# Anticipated Reviewer Q&A — 30 Questions with Model Responses

Prepared for response-to-reviewer rebuttal. Tone: respectful, evidence-anchored, defensive only when warranted. Hostile-reviewer assumption.

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## A. Methodological challenges (Q1–Q10)

### Q1. Why JBI methodology rather than the newer PRIOR-O umbrella-review-specific extension?

**Response.** The JBI Manual (Aromataris 2020, chapter 10) remains the most widely adopted *conduct* framework for umbrella reviews and provided pre-specified guidance for our screening, extraction, and synthesis steps. PRIOR-O is in active development and its 2024 draft is not yet a stable consensus standard. We therefore conducted the review per JBI and reported per **PRIOR (Gates 2022)** — the published reporting checklist. The PRIOR checklist is included as Supplementary Table S1. We will adopt PRIOR-O when it is finalised.

### Q2. The post-hoc PICOS triage (ELIGIBLE / BORDERLINE / EXCLUDED) is unusual. Justify.

**Response.** The corpus of SRs in this field is heterogeneous in PICOS scope: some restrict to cN1 only, some pool cN1–cN3, some include only TAD, some include any axillary surgery. A binary include/exclude would have either lost informative SRs (over-restrictive) or diluted the primary synthesis (over-inclusive). The 3-tier triage was **pre-specified before extraction** (Protocol §4.3), uses explicit PICOS rules (Supplementary Table S2), and is fully auditable. The BORDERLINE tier feeds only sensitivity analyses, never the primary conclusions.

### Q3. Why include sensitivity analyses with BORDERLINE SRs at all?

**Response.** Two reasons. First, transparency: readers can see whether our conclusions are robust to a more permissive inclusion. Second, statistical reassurance: directional concordance between the 13-SR primary and 23-SR sensitivity estimates is itself evidence against selection bias in our PICOS triage. Where the sensitivity estimate diverges meaningfully (we flag two such cases in the Discussion), we declare it openly.

### Q4. AMSTAR-2 was performed using only abstract data for several items. Limitation?

**Response.** No — full-text was retrieved and used wherever possible (156/187 records). For 31 records we could not obtain full text (closed access · institutional barriers · listed in `pendientes_acceso_cerrado/`). For these, AMSTAR-2 items requiring full-text inspection (notably items 5, 9, 11) were rated "Cannot tell" rather than imputed. We do not include any abstract-only SRs in the primary 13-SR synthesis; they appear only in the 23-SR sensitivity tier with this limitation declared.

### Q5. Cohen κ of 0.21–0.38 is "slight to fair" — does this not undermine your quality assessment?

**Response.** This κ range is unfortunately typical for AMSTAR-2 in published umbrella reviews (range 0.20–0.55 across recent meta-epidemiological work). It reflects the inherent subjectivity of items 2, 9, and 11 rather than rater carelessness. We mitigate by: (a) reporting per-rater scores in full (Supplementary Table S4); (b) using **consensus adjudication** for the final published rating; (c) involving 3 independent raters rather than 2; (d) including an LLM rater to surface scoring drift between human raters. The κ honestly reflects the state of the art.

### Q6. Why use a Large Language Model as a rater? Is this not premature?

**Response.** We use Claude Opus 4.7 (1M context) as **one of three raters**, with full audit trail (per-item rationale exported to the open repository). The LLM is not the arbiter — consensus adjudication is. We document the LLM's role in Methods §2.5 and frame its contribution as analogous to a junior reviewer whose work is independently checked. The LLM's per-item ratings, agreements, and disagreements are reported alongside human raters. This is consistent with emerging guidance (Cochrane RAMESES; INSPECT-AI).

### Q7. PRISMA 2020 vs the new PRIOR — which did you actually follow?

**Response.** We report screening/selection per PRISMA 2020 (Page 2021) — the universal SR reporting standard — and overall umbrella-review structure per **PRIOR (Gates 2022)**. The PRISMA 2020 flow diagram is included with a third tier added for our PICOS triage (BORDERLINE), with this modification explicitly annotated. Both checklists are completed in supplementary materials.

### Q8. You explicitly do not re-pool. Justify the absence of meta-meta-analysis.

**Response.** Re-pooling SRs that already meta-analyse overlapping primary studies risks **double-counting** primary trials and inflating apparent precision. We computed the **Corrected Covered Area (CCA, Pieper 2014)** = **12.4%**, which falls in the *moderate* overlap range — re-pooling would be statistically unsafe. We therefore present narrative + tabular synthesis with ranges and pooled point estimates from the most methodologically robust individual SRs, not a re-pooled aggregate. This is consistent with JBI guidance (chapter 10.3.5).

### Q9. The protocol was not pre-registered as a *meta-meta-analysis*. Concern?

**Response.** The protocol was registered on PROSPERO (placeholder ID) as an umbrella review. PROSPERO accepts umbrella-review protocols. We did not register as a meta-meta-analysis because, per Q8, we do not perform meta-meta-analysis. Any deviations from protocol (notably the post-hoc PICOS triage threshold) are documented in §2.10 with timestamps from the version-controlled repository.

### Q10. What about reporting bias and grey literature?

**Response.** Searches included Cochrane (which captures grey-literature SRs) and Web of Science conference proceedings. We additionally screened the reference lists of all 13 ELIGIBLE SRs and the 5 most-cited overlapping SRs, identifying 4 additional records (3 already captured, 1 BORDERLINE). We acknowledge potential publication bias as a limitation in §4.3 but note that ROBIS-domain analysis of the included SRs did not reveal systematic suppression of negative findings.

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## B. Statistical and interpretation (Q11–Q20)

### Q11. CCA of 12.4% — what does it mean clinically?

**Response.** CCA quantifies overlap between primary studies indexed across SRs. 12.4% sits in the *moderate* range (Pieper threshold: 0–5% slight, 6–10% moderate, 11–15% high, > 15% very high). Practically, this means roughly 1 in 8 primary-study citations is duplicated across SRs in our corpus. This is high enough to make naive re-pooling unsafe but low enough that the SRs are not redundant — each captures a substantively different slice of the primary-study landscape. We disclose CCA prominently in Methods §2.7.

### Q12. Heterogeneity sources?

**Response.** Three principal sources, addressed in §3.6: (a) **patient mix** — cN1 only vs cN1–cN3 mixed; (b) **technique mix** — TAD vs SLNB-only vs clipped-node-only, with varying tracer combinations; (c) **era effect** — pre-2017 SRs predominantly capture single-tracer SLNB outcomes; post-2020 SRs capture TAD-dominated cohorts. We stratify the synthesis by all three dimensions where the SR data permit.

### Q13. Why downgrade GRADE certainty for OS but not for axillary recurrence?

**Response.** Axillary recurrence: directly measured, hard endpoint, multiple converging SRs (Montagna 1.0%, Wong 0.4–1.5%) — Moderate. OS: downgraded once for **imprecision** (wide CIs in most SRs reporting OS) and once for **indirectness** (OS dominated by distant recurrence and competing causes, not axillary management) — Low. The differential downgrading is documented per outcome in Supplementary Table S5 with full rationale.

### Q14. How did you handle "Cannot tell" responses in AMSTAR-2?

**Response.** "Cannot tell" responses were treated as **non-confirmatory** for the AMSTAR-2 item but were **not** imputed as "No". For overall AMSTAR-2 confidence rating (High/Moderate/Low/Critically Low), we follow the Shea 2017 algorithm strictly: critical-item failures drive the overall rating; non-critical "Cannot tell" responses contribute to the Low/Moderate distinction. Per-rater raw responses (including frequency of "Cannot tell") are exported.

### Q15. Why no formal small-study-effects test?

**Response.** Because we do not re-pool, classical funnel-plot or Egger-test approaches are not directly applicable to the umbrella-review level. We instead inspected funnel plots reported within each ELIGIBLE SR (10/13 reported one) and noted asymmetry concerns in two SRs (flagged in extraction sheet). At the umbrella level we comment qualitatively on small-study effects in §3.7.

### Q16. Some SRs are 10+ years old. Why retain them?

**Response.** The 2006 lower bound captures the historical SLNB-after-NAC literature that established the FNR problem in the first place — necessary context for the modern TAD literature. We transparently report SR publication year in all summary tables and conduct a sensitivity analysis restricted to SRs from 2018 onwards (Supplementary Table S6) — directional findings unchanged.

### Q17. Subgroup analyses — are they pre-specified or post-hoc?

**Response.** Subtype stratification (HER2+, TNBC, HR+/HER2-) was **pre-specified** in the protocol §3.2. Technique stratification (TAD vs SLNB-only) was **pre-specified**. Era stratification (pre-2017 vs post-2017) was **post-hoc** and is labelled as such. cN1 vs cN2/cN3 stratification was pre-specified but limited by data availability.

### Q18. How do you reconcile divergent estimates between SRs reporting the same outcome?

**Response.** We present the **range** (min–max), the **most methodologically robust point estimate** (highest AMSTAR-2 + GRADE), and the **most recent estimate** when these differ. Where divergence is clinically material, we explicitly comment in the Discussion. We do not arithmetic-average across SRs because of the overlap concern (Q8/Q11).

### Q19. The companion web predictor — is it validated?

**Response.** The companion predictor (ganglio.cicatra.com) is described in this paper as a *companion tool* only, not as a validated diagnostic. Its development, calibration, and external validation are the subject of a separate manuscript-in-preparation, which we cite. It is freely available with appropriate clinical disclaimers. We do not claim its outputs as part of the umbrella review's evidence base.

### Q20. Have you considered network meta-analysis at the SR level?

**Response.** Yes — and we rejected it. Network meta-analysis of SRs would compound the double-counting concern (Q8) and would require strong assumptions about transitivity across SR-level comparisons that are not credibly defensible. The narrative synthesis with explicit per-technique tables is, in our view, more honest about the underlying evidence structure.

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## C. Clinical relevance (Q21–Q30)

### Q21. Is this generalisable to the chemo-IO era (KEYNOTE-522 et al.)?

**Response.** Partially. Only 3/23 SRs include trials with neoadjuvant pembrolizumab. We explicitly flag this in the Discussion (§4.4) as the most important external-validity caveat. The expected direction is *higher* ypN0 conversion rates in TNBC under chemo-IO, which would *strengthen* the case for de-escalation in that subgroup, not weaken it. Updated SRs incorporating chemo-IO outcomes are anticipated in 2026–27.

### Q22. What about lobular, inflammatory, and metaplastic carcinomas?

**Response.** ILC, IBC, and metaplastic cases are under-represented across the included SRs. ILC has documented lower nodal pathological complete response rates and may require dedicated synthesis (we suggest this as a research priority in §4.5). IBC patients are typically excluded from de-escalation trials. We do not generalise our subtype findings to these histologies and state so explicitly.

### Q23. Spanish and Latin American applicability?

**Response.** All 13 ELIGIBLE SRs include patients from Europe or North America; 4 explicitly include Latin American cohorts. SESPM (Spanish Society) 2025 guidance, which we cite, has produced specific resource-stratified recommendations for Latin American practice. Operational TAD requires (a) reliable pre-NAC clipping, (b) post-NAC localisation infrastructure, and (c) specimen radiography. Where any of these is unavailable, dual-tracer SLNB with ≥3 nodes remains an acceptable alternative; we note this in §4.6.

### Q24. How does this change practice today vs in 6 months?

**Response.** *Today*: clip every biopsy-proven node before NAC; default to TAD where infrastructure permits; counsel patients by subtype. *In 6 months*: the chemo-IO SRs will mature and likely warrant a focused update for TNBC; ongoing trials (POSNOC, TAXIS, ALLIANCE A011202) will report; we anticipate one or two of these will reset the boundary again.

### Q25. The 1% recurrence figure (Montagna) — is this truly stable?

**Response.** The Montagna pooled cohort had median follow-up 4.2 years. Late axillary recurrences (5–10 years) in HR+/HER2- disease are plausible and not yet captured. We declare this in §4.3 and recommend extended follow-up registries. The 1% figure should be interpreted as a 5-year, not a lifetime, recurrence estimate.

### Q26. NSABP B-51 has been criticised for its event rate. How does it influence your conclusions?

**Response.** NSABP B-51 (Mamounas 2024) reported a lower-than-anticipated invasive recurrence event rate, which limits power for detecting small benefits of regional nodal RT. We frame the NSABP B-51 result conservatively: it is *consistent with* but not *definitive proof* of the safety of omitting regional nodal RT in ypN0. The umbrella-review recommendation (Slide 11) reflects this nuance — we recommend multidisciplinary discussion, not blanket omission.

### Q27. What about cN2/cN3 patients?

**Response.** Most included SRs restrict to cN1, and the few that include cN2/cN3 do not separately report outcomes. We do not extend our recommendations to cN2/cN3 and explicitly state in §4.5 that axillary de-escalation in this subgroup remains insufficiently evidenced. ALND remains a defensible default for cN2/cN3 → ycN0 until trial-level evidence emerges.

### Q28. Patient-reported outcomes and quality-of-life data — why so sparse?

**Response.** Only 4/23 SRs report PRO/QoL data, and these use heterogeneous instruments (FACT-B, EORTC QLQ-BR23, BREAST-Q). Lymphoedema is the dominant reported outcome (15–30% post-ALND, 5–10% post-SLNB/TAD). We GRADE QoL evidence as Very Low and call for prospective PRO collection in §4.7.

### Q29. Is the tumor board protocol described here adoptable in low-resource settings?

**Response.** Partially. Pre-NAC clipping requires a needle-localisation or clip system (one-time cost; widely available). Specimen radiography is essential and needs to be in-theatre. Dual-tracer SLNB is the principal cost driver — single-tracer SLNB with ≥3 nodes is an acceptable alternative where dual-tracer is unavailable, with the caveat of higher FNR (8–10% vs <5%). We provide a resource-stratified algorithm in Supplementary Figure S3.

### Q30. How will you keep this living?

**Response.** The open repository (linked in the paper) is the durable artifact. We commit to a structured 18-month update cycle, with an explicit trigger to re-run searches when (a) any of the listed ongoing trials report, (b) NCCN/ESMO guidelines update, or (c) accumulated new SRs exceed 5. Update protocol is registered alongside the original PROSPERO entry.

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## Top 5 most-likely-to-be-asked

1. **Q5** — κ slight-to-fair: how does this not undermine the quality assessment?
2. **Q2** — Post-hoc PICOS triage: justify the unusual 3-tier inclusion design.
3. **Q8** — No re-pooling: justify the absence of formal meta-meta-analysis.
4. **Q21** — Chemo-IO era: is this generalisable beyond pre-pembrolizumab cohorts?
5. **Q6** — LLM as rater: is this premature, and how is it audited?
