and is open to academic partnership.

## 6. Review team members and contact
- **Sergio Cervera, MD** — Principal Investigator; breast surgical oncologist; clinical content lead, screening, AMSTAR-2 assessment, and senior interpretation.
- **David Duque, MD** — Data and methodology lead; protocol authoring, data extraction, statistical synthesis, and digital companion tool (https://ganglio.cicatra.com).
- **[Biostatistician — to be confirmed]** — Third reviewer for discrepancy adjudication, meta-bias assessment, and sensitivity analyses.
- **[Senior breast surgeon co-author — to be confirmed]** — External methodological validator and senior clinical interpretation.

All team members will sign an authorship and conflict-of-interest declaration prior to PROSPERO submission.

## 7. Funding sources / sponsors
None. The review receives no financial or in-kind support from industry, governmental agencies, or non-profit organizations.

## 8. Conflicts of interest
None declared. No author has equity, consultancy, speaker, or advisory-board ties to manufacturers of axillary localization devices (clip, radioactive seed, magnetic seed, radar reflector, or superparamagnetic iron oxide) or to providers of related diagnostic imaging.

## 9. Collaborators
The team is open to international collaboration, particularly contributors from breast surgical units that participated in TAD/MARI/RISAS validation cohorts and methodologists experienced in JBI umbrella-review methodology. Interested collaborators should contact the corresponding author.

## 10. Review question(s)
We will address the following overarching question: *In adult women with biopsy-proven node-positive (cN+) breast cancer who undergo neoadjuvant chemotherapy (NAC), what is the diagnostic accuracy and oncologic safety of de-escalated axillary surgical strategies — sentinel lymph node biopsy (SLNB) with single or dual tracer, marked lymph node biopsy (MLNB), targeted axillary dissection (TAD), MARI, and RISAS — compared with completion axillary lymph node dissection (ALND) for staging the axilla and informing adjuvant therapy?*

The PICOS frame:
- **P (Population):** Adult women (≥18 years) with biopsy-proven clinically node-positive (cN1–cN3) invasive breast cancer treated with neoadjuvant systemic chemotherapy (with or without HER2-directed therapy or immunotherapy).
- **I (Intervention):** Targeted axillary dissection (TAD); sentinel lymph node biopsy with single or dual tracer (radioisotope, blue dye, indocyanine green, superparamagnetic iron oxide); MARI procedure (marking the axillary node with radioactive iodine seeds); RISAS (radioactive iodine seed localization in the axilla after NAC); marked lymph node biopsy (MLNB) using clip, magnetic seed (Magseed, Sirius Pintuition), radar reflector (LOCalizer, SAVI SCOUT), carbon-ink tattoo, or wire localization.
- **C (Comparator):** Completion axillary lymph node dissection (ALND) as reference standard for diagnostic accuracy outcomes; or omission of ALND (i.e., observation/regional radiotherapy) as comparator for oncologic outcomes.
- **O (Outcomes):** *Primary* — axillary pathologic complete response rate (ypN0), false-negative rate (FNR), identification rate (IR). *Secondary* — locoregional recurrence, axillary recurrence, overall survival (OS), disease-free survival (DFS), lymphedema, predictors of ypN0 (molecular subtype, initial cN stage, regimen).
- **S (Study designs):** Systematic reviews with or without meta-analysis. Network meta-analyses are eligible. Reviews with explicit, reproducible search strategy and pre-specified eligibility criteria are required.

## 11. Searches
We will perform a structured search of four bibliographic databases:
- **PubMed/MEDLINE** (NLM)
- **EMBASE** (Elsevier; via institutional access)
- **Cochrane Database of Systematic Reviews (CDSR)** via the Cochrane Library
- **Epistemonikos** (full database, including LOVE platform)

**Date range:** 2006-01-01 to 2026-04-30. The lower bound (2006) corresponds to the publication of the first systematic synthesis on SLNB after NAC in cN+ disease (Xing 2006, Br J Surg). The upper bound (April 2026) is the last date of the formal search and will be re-run within 30 days of manuscript submission to capture late additions.

**Languages:** English, Spanish, and French — full text reading and extraction will be performed by team members fluent in all three; no automated translation will be relied upon for eligibility decisions.

**Search building blocks:**
- *Population:* breast neoplasms; breast cancer; mammary carcinoma; axillary lymph nodes
- *Exposure:* neoadjuvant therapy; neoadjuvant chemotherapy; preoperative chemotherapy; primary systemic therapy
- *Intervention:* axillary surgery; sentinel lymph node biopsy; targeted axillary dissection; TAD; marked lymph node biopsy; MARI; RISAS; clip; seed; magseed; SAVI; ALND; ypN0
- *Filter:* "systematic review"[Publication Type] OR "meta-analysis"[Publication Type] OR systematic review[Title/Abstract] OR meta-analysis[Title/Abstract]

**Hand-search:** reference lists of all included reviews; reference lists of recent NCCN, ESMO, ASCO, St Gallen, AGO, EUSOMA, EUBREAST, and EUSOBI guideline documents (2020–2026); table of contents of *Annals of Surgical Oncology, British Journal of Surgery, JAMA Surgery, The Breast, European Journal of Surgical Oncology* for the period 2024-Q4 to 2026-Q2.

**Grey literature:** PROSPERO registry (to identify ongoing or recently completed umbrella/SR efforts on the same question, ensuring novelty); ESMO and SABCS abstracts (2024–2026).

The complete database query strings are detailed in `search_strategy_pilot.md`.

## 12. Condition or domain being studied
Invasive breast cancer with documented axillary lymph node involvement at diagnosis (cN+), undergoing systemic neoadjuvant therapy with intent to downstage the axilla and offer surgical de-escalation. The clinical domain spans surgical oncology, radiation oncology, medical oncology, and diagnostic imaging.

## 13. Participants / population
**Inclusion criteria for the underlying populations of included reviews:**
- Adult women (≥18 years) with histologically confirmed invasive breast cancer (any subtype: HR+/HER2−, HR+/HER2+, HR−/HER2+, triple-negative).
- Biopsy- or cytology-confirmed clinically node-positive (cN1, cN2, or cN3) status documented prior to NAC by ultrasound-guided fine-needle aspiration or core-needle biopsy.
- Treatment with at least one cycle of neoadjuvant systemic chemotherapy (anthracycline-based, taxane-based, platinum-containing, dual HER2 blockade, or chemo-immunotherapy regimens are all eligible).
- Surgical axillary staging (SLNB, TAD, MARI, RISAS, MLNB, or ALND) after completion of NAC.

**Exclusion criteria:**
- Reviews restricted to clinically node-negative (cN0) disease only.
- Recurrent or metastatic disease at diagnosis.
- Male breast cancer (will be excluded only when reported as a separable subgroup; mixed-sex cohorts will be retained provided ≥95% female).
- Ductal or lobular carcinoma in situ (DCIS/LCIS) only.
- Reviews of neoadjuvant endocrine therapy (NET) only without comparison or pooling with NAC will be excluded from the primary synthesis but tabulated separately for context.

## 14. Intervention(s), exposure(s)
The de-escalated axillary surgical strategies under evaluation are:
- **TAD (Targeted Axillary Dissection):** combined SLNB plus selective excision of the previously biopsied and marked node, regardless of marker type or timing (one-step vs two-step procedure as defined by de Wild 2024 PMID 38531689).
- **SLNB (Sentinel Lymph Node Biopsy):** single tracer (radioisotope, blue dye, indocyanine green [ICG], or superparamagnetic iron oxide [SPIO]) or dual tracer combinations.
- **MLNB (Marked Lymph Node Biopsy):** excision of the marked node alone without sentinel mapping.
- **MARI / RISAS:** radioactive iodine seed localization protocols (Dutch single- and multi-centre protocols).
- **Marker technologies:** metallic clip, ¹²⁵I seed, magnetic seed (Magseed, Sirius Pintuition), radar reflector (LOCalizer, SAVI SCOUT), carbon-ink tattoo, hookwire.

## 15. Comparator(s) / control
- For diagnostic accuracy outcomes (FNR, IR, negative predictive value): **completion ALND** as reference standard performed in the same patients.
- For oncologic outcomes (recurrence, OS, DFS): **completion ALND** vs **no further axillary surgery** (with or without regional nodal irradiation), as reported in each underlying review.

## 16. Types of study to be included
- Systematic reviews with or without meta-analysis.
- Network meta-analyses.
- Pooled patient-level analyses described as systematic reviews.

A study is eligible as a "systematic review" if it reports: (i) an explicit research question; (ii) at least one bibliographic database searched with a reproducible query; (iii) explicit eligibility criteria; (iv) a structured selection process. Reviews that fail any of these four criteria will be classified as narrative reviews and excluded from the primary synthesis.

**Quality threshold:** AMSTAR-2 overall confidence rating of "moderate" or "high" for inclusion in the **primary synthesis**. Reviews scored "low" or "critically low" will be reported in a transparency table and used only in **sensitivity analyses** to evaluate the robustness of the primary findings.

## 17. Main outcome(s)
- **Axillary pathologic complete response rate (ypN0)** — proportion of patients with no residual disease on final axillary pathology after NAC, by molecular subtype, by initial cN stage, and overall.
- **False-negative rate (FNR)** of SLNB, TAD, MLNB, MARI, and RISAS using completion ALND as the reference standard.

Time points: outcomes will be extracted as reported by the underlying reviews (most are at the index surgical event for FNR/IR and at 3-, 5-, or 10-year follow-up for survival/recurrence outcomes).

## 18. Additional outcome(s)
- Identification rate (IR) of the marked node and of sentinel nodes.
- Number of nodes retrieved.
- Locoregional recurrence (LRR) and isolated axillary recurrence at 3, 5, and 10 years.
- Overall survival (OS), disease-free survival (DFS), distant disease-free survival (DDFS).
- Lymphedema incidence and severity.
- Predictors of ypN0 (molecular subtype, initial cN stage, tumour grade, Ki-67, regimen including pembrolizumab).
- Patient-reported outcomes (when reported in underlying reviews).

## 19. Data extraction (selection and coding)
- **Title/abstract screening:** dual independent screening by Sergio Cervera and David Duque using a structured form (Rayyan or equivalent). Inter-rater agreement will be reported (Cohen's κ).
- **Full-text screening:** dual independent against the eligibility criteria; reasons for exclusion documented.
- **Discrepancy resolution:** consensus discussion; persistent disagreements adjudicated by the third reviewer (biostatistician).
- **Data extraction:** independent dual extraction onto a piloted standardized form covering bibliographic metadata, PICOS domains, search characteristics, included primary studies (count, designs, total N), pooled estimates with 95% CIs, heterogeneity statistics (I², τ²), risk-of-bias methods used, AMSTAR-2 score, and authors' conclusions.
- **Overlap of primary studies:** the corrected covered area (CCA) will be computed for each outcome to quantify overlap among included reviews; reviews will be sorted chronologically and the most recent comprehensive review used as the index reference for overlapping populations.

## 20. Risk of bias (quality) assessment
- **AMSTAR-2** (16 items) for every included systematic review, performed independently by two reviewers; overall confidence rated as high, moderate, low, or critically low according to the 7 critical-domain logic.
- **ROBIS** (Risk of Bias In Systematic reviews) used in **sensitivity analysis** on a stratified random sample of included reviews to test concordance with AMSTAR-2.
- **GRADE** (Grading of Recommendations Assessment, Development and Evaluation) will be used to rate the certainty of evidence per outcome at the umbrella-review level (high, moderate, low, very low), considering the body of evidence across reviews rather than within a single primary study.

## 21. Strategy for data synthesis
This is an **umbrella review** following the **JBI methodology for systematic reviews of systematic reviews** and the **PRIOR (Preferred Reporting Items for Overviews of Reviews)** statement (Pollock 2022). No re-pooling of primary-study data will be performed; this is the deliberate methodological choice of an umbrella review and is justified by the substantial overlap of primary studies across the 33 candidate reviews and the existence of multiple recent high-quality meta-analyses with adequately pooled estimates.

The synthesis will be **structured by intervention** (SLNB, TAD, MARI/RISAS, MLNB) and within each intervention by outcome (ypN0, FNR, IR, recurrence, survival, lymphedema). For each outcome we will:
1. Tabulate every published pooled estimate with its 95% CI, I², and number of contributing primary studies.
2. Identify **convergence** (estimates agreeing within ±2 absolute percentage points or overlapping 95% CIs) and **divergence**.
3. Where divergence exists, attribute it to plausible methodological reasons: differences in eligibility criteria, search dates, inclusion of narrative or low-quality primary studies, choice of reference standard, statistical model (fixed vs random effects), outcome definition (e.g., FNR denominator), or population restrictions.
4. Visualize results with forest-style summary plots showing each review's pooled estimate side-by-side per outcome (no new pooling).
5. Provide a meta-bias assessment per outcome (e.g., publication bias judged at the level of underlying primary studies, where reported).

## 22. Analysis of subgroups or subsets
Pre-specified subgroup analyses (where review-level data permit):
- **By molecular subtype:** HR−/HER2+, HR+/HER2+, triple-negative, HR+/HER2−, luminal A vs luminal B (drawing on the Samiei 2021 stratification).
- **By initial cN stage:** cN1 vs cN2–cN3.
- **By NAC era:** pre-2018 conventional regimens vs post-2018 era including dual HER2 blockade and chemo-immunotherapy (KEYNOTE-522 era).
- **By geography of the underlying primary studies:** European, North American, Asian-Pacific, Latin American.
- **By marker technology:** clip vs radioactive seed vs magnetic/radar marker vs SPIO.

## 23. Type and method of review
Umbrella review (overview of systematic reviews) following the **JBI Manual for Evidence Synthesis (Aromataris 2024 update)** and reported per the **PRIOR statement (Pollock 2022)**. The choice of an umbrella review — rather than a new primary systematic review — is methodologically justified because: (i) at least 33 systematic reviews have been published on overlapping aspects of cN+ → ypN0 axillary management between 2006 and 2026; (ii) multiple recent reviews (Samiei 2021, Swarnkar 2021, de Wild 2024, Abdulla 2026, Boland 2025) provide adequately pooled estimates for the principal outcomes; (iii) the principal evidentiary gap is not the absence of pooled estimates but the **divergence among them and the absence of a structured synthesis comparing methodology, scope, and conclusions across reviews**; (iv) clinicians, guideline panels, and patients face a fragmented evidence landscape that an umbrella review is uniquely positioned to consolidate.

## 24. Language
Eligibility decisions and data extraction will be conducted on full texts in English, Spanish, and French. Reviews in other languages will be translated when feasible (e.g., German, Italian, Portuguese) and otherwise documented in the excluded-by-language table.

## 25. Country
International project. The review team is based in Spain and the United Kingdom (planned biostatistician slot to be filled within the EU). There is no geographic restriction on the populations or settings of the underlying reviews.

## 26. Other registration details
N/A. This is the first registration of this work. No related Cochrane title is currently registered on this exact topic; an Epistemonikos LOVE search will be re-run before registration to confirm.

## 27. Reference and/or URL for published protocol
To be added after PROSPERO acceptance. The full protocol manuscript will be deposited on the project repository at https://ganglio.cicatra.com/protocol upon registration.

## 28. Dissemination plans
- Open-access peer-reviewed journal submission, in order of preference: *British Journal of Surgery*, *ESMO Open*, *European Journal of Surgical Oncology*, *The Breast*, *Annals of Surgical Oncology*.
- Companion interactive web tool for clinicians and patients: https://ganglio.cicatra.com (probability calculator integrating subtype-specific ypN0 estimates and AMSTAR-2 weighted recommendations).
- Conference presentations targeted at the European Society of Surgical Oncology (ESSO) and EUBREAST annual meetings.
- Plain-language summary in Spanish and English aimed at patient associations.

## 29. Keywords
breast cancer; node-positive breast cancer; neoadjuvant chemotherapy; sentinel lymph node biopsy; targeted axillary dissection; TAD; MARI; RISAS; ypN0; axillary lymph node dissection; de-escalation; umbrella review; meta-analysis; AMSTAR-2.

## 30. Details of any existing review of the same topic by the same authors
None. This is the first systematic-review-level project on this topic by the named authors. Members of the team have authored individual primary studies and clinical commentaries on related topics, but no prior systematic review or umbrella review.

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## Timeline

| Phase | Dates | Status |
|---|---|---|
| Protocol registration (PROSPERO) | 2026-06 | submitted |
| Searches | 2026-06 | piloted |
| Screening (title/abstract) | 2026-06 | — |
| Full-text screening | 2026-07 | — |
| AMSTAR-2 assessment | 2026-07 | — |
| Data extraction | 2026-08 | — |
| Synthesis & writing | 2026-09 | — |
| Internal review | 2026-10 | — |
| Submission | 2026-11 | — |
| Estimated publication | 2027-Q1/Q2 | — |
